One-Pot Synthesis of Some Dynamic 2-Substituted Benzoxazinones and Their Corresponding Qinazolinones of Anticipated Biological Activity

Article abstract of DOI:10.1002/jhet.2389

(Chemical Equation Presented) Reactions of 6-bromo-2-isopropyl-4(3H)-3,1-benzoxazin-4-one toward mono- and di-dentate nitrogen nucleophiles, e.g. primary aliphatic and aromatic amines, 1,2-phenylenediamine, hydrazine hydrate, and formamide, have been investigated and afford the corresponding quinazolinones which are expected to have some interesting biological activity. The behavior of 3, 1-benzoxazin-4-one toward active methylene compounds, namely, acetylacetone in basic medium has been studied and gave 3-acetylquinoline. The last reaction is considered as an illustrative model of heterocyclic transformation reactions.

Full text of DOI:10.1002/jhet.2389

Month 2015
One-Pot Synthesis of Some Dynamic 2-Substituted Benzoxazinones and
Their Corresponding Qinazolinones of Anticipated Biological Activity
a
a
b
Maher A. El-Hashash, Mohamed E. Azab, and Jehan M. Morsy *
a
Department of Chemistry, Faculty of Science, Ain Shams University, Abbasiya 11566 Cairo, Egypt
b
Laboratory of Synthetic Organic Chemistry, Chemistry Department, Faculty of Education, 11711 Roxy, Cairo, Egypt
*
E-mail: morsy_jehan@yahoo.com
Received August 24, 2014
DOI 10.1002/jhet.2389
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
Reactions of 6-bromo-2-isopropyl-4(3H)-3,1-benzoxazin-4-one toward mono- and di-dentate nitrogen
nucleophiles, e.g. primary aliphatic and aromatic amines, 1,2-phenylenediamine, hydrazine hydrate, and
formamide, have been investigated and afford the corresponding quinazolinones which are expected to have
some interesting biological activity. The behavior of 3, 1-benzoxazin-4-one toward active methylene com-
pounds, namely, acetylacetone in basic medium has been studied and gave 3-acetylquinoline. The last reac-
tion is considered as an illustrative model of heterocyclic transformation reactions.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
-Substituted benzoxazinones are known as mechanism-
Reacting with different nitrogen nucleophiles, benzo-
xazinones are considered scaffold for the synthesis of the
corresponding quinazolinones which are potent inhibitors
of the epidermal growth factor (EGFR) [20–28]. The EGFR
is cellular trans-membrane tyrosine kinases that are over-
expressed in a significant number of human tumors, e.g.
breast, ovarian, colon, and prostate; their expression levels
often correlate with vascularity, and are associated with
poor prognosis in patients [29–32]. Inhibitors of the
EGFR-PTK are therefore expected to have great therapeutic
potential in the treatment of malignant and non-malignant
epithelial diseases. The most promising small molecule se-
lective EGFR-TK inhibitors include quinazolines [29]. The
pharmacophoric requirement of quinazolinones, and conse-
quently their corresponding benzoxazinones, as anti-tumor
agents with potential activity and selectivity toward cancer-
ous cells, consists in to confer different electronic environ-
ment that would affect the lipophilicity and hence the
activity of the target molecules [33]. Prompted by the above
findings, isopropyl group has been chosen to be the alkyl
group at 2-position in the synthesized benzoxazinones and
the corresponding quinazolinones which are expected to
have interesting biological and medicinal activity toward
different diseases.
2
based inhibitors of standard serine protease of the chymo-
trypsin superfamily [1,2] and inhibit by formation of an
acyl–enzyme complex through attack of the active site ser-
ine on the carbonyl [3,4]; therefore, the 2-substituted
benzoxazinones showed bioactivities on human leukocyte
elastase [2,4,5], Clr serine protease of the complement sys-
tem [6,7], Cathepsin G [5], human Chymase [5], tissue fac-
tor VIIa [8], anti-HCoVs, and ICAM-1 inhibitors [9]. On
the other hand, numerous evidence indicate that platelets
contribute significantly to the pathogenesis of arterial
thromboembotic diseases, such as acute coronary syndrome
and ischemic stroke, which are the major causes of death in
developed countries [10,11]. It is also well known that hu-
man neutrophils play an important role in a host’s defense
against invasion by microorganisms and in pathogenesis
of various diseases [12–16]. Activated neutrophils secrete
a series of haphazard cytotoxins, such as superoxide
.ꢀ
(
O2 ). The agents that exhibited the inhibitory effect on
the neutrophil activation have been proposed to ameliorate
these inflammatory diseases. Furthermore, neutrophil elas-
tase (NE) is a major secreted product of activated neutro-
phils and a major contributor to destruction of tissue in
chronic inflammatory disease; therefore, NE appears to be
a target for therapy of chronic inflammatory diseases [17].
Recently, it has been claimed that 2-substituted
benzoxazinones exhibited both anti-platelet aggregation
and anti-inflammatory effects [18]. This class of com-
pounds could also be virtual protease inhibitors against sim-
plex virus type 1 (HSV-1) protease [8], h CMV protease
RESULTS AND DISCUSSION
6-Bromo-2-isopropyl- 4H-3, 1-benzoxazin-4-one 1 was
prepared from the reaction of 5-bromoanthranilic acid with
isobutyroyl chloride to afford the anthranil derivative
which was cyclized under the effect of freshly distilled
acetic anhydride. The distal bromine substituent was
[
19], and anti-HCoVs agents (anti human Corona) [9].
©
2015 HeteroCorporation

M. A. El-Hashash, M. E. Azab, and J. M. Morsy
Vol 000
introduced to obtain benzoxazinones and quinazolinones
of expected bronchodilatory activity [34]. Compound 1 ex-
hibits unstability like other 2-alkylbenzoxazinones [34],
and this is probably due to the electronically unsaturated
character of these rings, and hence they are given the
name “dynamic benzoxazinones”. The structure of
benzoxazinone 1 was chemically confirmed via its conver-
sion to the corresponding stable derivatives. Aminolysis of
benzoxazinone 1 was conducted through its reaction with
primary aliphatic amine, namely, benzylamine in refluxing
ethyl alcohol to give N-benzyl benzamide derivative 2 [cf.
Scheme 1]. The IR spectrum of compound 2 showed
3a–d showed strong absorption bands at 1690–1670 and
ꢀ
1
ν
ν
1630–1615cm corresponding to C¼O and C¼N, re-
spectively. Reaction of o-phenylenediamine with dynamic
benzoxazinone 1 in refluxing benzene containing a cata-
lytic amount of orthophosphoric acid gave 2-isopropyl-
3-(2-aminophenyl)-6-bromo-4(3H)quinazolin-4-one 4. IR
spectrum of compound 4 exhibited strong absorption bands
ꢀ
1
ν
at 3338, 3245, 1675, and 1600cm attributable to NH ,
2
ν
ν
C¼O, and C¼N, respectively. When benzoxazinone 1
was allowed to react with hydrazine hydrate in ethanol at
refluxing temperature, it afforded 3-amino-6-bromo-2-
isoprpyl-4(3H) quinazolin-4-one 5. The structure of
quinazolinone 5 was elucidated from its quantitative elemen-
tal analysis together with spectral data. IR spectrum of com-
pound 5 exhibited strong absorption bands at 3447, 3350,
ꢀ
1
absorption bands at 3366, 3282, 1695, and 1684 cm
ν
ν
attributable to NH, and C¼O (two carbonyl groups),
respectively. When compound 1 was allowed to react with
primary aromatic amines, namely, aniline, p-toluidine, p-
chloroaniline, and PAB (p-aminobenzoic acid), the
quinazolinone derivatives 3a–d were obtained, respec-
tively. The formation of products 3a–d is due to oxazinone
ring cleavage by the attack of nitrogen nucleophile
ꢀ
1
ν
1684, and 1650cm corresponding to NH (asymmetric
ν
ν
and symmetric stretching), C¼O, and C¼N, respectively.
The electron impact fragmentation of compound 5 showed
the most prominent peaks at m/e 281 and 283 of almost
equal relative intensities attributable to (M ) and (M+2 ),
respectively. The mass spectrum of quinazolinone 5 also
exhibited peaks at m/e 265, m/e 253, and m/e 238 corre-
.+
.+
2
followed by cyclization on the highly electrophilic SP hy-
bridized carbonyl carbon of the intermediate to yield
quinazolinones 3a–d. The IR spectra of compounds
sponding to loss of NH , CO, and isopropyl radical,
2
respectively, from the molecular ion peak. The later radi-
cal cation underwent consecutively further losses of Br,
NH , HCN, and CO to give the daughter peaks at m/e
Scheme 1. Reactions of Benzoxazinone 1 with Nitrogen and Carbon
2
Nucleophiles.
159, 143, 116, and 88, respectively.
It has been reported that reaction of 3, 1-benzoxazin-4-
one with active methylene compounds, namely, ace-
tylacetone [35,36] in basic medium gave the corresponding
3
-acetyl-4-hydroxyquinolin derivative. On the other hand,
it has been claimed [37] that the same reaction afforded
, 3-diacetyl-4(3H)-quinoline-4-one derivative. In our
3
present work, reaction of acetylacetone with ben-
zoxazinone 1 in the presence of methanolic sodium
methoxide solution resulted in 3-acetyl-6-bromo-4-hy-
droxy-2-isopropylquinoline 6. This result is in agreement
with our previous publications [35] and [36] as well as
the literature [38]. The IR spectrum of quinoline 6 showed
ꢀ
1
strong absorption bands at 3338, 3265, and 1684 cm at-
ν
ν
1
tributable to OH, and C¼O, respectively. The H NMR
of quinoline 6 (DMSO-d ; , ppm) exhibited signals at 1.4
6
(
d, 6H, 2 CH of iso-pr.), 2.2 (s, 3H, COCH ), 1.7 (m, 1H,
3
3
methine-H of iso-pr.), 7.7–8.5 (m, 3H, Ar―H), and 10.4
br.s, 1H, OH). The formation of 4-hydroxyquinoline 6
(
could be explained as a result of attacking the carbanion
generated from acetylacetone on the benzoxazinone car-
bonyl functionality with benzoxazinone ring cleavage
followed by elimination of acetic acid molecule which re-
sults in 4-hydroxyquinoline 6 that is more stabilized than
its keto-form via intramolecular H-bondings. Refluxing a
mixture of benzoxazinone 1 and formamide and/or fusion
of a mixture of 1 and ammonium acetate at 150°C
afforded quinazolinone 7. The structure of compound 7
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
One-Pot Synthesis of Some Dynamic 2-Substituted Benzoxazinones and Their
Corresponding Qinazolinones of Anticipated Biological Activity
was assigned from its correct elemental analysis together
with its IR spectrum which exhibited strong absorption
Mannich bases 10a and 10b, respectively. The IR spectra of
Mannich bases 10a,b are devoid of bands corresponding to
NH and showed absorption bands at 1670, 1680 and 1605,
ꢀ
1
bands at 3292, 3179, 1677, and 1625 cm corresponding
ν
ν
ν
ꢀ1
ν
ν
to NH (bonded and non-bonded), C¼O, and C¼N,
respectively. Quinazolinone 7 exhibits, in solution, lactam–
lactim dynamic equilibrium. In polar solvents, the lactam
form is more predominant than the lactim one, and hence
by decreasing the solvent polarity, the lactim form becomes
more predominant [39]. Thus, when quinazolinone 7 was
submitted to react with benzyl chloride in pyridine under
refluxing temperature, the 3-benzyl-4(3H)-quinazolinone
1610 cm attributable to C¼O, and C¼N, respectively.
The present work was extended to include the behavior of
an ester derived from quinazolinone 7 toward aromatic
aldehydes, namely, benzaldehyde under Claisen and Stobb
reactions conditions. Thus, 6-bromo-4-ethoxycarbonyl-2-
isoprpyl-4(3H)-quinazoline 11 was synthesized from the reac-
tion of quinazoline 7 with ethyl chloroacetate in dry acetone
containing anhydrous K CO as a basic catalyst. The IR spec-
2
3
8
was isolated. However, when the reaction was conducted
trum of compound 11 showed well defined absorption bands
ꢀ
1
ν
in dry acetone in the presence of anhydrous K CO ,
the product was identified as 4-benzyloxy-quinazoline
9
at 1735 and 1615 cm corresponding to C¼O of ester func-
2
3
ν
tionality and C¼N, respectively, as well as the disappearance
ν
ν
1
[cf. Scheme 2].
of C¼O and NH of cyclic amide. The H NMR spectrum of
The IR spectrum of quinazolinone 8 showed strong
compound 11 provides an additional confirmatory evidence
for its structure. The H NMR spectrum (CDCl ; δ, ppm)
ꢀ
1
1
absorption bands at 1673 and 1600 cm attributable
3
ν
ν
C¼O, and C¼N, respectively and lacked a band corre-
exhibited signals at 1.3 (m, 9H, CH of ethyl group and 2
3
ν
sponding to NH. On the other hand the IR spectrum of
CH of iso-pr group), 3.2 (m, 1H, methine-H of iso-pr group),
3
quinazoline 9 exhibited absorption bands at 1620 and
4.2 (m, 2H, CH of ethyl group), 4.9 (s, 2H,OCH CO), and
2
2
ꢀ
1
ν
ν
1
250cm due to C¼N, and C―O. The formation of
7.6–8.4 (m, 3H, Ar―H). The reaction mostly proceeds via
1
2
products 8 and 9 is achieved via SN mechanism in which
benzyl cation is easily formed as a result of its special stability.
Mannich bases have interesting pharmacological properties,
and consequently this class of compounds could be used as
intermediates in drug synthesis [40]. In order to study the
behavior of quinazolinone 7 toward Mannich reaction, it
was allowed to react with secondary amines, namely, piperi-
dine and morpholine in ethyl alcohol at refluxing temperature
and formaldehyde in the presence of few drops of HCl to yield
SN mechanism as a result of nucleophilic attack of the
oxygen nucleophile of the predominant lactim form on the
electronically deficient carbon atom of methylene group in
ethyl chloroacetate. It is interesting to study the behaviour of
ester 11 toward benzaldehyde in the presence of different
basic catalysts [cf. Scheme 3].
The reaction of ester 11 with benzaldehyde in the
presence of sodium ethoxide resulted in Claisen–
Schmidt condensation product 12 as a sole product.
Scheme 2. Behaviour of Quinazolinone 7 toward Carbon Electrophiles.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. El-Hashash, M. E. Azab, and J. M. Morsy
Vol 000
Scheme 3. Claisen-Schmidt and Stobb Condensation Reactions of
Ester 11.
explained as it has been reported [42] that in Stobb
condensation with succinic ester, the intermediate is
Paraconic ester (ɤ-lactonic ring). In case of ester under
investigation 11, ß-lactonic ring is formed as an interme-
diate which is more easily formed than ɤ-lactonic ring,
but it is less stable, and consequently, side reactions such
as Claisen–Schmidt condensation compete with Stobb
condensation. Functional groups transformation reaction
was achieved when ester 11 was allowed to react with
hydrazine hydrate in refluxing temperature to yield the
corresponding hydrazide 14. The IR spectrum of compound
1
4 displayed well-defined absorption bands at 3282 and
ꢀ
1
ν
ν
1
635cm attributable to NH and C¼O, respectively.
1
The H NMR (CDCl ; δ, ppm) exhibited signals at 1.2
3
(
d, 6H, 2 CH of iso-pr group), 3.6 (m, 1H, methine-H
3
of iso-pr group), 5.1 (s, 2H, OCH CO), 7.7–8.4 (m, 3H,
2
Ar―H), 8.5 and 8.7 (2 br.s, 2H, D O exchangeable,
2
NH attached to asymmetric center), and 9.4 (br.s, 1H,
2
D O exchangeable, NH). The reaction likely proceeds
2
2
via a tetrahedral mechanism at the SP hybridized
carbonyl carbon of the ester group of compound 11. In
tetrahedral mechanism, N―C bond formation precedes
C―O bond breaking, and consequently accumulation of
energy in solution happens and that leads to decrease of
the activation energy of the reaction.
The structure assigned for compound 12 is confirmed
from its elemental analysis and spectral data. Thus, the
IR of product 12 exhibited well-defined absorption
EXPERIMENTAL
ꢀ
1
ν
bands at 1718 and 1640 cm attributable to C¼O of
All melting points are uncorrected and measured on Stuart
electric melting point apparatus. Infra red (IR) spectra were re-
corded on Bruker or Satellite 2000 spectrometer using KBr disks.
ν
ester functionality and C¼N, respectively. On the other
1
hand, the H NMR (CDCl ; δ, ppm) exhibited signals at
3
1
1
.1 (m, 9H, CH of ethyl group and 2 CH of iso-pr
3
3
H NMR spectra were measured on Varian Mercury 300-MHz
group), 3.1 (m, 1H, methine-H of iso-pr group), 4.1 (q,
spectrometer using TMS as internal standard and DMSO-d or
6
2
7
1
H, CH of ethyl group), 4.8 (s, 1H, olefinic H), and
.1–8.4 (m, 8H, Ar―H). The cinnamic acid derivative
3 was obtained by hydrolysis of the corresponding ester
CDCl as a solvent; chemical shifts are measured in δ, ppm.
3
2
Elemental analysis was carried out by the Microanalytical Center,
Faculty of Science, Cairo University.
6-Bromo-2-isopropyl-4H-3,1-benzoxazin-4-one (1). To a
using aqueous NaOH solution (10%). The IR spectrum
stirred solution of 5-bromoanthranilic acid (2.16 g; 10 mmol in
of acid 13 showed strong absorption bands at 3370,
2
1
0 mL dry pyridine), isobutyroyl chloride solution (1.6 g;
5 mmol in 10-mL dry pyridine) was added dropwise during a
ν
ν
1
686, and 1610 cm corresponding to, OH, C¼O, and
ν
C¼N, respectively. When the reaction of ester 11 with
benzaldehyde was conducted in the presence of potas-
sium tert-butoxide under Stobb condensation conditions,
the products were identified as cinnamic acid derivative
period of 30 min. The stirring was continued for further 2 h. The
reaction mixture was poured onto crushed ice/hydrochloric acid
with constant stirring. The solid which separated out was
filtered off, washed with cold water, and dried to give the
corresponding anthranil. The dry solid of the anthranil was
treated with freshly distilled acetic anhydride until it become
paste which was then heated on water bath for 1 h and left to
cool. The solid that separated out was filtered off and washed
with light petroleum 40/60 to afford benzoxazinone 1 which
then used in the same day with further reactions.
1
1
3 together with Claisen–Schmidt unsaponified product
2. A possible mechanism to interpret the formation of
acid 13 involves the attack of the carbanion produced
from ester 11 at the electronically deficient carbonyl car-
bon of benzaldehyde to give an intermediate which
cyclized via a nucleophilic attack of negatively charged
oxygen at the ester carbonyl carbon followed by elimina-
tion of ethoxy anion to afford the intermediate ß-lactone
that underwent ring cleavage to give cinnamic acid de-
rivative 13 [41]. The formation of Stobb product 13 to-
gether with Claisen–Schmidt product 12 in the
presence of the strong base tert-butoxide anion can be
5
-Bromo-2-(dimethylacetylamino)-N-benzylbenzamide
(
2). A mixture of benzoxazinone 1 (2.69 g; 10 mmol) and
benzylamine (1.07 g; 10 mmol) in ethanol (30 mL) was
heated at refluxing temperature for 5 h. The solid that
settled down after distilling off the excess solvent and
cooling was filtered off and recrystallized from toluene to
give 2 as white crystals, mp 190–192°C, yield 70%. FT-IR
ꢀ
1
(KBr, ν, cm ): 3366, 3282 (NH), 1695 (C¼O), 1684
Journal of Heterocyclic Chemistry DOI 10.1002/jhet

Month 2015
One-Pot Synthesis of Some Dynamic 2-Substituted Benzoxazinones and Their
Corresponding Qinazolinones of Anticipated Biological Activity
1
(
C¼O). H-NMR (300 MHz, DMSO-d ):1.3 (d, 6H, 2CH of
settled down on cooling was filtered off and crystallized from
light petroleum 60/80 to give 5 as white crystals, mp 120–121°C,
6
3
iso-pr), 2.9 (m, methine-H of iso-pr), 4.3 (s, 2H, NCH ), 7.1–
.1 (m, 8H, Ar―H), 8.3 and 8.4 (2s, 2H, D
2
ꢀ
1
8
2
(
2
O-exchangeable,
yield 70%. FT-IR (KBr, ν, cm ): 3447, 3350 (NH), 1684
.
+
.+
1
NH). MS (m/z, %): 374 (M , 20), 376 (M+2 , 19), 91
19BrN (375.29): C: 57.60,
H: 5.11, N: 7.47; found: C: 57.81, H: 5.43, N: 7.65.
-Aryl-6-bromo-2-isopropyl-4(3H)-quinazolin-4-one
3a-d). A solution of benzoxazinone 1 (2.68 g, 10 mmol) and
(C¼O), 1650 (C¼N). H-NMR (300 MHz, CDCl
2CH of iso-pr), 1.9 (m, methine-H of iso-pr), 2.2 (s, 2H,
D O-exchangeable, NH ), 7.2–8.3 (m, 3H, Ar―H). MS (m/z, %):
3
):1.2 (d, 6H,
100). Anal. Calcd. for C18
H
2
O
2
3
2
2
.+
.+
3
281 (M , 100), 283 (M+2 , 96), 265 (64), 253 (31), 238 (29),
(
159 (63), 143 (15), 116 (18), 88 (22). Anal. Calcd. for
the appropriate primary aromatic amine namely, aniline, p-
11 3
C H12BrN O (282.16): C: 46.82, H: 4.30, N: 14.90; found:
toluidine, p-chloroaniline, and/or p-aminobenzoic acid in ethanol
C: 47.13, H: 4.66, N: 15.11.
(
40 mL) was heated under reflux for 4 h and left to cool. The
2-Acetyl-6-bromo-2-isopropyl-4(3H)-quinolin-4-one (6). An
equimolar mixture of benzoxazinone 1 (2.68 g, 10 mmol) and
acetylacetone (1.00 g, 10 mmol) in absolute methanol (30 mL) was
treated with methanolic solution of sodium methoxide (0.23 g of
sodium metal/10 mL of absolute methanol) then, heated at refluxing
temperature for 4 h. Most of the solvent was distilled off, and the
reaction mixture was left to cool. The reaction mixture was stirred
with ice/dilute HCl. The solid that settled down was filtered off
and crystallized from toluene to give 6 as yellow crystals, mp
solid that settled down was filtered off and recrystallized from
the suitable solvent to afford 3a-d.
6
-Bromo-2-isopropyl-3-phenyl-4(3H)-quinazolin-4-one
3
a. Pale yellow, mp 193–194°C (light petroleum 60/80), yield
ꢀ
1
1
7
5%. FT-IR (KBr, ν, cm ): 1683 (C¼O), 1625 (C¼N). H-NMR
):1.1 (d, 6H, 2CH of iso-pr), 1.9 (m, methine-H
of iso-pr), 7.1–8.1 (m, 8H, Ar―H). MS (m/z, %): 342 (M , 38),
(
300MHz, CDCl
3
3
.+
.
+
3
44 (M+2 , 36), 314 (24), 299 (43), 265 (52), 222 (100). Anal.
ꢀ
1
Calcd. for C H BrN O (343.24): C: 59.48, H: 4.41, N: 8.16;
185–186°C, yield 73%. FT-IR (KBr, ν, cm ): 3338, 3265 (OH),
17
15
2
1
found: C: 59.61, H:4.55, N: 8.33.
-Bromo-2-isopropyl-3-(4-methylphenyl)-4(3H)-quinazolin-
-one 3b. Pale yellow, mp 150–151°C (benzene), yield 75%.
1684 (C¼O). H-NMR (300 MHz, DMSO-d ):1.4 (d, 6H, 2CH
6
3
6
3
of iso-pr), 2.2 (s, 3H, COCH ), 3.7 (m, 1H, methine-H of iso-pr),
4
2.2 (s, 2H, D
2
O-exchangeable, NH
O-exchangeable, OH). MS (m/z, %): 307 (M , 44),
2
), 7.7–8.5 (m, 3H, Ar―H),
ꢀ
1
1
.+
FT-IR (KBr, ν, cm ): 1690 (C¼O), 1618 (C¼N). H-NMR
10.4 (s, 1H, D
2
.+
(
300 MHz, CDCl ): 1.0 (d, 6H, 2CH of iso-pr), 1.7 (m,
309 (M+2 , 42), 292 (63), 264(100), 249 (38), 221 (24). Anal.
3
3
methine-H of iso-pr), 2.5 (s, 3H, Ar-CH ), 7.2–8.2 (m, 7H,
Calcd. for C H BrNO (308.19): C: 54.56, H: 4.59, N: 4.55;
found: C: 54.90, H: 4.71, N: 4.76.
3
14 14
2
.+
.+
Ar―H). MS (m/z, %): 356 (M , 24), 358 (M+2 , 23), 313
18), 265 (39), 224 (79), 222 (82), 91 (100). Anal. Calcd. for
C H BrN O (357.27): C: 60.51, H: 4.81, N: 7.84; found: C:
(
6-Bromo-2-isopropyl-4(3H)-quinazolin-4-one (7).
A
solution of benzoxazinone 1 (2.68 g, 10 mmol) in formamide
(20 mL) was heated at refluxing temperature for 2 h, left to cool,
poured onto cold water with stirring. The solid that separated
out was filtered off and crystallized from toluene to give 7 as
white crystals, mp 260–262°C, yield 65%. FT-IR (KBr, ν,
18
17
2
6
0.77, H:4.70, N: 7.93.
-Bromo-2-isopropyl-3-(4-chlorophenyl)-4(3H)-quinazolin-
-one 3c. Yellow, mp 210–211°C (benzene), yield 79%. FT-IR
6
4
ꢀ
1
1
(
KBr, ν, cm ): 1672 (C¼O), 1615 (C¼N). H-NMR (300 MHz,
ꢀ
1
CDCl ): 1.3 (d, 6H, 2CH of iso-pr), 1.9 (m, methine-H of iso-pr),
cm ): 3292, 3179 (NH non-bonded and bonded), 1677 (C¼O),
3
3
.
+
1
7
.1–8.2 (m, 7H, Ar―H). MS (m/z, %): 376 (M , 100), 378
1625 (C¼N). H-NMR (300 MHz, CDCl ):1.0 (d, 6H, 2CH of
3
3
.
+
(
M+2 , 96). Anal. Calcd. for C17
H: 3.74, N: 7.42; found: C: 54.32, H:3.94, N: 7.61.
-Bromo-3-(4-carboxyphenyl)2-isopropyl-4(3H)-quinazolin-
-one 3d. Yellow, mp 235–236°C (ethanol), yield 72%. FT-IR
H
14BrClN
2
O (377.68): C: 54.06,
iso-pr), 2.0 (m, 1H, methine-H of iso-pr), 7.2–8.3 (m, 3H,
2
Ar―H), 8.6 (s, 1H, D O-exchangeable, NH). MS (m/z, %): 266
.+
.+
6
(M , 100), 268 (M+2 , 98), 238 (39), 224(28), 223 (16), 222
4
(30). Anal. Calcd. for C H BrN O (267.14): C: 49.45, H:
11
11
2
ꢀ
1
1
(
KBr, ν, cm ): 1670 (C¼O), 1630 (C¼N). H-NMR (300 MHz,
CDCl ): 1.1 (d, 6H, 2CH of iso-pr), 1.8 (m, methine-H of iso-pr),
.2–8.3 (m, 7H, Ar―H), 11.5 (s, 1H, D O-exchangeable,
4.16, N: 10.49; found: C: 49.69, H: 4.34, N: 10.72.
3
3
3-Benzyl-6-bromo-2-isopropyl-4(3H)-quinazolin-4-one
7
2
(8).
An equimolar mixture of benzoxazinone 1 (2.68 g,
.+
.+
COOH). MS (m/z, %): 386 (M , 19), 388 (M+2 , 18), 342
10 mmol) and benzyl chloride (1.27 g, 10 mmol) in dry pyridine
was heated at refluxing temperature for 3 h. The solid that settled
down after cooling and pouring onto cold dilute HCl was filtered
off and crystallized from benzene to give 8 as white crystals, mp
(
100). Anal. Calcd. for C H BrN O (387.25): C: 55.82, H:
18 15 2 3
3
.91, N: 7.24; found: C: 56.12, H:4.22, N: 7.43.
-(2-Aminophenyl)--6-bromo-2-isopropyl-4(3H)-quinazolin-
-one (4). A mixture of benzoxazinone 1 (2.68 g, 10 mmol) and o-
3
ꢀ
1
4
140–141°C, yield 70%. FT-IR (KBr, ν, cm ): 1673 (C¼O),
1
phenylenediamine (1.08 g, 10 mmol) in dry benzene (30 mL) was
treated with 1 mL of orthophosphoric acid, heated under reflux for
1600 (C¼N). H-NMR (300 MHz, CDCl ):1.1 (d, 6H, 2CH of
3
3
iso-pr), 1.9 (m, 1H, methine-H of iso-pr), 4.3 (s, 2H, N―CH ),
2
7.2–8.2 (m, 8H, Ar―H). MS (m/z, %): 356 (M , 62), 358
.+
8
h, and left to cool. The solid that separated out was filtered off
.+
and crystallized from benzene/drops of ethanol to give 4 as brown
(M+2 , 60), 328 (38), 313 (14), 265 (74), 91 (100). Anal.
Calcd. for C18 17BrN O (357.27): C: 60.51, H: 4.81, N: 7.84;
ꢀ
1
crystals, mp 242–244°C, yield 81%. FT-IR (KBr, ν, cm ): 3338,
H
2
1
3
345 (NH ), 1675 (C¼O), 1600 (C¼N). H-NMR (300 MHz,
found: C: 60.76, H: 4.98, N: 7.93.
2
CDCl ): 1.3 (d, 6H, 2CH of iso-pr), 1.9 (m, methine-H of iso-pr),
4-Benzyloxy-6-bromo-2-isopropyl-4(3H)-quinazolin-4-one
3
3
4
(
(
.2 (s, 2H, D
m/z, %): 357 (M , 100), 359 (M+2 , 97), 341 (18), 315 (43), 265
51). Anal. Calcd. for C17 16BrN O (358.26): C: 56.99, H: 4.51,
N: 11.73; found: C: 57.29, H:4.74, N: 11.91.
2
O-exchangeable, NH
2
), 6.3–8.2 (m, 7H, Ar―H). MS
(9).
A mixture of benzoxazinone 1 (2.68 g, 10mmol), benzyl
.+
.+
chloride (1.9g, 15 mmol), and anhydrous potassium carbonate
(4.1g, 30 mmol) in dry acetone (50 mL) was heated under reflux
for 24h on a water bath. Most of the solvent was distilled off,
and the reaction mixture was left to cool and poured onto cold
water with stirring. The solid that separated out was filtered off
and crystallized from light petroleum 60/80 / drops of benzene to
afford 9 as white crystals, mp 153–155°C, yield 73%.
H
3
3
-Amino-6-bromo-2-isopropyl-4(3H)-quinazolin-4-one
(
5).
An equimolar mixture of benzoxazinone 1 (2.68 g,
0 mmol) and hydrazine hydrate (0.75 g, 10 mmol) in ethanol
1
was heated at refluxing temperature for 3 h. The solid that
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. El-Hashash, M. E. Azab, and J. M. Morsy
Vol 000
ꢀ
1
1
FT-IR (KBr, ν, cm ): 1620 (C¼N), 1250 (C―O), H-NMR
(m, 1H, methine-H of iso-pr), 4.1 (q, 2H, CH
2
of Et), 6.5
(
300 MHz, CDCl
3
): 1.4 (d, 6H, 2CH
methine-H of iso-pr), 5.1 (s, 2H, OCH ), 7.3–8.4 (m, 8H,
Ar―H). MS (m/z, %): 356 (M , 39), 358 (M+2 , 37), 91
100). Anal. Calcd. for C18 17BrN O (357.27): C: 60.51, H:
.81, N: 7.84; found: C: 60.83, H:4.94, N: 7.98.
-(N-methylpiperidino)-6-bromo-2-isopropyl-4(3H)-quinazolin-
3
of iso-pr), 3.2 (m, 1H,
(s, 1H, olefinic-H), 7.1–8.4 (m, 8H, Ar―H). MS (m/z, %): 440
.
+
.+
(M , 21), 442 (M+2 , 20), 412 (63), 368 (51), 266 (32), 223
(100). Anal. Calcd. for C22 21BrN (441.35): C: 59.87, H:
2
.+
.+
H
O
2 3
(
4
H
2
4.81, N: 6.35; found: C: 60.23, H:4.95, N: 6.54.
Ethyl 2-(6-bromo-2-isopropylquinazolin-4-yloxy)-3-
phenylacrylate (12) and Ethyl 2-(6-bromo-2-isopro
3
4
4
1
-one (10a) and 3-(N-methylmorpholino)-6-bromo-2-isopropyl-
(3H)-quinazolin-4-one (10b). A solution of benzoxazinone
(2.68 g, 10 mmol), formaldehyde (0.3 g, 10 mmol), and the
pylquinazolin-4-yloxy)-3-phenylacrylic acid (13).
A
solution of ester 11 (3.47 g, 10 mmol) and benzaldehyde (1.06 g,
10 mmol) in dry tert-butanol (30 mL) was added dropwise during
1/2 h to stirred boiling solution of tert-BuOK (prepared from
potassium metal; 3.9 g, 10 mmol in 40 mL dry tert-butanol). Stirring
and boiling of the reaction mixture were continued for further 3 h,
then most of the alcohol was distilled off. The cold residue
was poured onto water and extracted with ether. The
ethereal layer was washed with water, dried over anhydrous
Mg SO , and left to air evaporation to give a pale yellow
appropriate secondary amine, namely, piperidine and/or morpholine
in ethanol (40 mL) in the presence of few drops of HCl was
heated at refluxing temperature for 4 h and left to cool. The solid
that settled down was filtered off and crystallized from the
suitable solvent to afford 10a, b.
1
0a: yellow, mp 130–132°C (benzene), yield 82%. FT-IR
ꢀ
1
1
(
KBr, ν, cm ): 1670 (C¼O), 1605 (C¼N). H-NMR (300 MHz,
CDCl ):1.0 (d, 6H, 2CH of iso-pr), 1.6 (m, 6H, 3CH piperidine),
.9 (m, 1H, methine-H of iso-pr), 2.4 (m, 4H, CH ―N―CH
piperidine), 4.3 (s, 2H, N―CH ―N), 7.4–8.5 (m, 3H, Ar―H).
2
4
3
3
2
oil which was triturated with ethanol to afford white solid.
The later was crystallized from light petroleum 60/80 to
yield quinazolinone 12. The aqueous layer was acidified
1
2
2
2
.+
.+
MS (m/z, %): 363 (M , 29), 365 (M+2 , 27), 224 (100). Anal.
with dilute HCl to give a solid product which was
Calcd. for C H BrN O (364.32): C: 56.04, H: 6.10, N: 11.54;
crystallized from ethanol to give acid 13.
17
22
3
found: C: 56.29, H:6.37, N: 11.74.
13: white, mp 200–202°C (ethanol), yield 72%. FT-IR (KBr, ν,
ꢀ
1
1
1
0b: yellow, mp 170–171°C (benzene), yield 84%. FT-IR
cm ): 3370 (OH), 1686 (C¼O), 1610 (C¼N). H-NMR
ꢀ
1
1
(
KBr, ν, cm ): 1680 (C¼O), 1610 (C¼N). H-NMR (300 MHz,
(300 MHz, CDCl ):1.3 (d, 6H, 2CH of iso-pr), 3.2 (m, 1H,
3
3
CDCl ):1.1 (d, 6H, 2CH of iso-pr), 1.6 (m, 6H, 3CH piperidine),
methine-H of iso-pr), 6.4 (s, 1H, olefinic-H), 7.2–8.3 (m, 8H,
3
3
2
1
3
.7 (m, 1H, methine-H of iso-pr), 2.5 (m, 2H, CH ―N―CH ),
Ar―H), 11.4 (s, 1H, D O-exchangeable, OH). MS (m/z, %):
2
2
2
.+
.+
.7 (m, 4H, CH
2
―O―CH
2
), 4.4 (s, 2H, N―CH
2
―N),7.2–8.3
412 (M , 28), 414 (M+2 , 27), 395 (12), 368 (62), 367 (37),
266 (8), 223 (29), 209 (98), 207 (100). Anal. Calcd. for
C H BrN O (413.29): C: 58.12, H: 4.15, N: 6.78; found: C:
.+
.+
(
m, 3H, Ar―H). MS (m/z, %): 365 (M , 81), 367 (M+2 , 79),
2
3 2
24 (100). Anal. Calcd. for C16H20BrN O (366.29): C: 52.46, H:
20
17
2 3
5
.51, N: 11.47; found: C: 52.71, H:5.76, N: 11.63.
58.34, H:4.28, N: 6.93.
Ethyl 2-(6-bromo-2-isopropylquinazolin-4-yloxy)acetate
4-O-(Hydrazino-carbonyl)methyl-6-bromo-2-isopropyl-4
(3H)-quinazolin-4-one (14). An equimolar mixture of ester 11
(3.47 g, 10 mmol) and hydrazine hydrate (0.50 g, 10 mmol) in
ethanol (50 mL) was heated under reflux for 4 h. The reaction
solution was concentrated and left to cool. The solid that
separated out was filtered off and crystallized from ethanol to
afford 14 as yellow crystals, mp 170–171°C, yield 81%. FT-IR
(
11).
A mixture of benzoxazinone 1 (2.68 g, 10 mmol),
ethyl chloroacetate (1.90 g, 15 mmol), and anhydrous
potassium carbonate (5.52 g, 40 mmol) in dry acetone (50 mL)
was heated under reflux for 24 h on a water bath. Most of the
solvent was distilled off, and the reaction mixture was left to
cool and poured onto cold water with stirring. The solid that
separated out was filtered off and crystallized from light
petroleum 60/80 to afford 11 as white crystals, mp 185–186°C,
ꢀ
1
1
(KBr, ν, cm ): 3282 (NH), 1635 (C¼O). H-NMR (300 MHz,
CDCl ): 1.2 (d, 6H, 2CH of iso-pr), 3.6 (m, 1H, methine-H of
3
3
ꢀ
1
yield 73%. FT-IR (KBr, ν, cm ): 1735 (C¼O), 1615 (C¼N).
iso-pr), 5.1 (s, 2H, OCH CO), 7.7–8.4 (m, 3H, Ar―H), 8.5 and
2
1
H-NMR (300 MHz, CDCl
and 2 CH of iso-pr group), 3.2 (m, 1H, methine-H of iso-pr
group), 4.2 (m, 2H, CH of ethyl group), 4.9 (s, 2H,OCH CO),
.6–8.4 (m, 3H, Ar―H).MS (m/z, %): 352 (M , 37), 354
3
): 1.3 (m, 9H, CH
3
of ethyl group
8.7 (2s, 2H, D O-exchangeable, NH2 attached to asymmetric
2
3
center), 9.4 (s, 1H, D O-exchangeable, NH). MS (m/z, %): 338
2
.+
.+
2
2
(M , 100), 340 (M+2 , 97), 307 (29), 280 (19), 279 (45), 250
.
+
7
(
(100), 207 (7). Anal. Calcd. for C H BrN O (339.22): C:
13
15
4 2
.
+
M+2 , 36), 324 (74), 280 (100), 251 (38), 250 (23), 237 (52).
Anal. Calcd. for C15 17BrN (353.24): C:51.14, H: 4.86, N:
.93; found: C: 51.36, H:5.24, N: 8.21.
Ethyl 2-(6-bromo-2-isopropylquinazolin-4-yloxy)-3-
phenylacrylate (12). An equimolar mixture of ester 11
3.47 g, 10mmol) and benzaldehyde (1.06 g, 10mmol) in
46.03, H: 4.47, N: 16.52; found: C: 46.19, H:4.71, N: 16.69.
H
2 3
O
7
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Journal of Heterocyclic Chemistry
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Month 2015
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