Design and Synthesis of Novel Triazolyl Benzoxazine Derivatives and Evaluation of Their Antiproliferative and Antibacterial Activity

Article abstract of DOI:10.1002/jhet.2387

A series of novel triazolyl benzoxazine derivatives have been synthesized via Cu(I)-catalyzed ‘Click’ cycloaddition. All of the compounds were fully characterized from their spectral data, and their antiproliferative activity was evaluated against three selected human cancer cell lines: cervical cancer cells (HeLa), colorectal adenocarcinoma (HT-29), and ovarian adenocarcinoma (SKOV-3). A few representative compounds have also been evaluated for their antibacterial potential against two bacterial strains Pseudomonas aeruginosa and Bacillus subtilis.

Full text of DOI:10.1002/jhet.2387

Month 2015
Design and Synthesis of Novel Triazolyl Benzoxazine Derivatives and
Evaluation of Their Antiproliferative and Antibacterial Activity
*
Abdullah Khan, Suchita Prasad, Virinder S. Parmar, and Sunil K. Sharma
Department of Chemistry, University of Delhi, Delhi 110007, India
*
E-mail: sk.sharma90@gmail.com
Received August 11, 2014
DOI 10.1002/jhet.2387
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel triazolyl benzoxazine derivatives have been synthesized via Cu(I)-catalyzed ‘Click’ cycload-
dition. All of the compounds were fully characterized from their spectral data, and their antiproliferative activity
was evaluated against three selected human cancer cell lines: cervical cancer cells (HeLa), colorectal adenocarci-
noma (HT-29), and ovarian adenocarcinoma (SKOV-3). A few representative compounds have also been evalu-
ated for their antibacterial potential against two bacterial strains Pseudomonas aeruginosa and Bacillus subtilis.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
representations. Nitrogen-containing heterocyclic com-
pounds have maintained the interest of researchers through
decades of historical development of organic synthesis.
Among the nitrogen heterocycles, 1,4-benzoxazine is the
important scaffold present in various agrochemicals and
primarily used by plants as natural defense chemicals
[2, 3]. In particular, the utility of the 2H-1,4-benzoxazin-3-
(4H)-one scaffold as a privileged structure for the generation
of drug-like libraries in drug-discovery programs has been
amply demonstrated. 1,4-Benzoxazin-3(4H)-one derivatives
have shown various biological activities; for example, both
the derivatives of compound 1 are potential non-nucleoside
SGLT2 inhibitors for the treatment of type 2 diabetes [4].
Heterocycles form by far the largest of classical
divisions of organic chemistry and are of immense
importance biologically and industrially. The majority of
pharmaceuticals and biologically active agrochemicals are
heterocyclic as well the countless additives and modifiers
used in industrial applications ranging from cosmetics to
information storage and plastics [1]. One striking structural
feature inherent to heterocycles, which continue to be
exploited to great advantage by the pharmaceutical
industry, lies in their ability to manifest substituents
around a core scaffold in defining three-dimensional
© 2015 HeteroCorporation

A. Khan, S. Prasad, V. S. Parmar, and S. K. Sharma
Vol 000
Similarly, investigation of a series of 4,6-disubstituted-
4H-benzo[1,4]oxazin-3-ones (2) has led to the identification
of inhibitors of PI3 kinases [5]. The compound 3 displayed
significant anticonvulsant activity [6]. Recently, a compound
cappamensin A (4) isolated from the roots of Capparis
sikkimensis displayed significant in vitro antitumor activity
in various human cell lines [7]. Moreover, benzoxazine
derivatives are also known to exhibit other activities such
as anti-inflammatory [8], antiulcer [9], antipyretic [10],
antihypertensive [11], antifungal [12], potassium channel
modulators [13], antirheumatic agents [14], and plant
resistance factors against microbial diseases and insects [15].
Diverse biological activities of 2H-1,4-benzoxazin-3-
(4H)-one scaffold have encouraged us to develop newer
analogs that may follow novel mechanisms of action to
combat diseases; this is indeed required as most drugs
become ineffective because of the acquired drug resistance.
Molecular hybridization, which covalently combines two
or more drug pharmacophores into a single molecule, is
an effective tool to design highly active novel entities.
The clubbed pharmacophores may act on multiple thera-
peutic targets and offer the advantage of overcoming
inevitable drug resistance [16]. In addition, the hybrids
may also minimize unwanted side effects and allow for
synergistic action [17]. The molecular hybrid approach
has already been applied in developing novel antimalarial
agents to overcome drug resistance [18]. In recent years,
1,2,3-triazole has emerged as an interesting scaffold for
medicinal chemists owing to its numerous biological activ-
ities and synthetic accessibility by ‘Click chemistry’ [19].
1,2,3-Triazole’s pharmacological profile has made it much
more appealing and promising for finding potential anti-
cancer and antibacterial lead agents. 1,2,3-Triazoles
conjugated with a wide range of moieties are reported to
exhibit potent anticancer and antibacterial activities [20].
Encouraged by the recent research in this area by our group
and the newest literature reports on benzo[b][1,4]oxazine
scaffold, we envision observing the potential synergistic
effect by clubbing together the 1,2,3-triazole and 2H-1,
4-benzoxazin-3-(4H)-one moieties on the antiproliferative
activity against cancerous human cell lines. Because such
scaffolds are also known to possess antimicrobial activity,
we thus planned to study the antibacterial activity of the
compounds synthesized by combining two pharmacophores.
This is the first such study where the triazolyl benzoxazine
moieties have been clubbed together and the resulting
compounds evaluated for antiproliferative and antibacterial
activities.
7-nitro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-
one (12) with various aromatic and aliphatic azides (13–16)
via copper(I)-catalyzed 1,3-dipolar cycloaddition (Scheme 1).
The key propargyl benzoxazine intermediate was prepared
from 2-amino-4-chlorophenol (5) and 2-amino-5-
nitrophenol (6). In the first step, amidation of phenol (5/6)
with 2-chloroacetyl chloride leads to the formation of the
corresponding amide (7/8). The amide (7/8) was then
dissolved in DMF and K2CO3 added to it. The reaction
mixture was stirred at the 90°C for 5h to yield the cyclized
product, that is, benzoxazine (9/10). Benzoxazine was then
reacted separately with propargyl bromide in anhydrous
acetone and K2CO3 under reflux conditions to yield the
desired 6-chloro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-
3(4H)-one (11) and 7-nitro-4-(prop-2-yn-1-yl)-2H-benzo[b]
[1,4]oxazin-3(4H)-one (12), which was purified by column
chromatography using ethyl acetate :petroleum ether (1:10)
as eluting solvent (Scheme 2). Additionally, the azides
13–16 were in turn prepared following Schemes 3–5.
Synthesis of 2-azidopropane-1,3-diyl diacetate (13)/2-
azidopropane-1,3-diol (14).
The chemo-enzymatic meth-
odology was utilized (Scheme 3) to synthesize the target
2-azidopropane-1,3-diol by following the literature report
[21]. Glycerol was used as the starting material to form
the azide (13 and 14) using immobilized Candida
antarctica lipase B (CAL B) marketed by Novo Nordisk
(Denmark) as Novozym 435. The first step involved the
selective acetylation of the primary hydroxyl groups of
glycerol using vinyl acetate and Novozym 435 to form
1,3-diacetoxy glycerol. It was then subjected to
mesylation of the available secondary hydroxyl group
followed by azidation in DMF to yield the diacetoxy
azido derivative 13, which on deacylation gives
2-azidopropane-1,3-diol 14.
Synthesis of aliphatic azides (15).
These azides were
synthesized by following the method of Wilkening et al.
[22]. Various para-substituted benzyl azide, hexyl azide,
and 2-azido ethyl acetate were obtained from the
corresponding bromo precursor by treatment with sodium
azide (Scheme 4).
Synthesis of aromatic azides (16). The aromatic azides
(16) were synthesized by following the literature
procedure (Scheme 5) [22].
Scheme 1. The synthetic route of compounds 17–50. Reagents: (a)
CuSO4·5H2O, sodium ascorbate, THF : H2O (1:1), 35–40°C.
RESULTS AND DISCUSSION
Chemistry. A series of triazolyl benzoxazine derivatives
(17–50) were synthesized by reacting 6-chloro-4-(prop-2-
yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (11) and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Design and Synthesis of Novel Triazolyl Benzoxazine Derivatives and Evaluation of
Their Antiproliferative and Antibacterial Activity
Month 2015
Scheme 2. The synthetic route of compounds 11 and 12. Reagents: (a) Chloroacetyl chloride, K2CO3, CH3CN, 25°C; (b) K2CO3, DMF, 90°C; (c) propargyl
bromide, K2CO3, anhydrous acetone, reflux.
Scheme 3. Synthesis of 2-azidopropane-1,3-diol. Reagents: (a) Novozym
435, vinyl acetate, THF, 25°C; (b) MsCl, TEA, CHCl3, 25°C; (c) NaN3,
DMF, 80-120°C; (d) K2CO3, abs. EtOH.
mixed with Cell Titer 96 aqueous solution but no cells.
Results were expressed as the percentage of the control
(without a compound set at 100%).
Out of 34 triazolyl benzoxazine derivatives synthesized
(Table 1), 32 derivatives were evaluated against three hu-
man carcinoma cell lines, namely cervical cancer cells,
HeLa, colorectal adenocarcinoma, HT-29, and ovarian ad-
enocarcinoma SKOV-3 at a concentration of 50DM. All
the compounds tested for their antiproliferative activity
displayed almost negligible activity against the three cell
lines studied (Figs. 1–3).
Scheme 4. The synthetic route of compound 15. Reagents: (a) NaN3, DMSO,
25°C.
Table 1
List of triazolyl benzoxazine derivatives synthesized.
Scheme 5. The synthetic route of compound 16. Reagents: (a) NaNO2,
HCl, NaN3, 0–25°C.
Compound
R2
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
–CH(CH2OH)2
4-NO2-benzyl
4-C6H4OMe
4-C6H4Cl
4-C6H4F
3-C6H4OMe
4-C6H4COOMe
2-C6H4OH
2-C6H4OMe
2,5-C6H4(OMe)2
Benzyl
4-F-benzyl
4-C6H4Br
–C6H5
–CH2COOEt
–CH(CH2OAc)2
4-C6H4 NO2
Hexyl
4-C6H4OH
3-C6H4OH
–CH2COOEt
3-C6H4OMe
2-C6H4OMe
4-C6H4OMe
Benzyl
Antiproliferative activity evaluation of the triazolyl
benzoxazine derivatives. Cell culture.
The cells were
grown on 75-cm2 cell culture flasks with Eagle’s minimum
essential medium, supplemented with 10% fetal bovine
serum and 1% penicillin/streptomycin solution (10,000 units
of penicillin and 10mg of streptomycin in 0.9% NaCl) in a
humidified atmosphere of 5% CO2, 95% air at 35°C.
Cell proliferation assay.
Cell proliferation assay was
carried out using CellTiter 96 aqueous one solution cell
proliferation assay kit (Promega Corporation, Madison,
WI, USA). Briefly, upon reaching about 75–80%
confluence, 5000 cells per well were plated in a 96-well
microplate in 100 μL media. After seeding for 72h, the
cells were treated with 50 μM compound in triplicate.
Doxorubicin (10 μM) was used as the positive control. At
the end of the sample exposure period (72 h), 20 μL
CellTiter 96 aqueous solutions were added. The plate was
returned to the incubator for 1 h in a humidified
atmosphere at 37°C. The absorbance of the formazan
product was measured at 490nm using a microplate
reader. The blank control was recorded by measuring at
the same wavelength with wells containing a medium
4-F-benzyl
4-NO2-benzyl
4-C6H4Cl
4-C6H4Br
3-C6H4OH
4-C6H4NO2
2,5-C6H4(OMe)2
4-C6H4F
–C6H5
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A. Khan, S. Prasad, V. S. Parmar, and S. K. Sharma
Vol 000
Figure 1. Cell viability results of compounds 17–24 against three cell lines HeLa, HT-29, and SKOV-3.
Figure 2. Cell viability results of compounds 25–34, 37–39, 40 & 42 against three cell lines HeLa, HT-29, and SKOV-3.
Antibacterial activity evaluation of the triazolyl benzoxazine
derivatives. The antibacterial activity screening of few
Sample preparation for antimicrobial activity. Preparation
of test organism.
The antimicrobial activity test was
representative compounds was carried out against
pathogenic bacteria by a disk diffusion method as
described by the Kirby–Bauer method [23]. Briefly, the
inoculums were prepared by growing bacteria at 37°C for
14–16h. The OD of overnight culture was adjusted to 0.4–
0.6 at a transmission wavelength of 600nm. Sterilized
disks (6mm in diameter) were impregnated with the
solution of compounds and incubated at 37°C for 16–17h.
The zone of inhibition developed by compounds was
examined at a concentration of 250μg/d, and gentamicin
was used in the assay as the standard control drug. An
equivalent amount of solvent was employed as the negative
control in the assay.
performed by disk diffusion using two strains, that is,
the Gram-positive bacterial strain of Bacillus subtilis
and Gram-negative bacterial strain of Pseudomonas
aeruginosa. The test organisms were inoculated in nutrient
broth and kept at an orbital shaker (ISF1-X (Climo-
Shaker), Kuhner, Dinkelbergstrasse 1, CH-4127 Birsfelden
(Basel), Switzerland) at 200rpm/min at 37°C for 14–16h.
Kirby–Bauer disk diffusion assay. Antimicrobial activity
was performed by using the Kirby–Bauer disk susceptibility
test with some minor modifications.
Different antibiotic disks were placed on the respective
grid of each Mueller Hinton Agar plates seeded with the
test organism and then kept for overnight incubation at
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Design and Synthesis of Novel Triazolyl Benzoxazine Derivatives and Evaluation of
Their Antiproliferative and Antibacterial Activity
Month 2015
Figure 3. Cell viability results of compounds 35, 36, 43–47, 49 & 50 against three cell lines HeLa, HT-29, and SKOV-3.
Table 2
Antibacterial activity results.
Zone of inhibition (mm)a
Sample
no.
Sample code
Solubility
Pseudomonas aeruginosa
Bacillus subtilis
1
2
3
4
5
6
7
8
9
17
21
24
28
34
35
36
50
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
—
NA
NA
NA
NA
NA
NA
NA
NA
28
NA
NA
NA
NA
NA
NA
NA
NA
35
Gentamicin (+ve)
Concentration of gentamicin: 100 μg/d.
aConcentration of the compound: 250 μg/d.
37°C. In antibiotics that inhibited the growth of organisms,
a “zone of inhibition” was observed, which was a clear, dis-
tinct zone, and some antibiotics were not effective in
inhibiting the growth of the organisms; hence, no zone of
inhibition was found.
A few representative compounds were evaluated
for their antibacterial activity against two bacterial strains
P. aeruginosa and B. subtilis. The zone of inhibition was
evaluated by the disk diffusion method. All the compounds
evaluated did not show any noticeable antibacterial activity
at the concentrations screened (Table 2).
and FT-IR spectral data. Out of 34 compounds, 32 have
been evaluated for their antiproliferative activity against
a panel of three human cancer cell lines, that is, HeLa,
HT-29, and SKOV-3. Eight representative compounds
were also evaluated for their antibacterial activity against
two bacterial strains P. aeruginosa and B. subtilis.
However, these compounds do not exhibit a noticeable
antiproliferative or antibacterial activity. This information
may be useful for researchers working in a related area
for the further design and development of antiproliferative
and antibacterial compounds.
CONCLUSIONS
EXPERIMENTAL
A series of 34 novel triazolyl benzoxazine derivatives
were synthesized. All the compounds were characterized
All the chemicals and reagents were procured from
Spectrochem Pvt. Ltd. (Mumbai, India) and Sigma-Aldrich
Chemicals Pvt. Ltd. (St. Louis, MO, USA). The organic
1
on the basis of their H NMR, 13C NMR, HRMS, UV,
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A. Khan, S. Prasad, V. S. Parmar, and S. K. Sharma
Vol 000
General procedure for the synthesis of triazolyl benzoxazine
(17-50). To a solution THF/H2O (2:1v/v) was added a
solvents were dried and distilled prior to their use. Reactions
were monitored by precoated TLC plates (Merck silica gel
60F254); the spots were visualized with UV light. Silica
gel (100–200mesh) was used for column chromatography.
Melting points were measured on a Buchi M-560 apparatus
(BUCHI, Switzerland) and are uncorrected. Infrared spectra
were recorded on a Perkin-Elmer FT-IR model 9 spectropho-
propargyl derivative (11–12) (1equiv.) and respective azide
(13–16) (1equiv.) followed by the addition of sodium
ascorbate (0.1 equiv.) and CuSO4·5H2O (0.2equiv.) with
stirring at 35–40°C for 6–12 h. After completion of the
reaction, observed through TLC (MeOH:CHCl3, 1:20), the
solvent was evaporated under reduced pressure. The crude
solid obtained was then dissolved in distilled water and
extracted with ethyl acetate (3× 100mL). The combined
organic layer was washed with saturated sodium
bicarbonate solution (3×50mL) and with brine (50mL).
After drying the solution over anhydrous sodium sulfate, the
solvent was removed under reduced pressure, and the
desired compound (17–50) was obtained as crude solid. The
crude product was purified by column chromatography over
silica gel 100–200mesh in 5–10% methanol/chloroform to
1
tometer (PerkinElmer, Waltham, MA, USA). The H and
13C NMR spectra were recorded on a Jeol-400 (400MHz,
100.5MHz) NMR spectrometer (JEOL USA Inc., Peabody,
MA, USA) using TMS as internal standard. The chemical
shift values are on the δ scale, and the coupling constant
values (J) are in hertz. The HRMS data were obtained using
a JEOL JMS-SX-102A spectrometer at the Institute fur
Chemie und Biochemie, Freie Universitat Berlin, Germany.
General procedure for the synthesis of 6-chloro/7-nitro 4-(prop-
2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (11/12).
The
yield the desired compound in 85–95% isolated yield.
target compound was synthesized by following the method
of Vara et al. [24]. In a 500-mL RB flask, benzoxazine-
3(4H)-one derivative (9 and 10) (1equiv.) was dissolved in
anhydrous acetone (200 mL) at 25°C followed by the
addition of anhydrous K2CO3 (1.5equiv.) along with
stirring. The solution was stirred for 10min, and then
6-Chloro-4-[(1-(1,3-dihydroxypropan-2-yl)-1H-1,2,3-triazol-4-
yl)methyl]-2H-benzo[b] [1,4]oxazin-3(4H)-one (17).
White
solid; Yield: 85%; Melting point: 177–179°C; UV
(MeOH) λmax: 258 and 297nm; IR (KBr) νmax (cmÀ1):
3350, 2922, 1685, 1382, 1275; 1H NMR (400MHz,
DMSO-d6): δ 3.76 (d, J=4.3Hz, 4H, H-1″ and H-3″),
4.53–4.59 (m, 1H, H-2″), 4.72 (s, 2H, –OH), 5.02 (d,
J=5.1Hz, 2H, H-4a), 5.13 (s, 2H, H-2), 7.01–7.06 (m, 2H,
H-7 and H-8), 7.50 (d, J=1.4Hz, 1H, H-5), 8.02 (s, 1H,
H-5′); 13C NMR (100.5MHz, DMSO-d6): δ 36.38 (C-4a),
60.60 (C-1″ and C-3″), 64.97 (C-2), 67.05 (C-2″), 115.86
(C-8), 117.91 (C-5), 123.16 (C-7), 123.26 (C-5′), 126.34
(C-6), 129.95 (C-9), 141.37 (C-4′), 143.77 (C-10), 163.94
(C-3); HRMS (m/z): Calculated for C14H15ClN4O4 [M
propargyl bromide (1.2equiv.) was added dropwise. The
reaction mixture was stirred at 65°C, and then the progress
of the reaction was followed by TLC (ethyl acetate:
petroleum ether, 1:4). On completion of the reaction, the
reaction mixture was allowed to cool to room temperature
followed by evaporation of the solvent under reduced
pressure. The crude solid so obtained was cooled in an
ice bath, and then distilled water (100mL) was added.
The resulting solution was extracted with chloroform
(3×100mL), and the combined organic layer was washed
with water (2×100mL) and brine (100mL). After drying
the solution over anhydrous sodium sulfate, the solvent was
evaporated under reduced pressure, and the crude product
so obtained was subjected to column chromatography
(MeOH:CHCl3, 1:20). The desired compound (11–12) was
obtained in 90–95% isolated yield as a light brown solid.
6-Chloro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-
one (11). Light brown solid; Yield: 95%; Melting point:
+Na]+ 361.0680, found 361.0650 [M+Na]+.
6-Chloro-4-[(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl]-
2H-benzo[b][1,4]oxazin-3(4H)-one (18). Yellow solid; Yield:
95%; Melting point: 184–186°C; UV (MeOH) λmax: 263 and
302nm; IR (KBr) νmax (cmÀ1): 3072, 1691, 1370, 1265; 1H
NMR (400 MHz, DMSO-d6): δ 4.70 (s, 2H, H-4a), 5.16 (s,
2H, H-2), 5.74 (s, 2H, H-1′a), 7.02–7.03 (m, 2H, H-8 and
H-7), 7.39 (d, J=1.4Hz, 1H, H-5), 7.48 (d, J=8.7Hz, 2H,
H-2″ and H-6″), 8.18 (s, 1H, H-5′), 8.20 (d, J=8.7Hz, 2H,
H-3″ and H-5″); 13C NMR (100.5MHz, DMSO-d6): δ
36.04 (C-4a), 51.65 (C-1′a), 66.69 (C-2), 115.75 (C-8),
117.63 (C-5), 123.15 (C-7), 124.01(C-5′), 124.54 (C-5″
and C-3″), 126.40 (C-6), 129.12 (C-2″ and C-6″), 129.76
(C-9), 142.56 (C-4′), 143.45 (C-1″), 143.84 (C-10), 147.26
(C-4″), 164.02 (C-3); HRMS (m/z): Calculated for
C18H14ClN5O4 [M+Na]+ 422.0632, found 422.0644 [M
+Na]+.
98–99°C (100–101°C) [25]; UV (MeOH) λmax: 297 nm;
IR (KBr) νmax (cmÀ1): 3229, 2854, 2115, 1684, 1384,
1
1272; H NMR (400 MHz, CDCl3): δ2.30 (t, 1H, H-3′),
4.63 (s, 2H, H-2), 4.66 (d, J = 2.2 Hz, 2H, H-1′), 6.93
(d, J = 8.8 Hz, 1H, H-8), 7.00 (dd, J = 8.8 and 2.2 Hz, 1H,
H-7), 7.18 (d, J = 2.2 Hz, H-5).
7-Nitro-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-
one (12). Light brown solid; Yield: 90%; Melting point:
149–150°C; UV (MeOH) λmax: 337nm; IR (KBr) νmax
6-Chloro-4-[(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)
1
(cmÀ1): 3301, 2915, 1700, 1501, 1339, 1320; H NMR
methyl]-2H-benzo[b][1,4]oxazin-3(4H)-one
(19).
Light
(400MHz, CDCl3): δ 2.31 (t, J=2.5Hz, 1H, H-3′), 4.73 (s,
2H, H-2), 4.75 (d, J=2.2Hz, 2H, H-1′), 7.29 (d, J=8.4Hz,
1H, H-5), 7.85 (d, J=2.9Hz, 1H, H-8), 7.97 (dd, J=7.6
and 2.2Hz, 1H, H-6).
yellow solid; Yield: 93%; Melting point: 164–166°C; UV
(MeOH) λmax: 263nm; IR (KBr) νmax (cmÀ1): 3126, 1685,
1
1387, 1263; H NMR (400MHz, CDCl3): δ 3.85 (s, 3H, –
OMe), 4.61 (s, 2H, H-4a), 5.20 (s, 2H, H-2), 6.90
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Design and Synthesis of Novel Triazolyl Benzoxazine Derivatives and Evaluation of
Their Antiproliferative and Antibacterial Activity
Month 2015
(d,J=8.7Hz, 1H, H-8), 6.96 (dd, J=8.7 and 2.2Hz, H-7),
6.99 (d, J=8.7Hz, 2H, H-3″ and H-5″), 7.60 (d, J=8.7Hz,
2H, H-2″ and H-6″), 7.62 (d, J=2.2Hz, 1H, H-5), 7.95
(s, 1H, H-5′); 13C NMR (100.5MHz, CDCl3): δ 37.55 (C-
4a), 55.54 (–OCH3), 67.61 (C-2), 114.69 (C-3″ and C-5″),
116.12 (C-5), 117.76 (C-7 and C-8), 121.64 (C-5′),
122.04 (C-2″ and C-6″), 123.91 (C-6), 128.17 (C-1″),
129.67 (C-9), 143.09 (C-4′), 143.66 (C-10), 159.83 (C-4″),
164.53 (C-3); HRMS (m/z): Calculated for C18H15ClN4O3
[M+Na]+ 393.0730, found 393.0707 [M+Na]+.
(C-1″ and C-3″), 130.96 (C-10), 137.55 (C-4′), 143.31 (C-
5″ and C-4″), 143.92 (C-9), 158.55 (C-3″), 164.20 (C-3);
HRMS (m/z): Calculated for C18H15ClN4O3 [M+Na]+
393.0730, found 393.0735 [M+Na]+.
Methyl 4-(4-[(6-chloro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)
methyl]-1H-1,2,3-triazol-1-yl)benzoate (23).
Light yellow
solid; Yield: 95%; Melting point: 209–210°C; UV
(MeOH) λmax: 265 nm; IR (KBr) νmax (cmÀ1): 2952,
1
1719, 1689, 1364, 1274; H NMR (400MHz, CDCl3): δ
3.94 (s, 3H, H-1″″), 4.62 (s, 2H, H-4a), 5.22 (s, 2H, H-2″),
6.91 (d, J=8.7Hz, 1H, H-8″), 6.97 (dd, J=8.0 and 2.2Hz,
1H, H-7″), 7.59 (d, J=2.2Hz, 1H, H-5″), 7.82
(d, J=8.7Hz, 2H, H-3 and H-5), 8.11 (s, 1H, H-5′), 8.19
(d, J=8.7Hz, 2H, H-2 and H-6); 13C NMR (100.5MHz,
CDCl3): δ 37.46 (C-4a), 52.41 (C-1″″), 67.62 (C-2″),
116.03 (C-8″), 117.88 (C-4′), 119.85 (C-3 and C-5),
121.48 (C-7″), 124.04 (C-5″), 128.22 (C-6″), 129.60 (C-1),
130.36 (C-10″), 131.29 (C-2 and C-6), 139.79 (C-4),
143.68 (C-9″), 164.63 (C-3″), 165.77 (C-1″′); HRMS (m/z):
Calculated for C19H15ClN4O4 [M+Na]+ 421.0680, found
6-Chloro-4-[(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl]-
2H-benzo[b][1,4]oxazin-3(4H)-one (20). Light yellow solid;
Yield: 92%; Melting point: 192–194°C; UV (MeOH) λmax
:
256 and 300nm; IR (KBr) νmax (cmÀ1): 3147, 1677, 1377,
1
1264; H NMR (400MHz, CDCl3): δ 4.61 (s, 2H, H-4a),
5.20 (s, 2H, H-2), 6.90 (d, J=8.7Hz, 1H, H-8), 6.97
(dd, J=8.7 and 2.20Hz, 1H, H-7), 7.48 (d, J=8.7Hz, 2H,
H-2″ and H-6″), 7.59 (d, J=2.2Hz, 1H, H-5), 7.66 (d,
J=8.7Hz, 2H, H-3″ and H-5″), 8.02 (s, 1H, H-5′); 13C
NMR (100.5MHz, CDCl3): δ 37.46 (C-4a), 67.60 (C-2),
116.03 (C-5 and C-8), 117.84 (C-5′), 121.57 (C-2″ and C-6″),
124.00 (C-6 and C-7), 128.19 (C-3″ and C-5″), 129.60 (C-9),
129.89 (C-4′), 134.66 (C-4″), 135.22 (C-1″), 143.65 (C-10),
164.59 (C-3); HRMS (m/z): Calculated for C17H12Cl2N4O2
421.0616 [M+Na]+.
6-Chloro-4-[(1-(2-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)methyl]-
2H-benzo[b][1,4]oxazin-3(4H)-one (24). Light yellow solid;
Yield: 70%; Melting point: 214–215°C; UV (MeOH) λmax
:
249 and 294nm; IR (KBr) νmax (cmÀ1): 3299, 1663, 1431,
[M +Na]+ 397.0235, found 397.0231 [M+ Na]+.
6-Chloro-4-[(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl]-
2H-benzo[b][1,4]oxazin-3(4H)-one (21). Light yellow solid;
1
1361, 1272; H NMR (400MHz, DMSO-d6): δ 4.73 (s,
2H, H-4a), 5.25 (s, 2H, H-2), 6.94–6.98 (m, 1H, H-4″),
7.01–7.06 (m, 2H, H-5″ and H-6″), 7.09 (d, J=8.2Hz, 1H,
H-8), 7.30–7.34 (m, 1H, H-3″), 7.52 (d, J = 1.8 Hz, 1H,
H-5), 7.58 (dd, J = 7.7, 1.37 Hz, 1H, H-7), 8.42 (s, 1H,
H-5′), 10.57 (s, 1H, OH); 13C NMR (100.5 MHz,
DMSO-d6): δ 36.08 (C-4a), 67.05 (C-2), 115.82 (C-8),
117.05 (C-1″), 117.90 (C-3″), 119.55 (C-5), 123.12 (C-
5′), 124.34 (C-5″), 124.94 (C-6), 125.28 (C-6), 126.33
(C-6″), 129.84 (C-10), 130.13 (C-4″), 141.75 (C-4′), 143.81
(C-9), 149.41 (C-2″), 164.03 (C-3); HRMS (m/z):
Calculated for C17H13ClN4O3 [M + Na]+ 379.0574,
Yield: 89%;Melting point: 148–149°C; UV (MeOH) λmax
:
252 and 299nm; IR (KBr) νmax (cmÀ1): 1686, 1387,
1
1269; H NMR (400 MHz, CDCl3): δ 4.61 (s, 2H, H-4a),
5.20 (s, 2H, H-2), 6.90 (d, J =8.7 Hz, 1H, H-8), 6.97
(dd, J=8.7 and 2.2Hz, 1H, H-7), 7.20 (t, 3JHF =8.7Hz, 2H,
H-2″ and H-6″), 7.60 (d, J= 2.2 Hz, 1H, H-5), 7.67–7.70
(m, 2H, H-3″ and H-5″), 8.00 (s, 1H, H-5′); 13C NMR
(100.5MHz, CDCl3): δ 37.52 (C-4a), 67.64 (C-2), 116.09
(C-8), 116.73 (d, JCF = 23.0 Hz C-3″ and C-5″), 117.87
(C-7), 121.77 (C-5), 122.46 (d, JCF = 8.6 Hz, C-2″ and C-
6″), 124.03 (C-5′), 128.24 (C-6), 129.64 (C-4′), 133.07
(d, JCF = 2.8Hz, C-1″), 143.48 (C-10), 143.69 (C-9),
162.47 (d, JCF = 250.16 Hz, H-4″), 164.63 (C-3); HRMS
(m/z): Calculated for C17H12ClFN4O2 [M+Na]+ 381.0531,
found 379.0550 [M + Na]+.
6-Chloro-4-[(1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl]-
2H-benzo[b][1,4]oxazin-3(4H)-one (25). White solid; Yield:
85%; Melting point: 170–171°C; UV (MeOH) λmax: 250
and 251nm; IR (KBr) νmax (cmÀ1): 2901, 1685, 1386,
1288; 1H NMR (400MHz, CDCl3): δ 3.87 (s, 3H, OCH3),
4.61 (s, 2H, H-4a), 5.23 (s, 2H, H-2), 6.90 (d, J =8.7 Hz,
1H, H-8), 6.96 (dd, J = 8.7 and 2.2 Hz, 1H, H-5″), 7.05–
7.10 (m, 2H, H-4″ and H-6″), 7.39–7.43 (m, 1H, H-3″),
7.65 (d, J= 2.2 Hz, 1H, H-5), 7.75 (dd, J = 8.0 and 1.4Hz,
1H, H-7), 8.15 (s, 1H, H-5′); 13C NMR (100.5 MHz,
CDCl3): δ 37.51 (C-4a), 55.91 (OCH3), 67.63 (C-2),
112.15 (C-8), 116.27 (C-3″), 117.72 (C-7), 121.12 (C-5),
123.81 (C-5′), 125.34 (C-5″), 125.50 (C-6), 126.06 (C-6″),
128.11(C-1″), 129.78 (C-4″), 130.15 (C-10), 141.92 (C-4′),
143.72 (C-9), 150.97 (C-2″), 164.38 (C-3); HRMS (m/z):
Calculated for C18H15ClN4O3 [M+Na]+ 393.0730, found
393.0730 [M+Na]+.
found 381.0519 [M+Na]+.
6-Chloro-4-[(1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl)
methyl]-2H-benzo[b][1,4]oxazin-3(4H)-one (22). Light yellow
solid; Yield: 91%; Melting point: 194–195°C; UV
(MeOH) λmax: 255 and 295nm; IR (KBr) νmax (cmÀ1):
1
2974, 1689, 1375, 1273; H NMR (400 MHz, CDCl3): δ
3.87 (s, 3H, OCH3), 4.62 (s, 2H, H-4a), 5.21 (s, 2H, H-2),
6.91 (d, J =8.7 Hz, 1H, H-8), 6.95–6.98 (m, 2H, H-4″ and
H-5″), 7.23 (dd, J = 8.0 and 2.2 Hz, 1H, H-7), 7.32
(t, J = 2.2Hz, 1H, H-2″), 7.39 (t, J= 8.0 Hz, 1H, H-6″),
7.62 (d, J = 2.2 Hz, 1H, H-5), 8.03 (s, 1H, H-5′); 13C
NMR (100.5MHz, CDCl3):
δ 36.40 (C-4a), 55.40
(–OCH3), 67.16 (C-2), 115.80 (C-8), 115.88 (C-7), 118.09
(C-5), 121.88 (C-5′), 123.34 (C-6″), 126.44 (C-6), 129.90
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Khan, S. Prasad, V. S. Parmar, and S. K. Sharma
Vol 000
6-Chloro-4-[(1-(2,5-dimethoxyphenyl)-1H-1,2,3-triazol-4-
yl)methyl]-2H-benzo[b][1,4] oxazin-3(4H)-one (26). Light
5.20 (s, 1H, H-2), 6.90 (d, J = 8.7 Hz, 1H, H-8), 6.96
(dd, J = 8.7 and 2.2 Hz, 1H, H-7), 7.59–7.65 (m, 5H, H-5,
H-2″, H-3″, H-5″ and H-6″), 8.03 (s, 1H, H-5′); 13C NMR
(100.5 MHz, CDCl3): δ 37.49 (C-4a), 67.63 (C-2), 116.06
(C-8), 117.86 (C-5′), 121.44 (C-7), 121.82 (C-5), 122.57
(C-4″), 124.02 (C-6), 128.22 (C-2″ and C-6″), 129.63 (C-10),
132.89 (C-3″ and C-5″), 135.74 (C-4′), 143.62 (C-1″),
143.68 (C-9),164.60 (C-3); HRMS (m/z): Calculated for
C17H12BrClN4O2 [M + Na]+ 440.9730, found 440.9731
yellow solid; Yield: 87%; Melting point: 145–146°C;
UV (MeOH) λmax: 251 and 301 nm; IR (KBr) νmax
(cmÀ1): 2933, 1695, 1508, 1365, 1228; 1H NMR
(400 MHz, CDCl3): δ 3.80 (s, 3H, OCH3), 3.82 (s, 3H,
OCH3), 4.61 (s, 2H, H-4a), 5.23 (s, 2H, H-2), 6.90 (d,
J = 8.7 Hz, 1H, H-3″), 6.92-7.00 (m, 3H, H-7, H-8 and
H-4″), 7.39 (d, J=2.9Hz, 1H, H-6″), 7.65 (d, J=1.8Hz,
1H, H-5), 8.21 (s, 1H, H-5′); 13C NMR (100.5MHz,
CDCl3): δ 37.46 (C-4a), 55.90 (OMe), 56.41 (OMe), 67.61
(C-2), 110.08 (C-8), 113.48 (C-6″), 115.79 (C-4″), 116.24
(C-3″), 117.73 (C-1″), 123.81 (C-5′), 125.48 (C-5), 126.19
(C-7), 128.08 (C-6), 129.74 (C-10), 141.98 (C-4′), 143.70
(C-9), 144.72 (C-2″), 153.75 (C-5″),164.38 (C-3); HRMS
(m/z): Calculated for C19H17ClN4O4 [M+Na]+ 423.0836,
[M + Na]+.
6-Chloro-4-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-2H-benzo
[b][1,4]oxazin-3(4H)-one (30).
White solid; Yield: 82%;
Melting point: 171–172°C; UV (MeOH) λmax: 250 and
297 nm; IR (KBr) νmax (cmÀ1): 3081, 1693, 1498, 1381,
1
1267; H NMR (400 MHz, CDCl3): δ 4.62 (s, 2H, H-4a),
5.22 (s, 2H, H-2), 6.91 (d, J = 8.0 Hz, 1H, H-8), 6.97
(dd, J= 8.0 and 2.2 Hz, 1H, H-7), 7.41–7.45 (m, 1H, H-4″),
7.49–7.53 (m, 2H, H-3″ and H-5″), 7.62 (d, J= 2.2Hz, 1H,
H-5), 7.70–7.72 (m, 2H, H-2″ and H-6″), 8.04 (s, 1H, H-5′);
13C NMR (100.5 MHz, CDCl3): δ 37.52 (C-4a), 67.61
(C-2), 116.10 (C-8), 117.79 (C-7), 120.42 (C-2″ and
C-6″), 121.53 (C-5), 123.93 (C-5′), 128.18 (C-6),
128.85 (C-4′), 129.69 (C-3″, C-4″, and C-5″), 136.78
(C-10), 143.33 (C-1″), 143.67 (C-9),164.53 (C-3);
HRMS (m/z): Calculated for C17H13ClN4O2 [M+ Na]+
found 423.0820 [M+Na]+.
4-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-chloro-2H-benzo
[b][1,4]oxazin-3(4H)-one (27). Light yellow solid; Yield:
92%; Melting point: 152–153°C; UV (MeOH) λmax: 256
and 295nm; IR (KBr) νmax (cmÀ1): 3089, 1680, 1385,
1
1272; H NMR (400MHz, CDCl3): δ 4.56 (s, 2H, H-4a),
5.10 (s, 2H, H-2), 5.48 (s, 2H, H-1′a), 6.88 (d, J=8.0Hz,
1H, H-8), 6.95 (dd, J=8.7 and 2.2Hz, 1H, H-7), 7.24–
7.26 (m, 2H, H-2″ and H-6″), 7.35–7.36 (m, 3H, H-3″, H-
4″ and H-5″), 7.49 (s, 1H, H-5′), 7.53 (d, J=2.2Hz, 1H,
H-5); 13C NMR (100.5MHz, CDCl3): δ 37.60(C-4a),
54.27 (C-1′a), 67.59 (C-2), 116.17 (C-8), 117.73 (C-7),
123.12 (C-5), 123.88 (C-4″), 128.15 (C-6), 128.83 (C-2″
and C-6″), 129.12 (C-3″ and C-5″), 129.68 (C-10), 134.21
(C-4′), 143.02 (C-1″), 143.66 (C-9), 164.43 (C-3); HRMS
(m/z): Calculated for C18H15ClN4O2 [M+Na]+ 377.0781,
363.0625, found 363.0629 [M +Na]+.
Ethyl 2-(4-[(6-chloro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-
yl)methyl]-1H-1,2,3-triazol-1-yl)acetate (31).
Light yellow
solid; Yield: 88%; Melting point: 125–126°C; UV
(MeOH) λmax: 256 and 297nm; IR (KBr) νmax (cmÀ1):
1
3149, 2983, 1758, 1685, 1381, 1205; H NMR (400MHz,
CDCl3): δ 1.28 (t, J=7.32Hz, 3H, H-2″′), 4.25 (q,
J=7.32Hz, 2H, H-1″′), 4.59 (s, 2H, H-4a), 5.12 (s, 2H,
H-2), 5.16 (s, 2H, H-2″), 6.89 (d, J=8.79Hz, 1H, H-8″),
6.95 (dd, J=8.0 and 2.2Hz, 1H, H-7″), 7.53 (d, J=2.2Hz,
1H, H-5″), 7.74 (s, 1H, H-5′); 13C NMR (100.5MHz,
CDCl3): δ 13.90 (C-2″′), 37.37 (C-4a), 50.77 (C-2), 62.31
(C-1″′), 67.49 (C-2″), 115.95 (C-8″), 117.66 (C-5″), 123.72
(C-7″), 124.71 (C-5′), 127.96 (C-6″), 129.61 (C-10″),
142.93 (C-4′), 143.59 (C-9″), 164.32 (C-3″), 165.64
(C-1); HRMS (m/z): Calculated for C15H15ClN4O4
[M + Na]+ 373.0680, found 373.0676 [M +Na]+.
found 377.0750 [M+Na]+.
6-Chloro-4-[(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl]-
2H-benzo[b][1,4]oxazin-3(4H)-one (28). White solid; Yield:
93%; Melting point: 157–158°C; UV (MeOH) λmax: 255
and 294nm; IR (KBr) νmax (cmÀ1): 3035, 1677, 1500,
1
1386; H NMR (400MHz, CDCl3): δ 4.57 (s, 2H, H-4a),
5.10 (s, 2H, H-2), 5.45 (s, 2H, H-1′a), 6.88 (d, J=8.0Hz,
1H, H-8), 6.95 (dd, J=8.0 and 2.2Hz, 1H, H-7), 7.03-7.07
3
(t, JHF = 8.7Hz, 2H, H-3″ and H-5″), 7.23-7.26 (m, 2H,
H-2″ and H-6″), 7.50 (s, 1H, H-5′), 7.53 (d, J=2.2Hz, 1H,
H-5); 13C NMR (100.5MHz, CDCl3): δ 37.51(C-4a),
53.44 (C-1′a), 67.55 (C-2), 115.98 (C-8), 116.09 (C-5),
116.20 (d, JCF =22.04Hz, C-3″ and C-5″), 117.73 (C-7),
123.04 (C-5′), 123.85 (C-6), 128.06 (C-4′), 129.63 (C-1″),
130.01 (d, JCF =8.63Hz, C-2″ and C-6″), 143.09 (C-10),
143.62 (C-9), 162.80 (d, JCF =248.24Hz, C-4″), 164.40 (C-3);
HRMS (m/z): Calculated for C18H14ClFN4O2 [M + Na]+
2-(4-[(6-Chloro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl]
methyl)-1H-1,2,3-triazol-1-yl) propane-1,3-di-yl-diacetate (32).
White solid; Yield: 91%; Melting point: 111–112°C; UV
(MeOH) λmax: 257 and 297nm; IR (KBr) νmax (cmÀ1):
3148, 2967, 1735, 1690, 1500, 1376, 1240; 1H NMR
(400MHz, CDCl3): δ 2.01 (s, 6H, H-2″′), 4.48–4.50 (m,
4H, H-1 and H-3), 4.60 (s, 2H, H-4a), 5.03 (m, 1H, H-2),
5.14 (s, 2H, H-2″), 6.90 (d, J=8.0Hz, 1H, H-8″), 6.95
(dd, J=8.7 and 2.2Hz, 1H, H-7″), 7.52 (d, J=2.2Hz, 1H,
H-5″), 7.68 (s, 1H, H-5′); 13C NMR (100.5MHz, CDCl3):
δ 20.47 (C-2″′), 37.45 (C-4a), 58.54 (C-2), 62.29 (C-1
and C-3), 67.57 (C-2″), 116.04 (C-8″), 117.78 (C-5″),
123.09 (C-7″), 123.87 (C-5′), 128.06 (C-6″), 129.64 (C-10″),
395.0687, found 395.0660 [M + Na]+.
4-[(1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl)methyl]-6-chloro-
2H-benzo[b][1,4]oxazin-3(4H)-one (29). Light yellow solid;
Yield: 97%; Melting point: 208–210°C; UV (MeOH) λmax
:
256 and 298nm; IR (KBr) νmax (cmÀ1): 3135, 1672, 1498,
1
1383; H NMR (400MHz, CDCl3): δ 4.61 (s, 1H, H-4a),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Design and Synthesis of Novel Triazolyl Benzoxazine Derivatives and Evaluation of
Their Antiproliferative and Antibacterial Activity
Month 2015
142.72 (C-4′), 143.67 (C-9″), 164.46 (C-3″),170.05 (C-1″′);
HRMS (m/z): Calculated for C18H19ClN4O6 [M+Na]+
(s, 2H, H-4a), 5.22 (s, 2H, H-2), 6.85 (dd, J =7.3 and
2.2 Hz, 1H, H-7), 7.01–7.06 (m, 2H, H-5 and H-8),
7.24–7.26 (m, 2H, H-5″ and H-6″), 7.32–7.37 (m, 1H,
H-4″), 7.40 (s, 1H, H-2″), 8.64 (s, 1H, H-5′), 10.11 (s,
1H, OH); 13C NMR (100.5MHz, DMSO-d6): δ 36.40 (C-
4a), 67.16 (C-2), 107.02 (C-8), 110.53 (C-2″), 115.80 (C-
4″), 115.87 (C-5), 118.09 (C-7), 121.88 (C-6″), 123.34
(C-5′), 126.36 (C-6), 129.90 (C-1″), 130.96 (C-10),
137.54 (C-4′), 143.30 (C-5″), 143.98 (C-9), 158.56 (C-
3″), 164.25 (C-3); HRMS (m/z): Calculated for
C17H13ClN4O3 [M + Na]+ 379.0574, found 379.0524 [M
+ Na]+.
445.0891, found 445.0879 [M+Na]+.
6-Chloro-4-[(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl]-
2H-benzo[b][1,4]oxazin-3(4H)-one (33). Light yellow solid;
Yield: 81%; Melting point: 214–215°C; UV (MeOH) λmax
:
292nm; IR (KBr) νmax (cmÀ1): 3073, 2927, 1683, 1500,
1
1388, 1271; H NMR (400 MHz, CDCl3): δ 4.62 (s, 2H,
H-4a), 5.23 (s, 2H, H-2), 6.92 (d, J = 8.0 Hz, 1H, H-8),
6.98 (dd, J= 8.0 and 2.2 Hz, 1H, H-7), 7.58 (d, J= 2.2 Hz,
1H, H-5), 7.96 (d, J= 9.5 Hz, 2H, H-2″ and H-6″), 8.17 (s,
1H, H-5′), 8.41 (d, J = 8.7 Hz, 2H, H-3″ and H-5″), 13C
NMR (100.5 MHz, CDCl3): δ 37.44 (C-4a), 67.65 (C-2),
115.98 (C-8), 117.99 (C-7), 120.51 (C-5), 121.61 (C-2″
and C-6″), 124.17 (C-5′), 125.54 (C-6), 128.29 (C-3″ and
C-5″), 129.55 (C-10), 140.78 (C-4′), 143.74 (C-1″),
144.31 (C-9), 147.30 (C-4″), 164.72 (C-3); HRMS (m/z):
Calculated for C17H12ClN5O4 [M +Na]+ 408.0476, found
Ethyl 2-(4-[(7-nitro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)
methyl]-1H-1,2,3-triazol-1-yl) acetate (37).
Light yellow
solid; Yield: 89%; Melting point: 116–117°C; UV (MeOH)
λ
max: 243, 303 and 338 nm; IR (KBr) νmax (cmÀ1): 3082,
1
2971, 1748, 1683, 1534, 1389, 1247; H NMR (400MHz,
CDCl3): δ 1.29 (t, J=7.3Hz, 3H, (H-2″′), 4.26 (q,
J=7.3Hz, 2H, H-1″′), 4.70 (s, 2H, H-4a), 5.13 (s, 2H, H-
2), 5.23 (s, 2H, H-2″), 7.76 (d, J=8.0Hz, 1H, H-5″), 7.84
(s, 1H, H-5′), 7.97 (d, J=7.3Hz, 2H, H-6″ and H-8″);
13C NMR (100.5MHz, CDCl3): δ 13.90 (C-2″′), 37.43
(C-4a), 50.80 (C-2), 62.42 (C-1″′), 67.31 ( C-2″), 115.83
(C-8″ and C-6″), 118.83 (C-4′ and C-5″), 134.16 (C-10″),
143.48 (C-7″), 144.68 (C-9″), 164.03 (C-3″), 165.93 (C-
1); HRMS (m/z): Calculated for C15H15N5O6 [M+Na]+
408.0464 [M +Na]+.
6-Chloro-4-[(1-hexyl-1H-1,2,3-triazol-4-yl)methyl]-2H-benzo
[b][1,4]oxazin-3(4H)-one (34).
White solid; Yield: 98%;
Melting point: 86–87°C; UV (MeOH) λmax: 256 and
297nm; IR (KBr) νmax (cmÀ1): 3073, 2935, 1680, 1498,
1362, 1265; 1H NMR (400 MHz, CDCl3): δ 0.84 (t,
J =7.3 Hz, 3H, H-6″),1.27 (s, 6H, H-2″, H-3″ and H-4″),
1.85 (m, 2H, H-5″), 4.28 (t, J= 7.32Hz, 2H, H-1″), 4.57
(s, 2H, H-4a), 5.11 (s, 2H, H-2), 6.86 (d, J =8.7 Hz, 1H,
H-8), 6.92 (d, J= 2.2 Hz, 1H, H-5), 7.55 (s, 2H, H-5′ and
H-7); 13C NMR (100.5MHz, CDCl3): δ 13.87 (C-6″),
22.32 (C-5″), 26.08 (C-3″), 30.08 (C-2″), 31.04 (C-4″),
37.65 (C-4a), 50.43 (C-1″), 67.62 (C-2), 116.18 (C-8),
117.72 (C-5), 123.00 (C-7), 123.86 (C-5′), 128.17 (C-6),
129.71 (C-10), 142.55 (C-4′), 143.67 (C-9), 164.47 (C-3);
HRMS (m/z): Calculated for C17H21ClN4O2 [M + Na]+
384.0920, found 384.0887 [M+Na]+.
4-[(1-(3-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl]-7-nitro-
2H-benzo[b][1,4]oxazin-3(4H)-one (38). Light yellow solid;
Yield: 85%; Melting point: 199–201°C; UV (MeOH)
λ
max: 249 and 279nm; IR (KBr) νmax (cmÀ1): 3085, 2926,
1
1690, 1500, 1388, 1241; H NMR (400MHz, CDCl3): δ
3.87 (s, 3H, OCH3), 4.72 (s, 2H, H-4a), 5.28 (s, 2H, H-2),
6.97 (dd, J = 8.0 and 2.0 Hz, 1H, H-6″), 7.23 (dd, J= 8.0
and 1.4 Hz, 1H, H-4″), 7.30 (d, J =2.9 Hz, 1H, H-2″), 7.40
(t, J =8.0 Hz, 1H, H-5″), 7.82–7.85 (m, 2H, H-5 and H-8),
8.00 (dd, J = 8.7 and 2.2 Hz, 1H, H-6), 8.06 (s, 1H, H-5′);
371.1251, found 371.1233 [M + Na]+.
6-Chloro-4-[(1-(4-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)
methyl]-2H-benzo[b][1,4]oxazin-3(4H)-one (35). White solid;
Yield: 81%; Melting point: 280–282°C; UV (MeOH) λmax
:
13C NMR (100.5MHz, CDCl3):
δ 37.34 (C-4a),
257 and 296nm; IR (KBr) νmax (cmÀ1): 3320, 3050, 1663,
1390, 1270; 1H NMR (400 MHz, DMSO-d6): δ 4.73
(s, 2H, H-4a), 5.21 (s, 2H, H-2), 6.90 (d, J =8.7Hz, 2H,
H-2″ and H-6″), 7.01–7.06 (m, 2H, H-7 and H-8), 7.43
(d, J =1.4 Hz, 1H, H-5), 7.62 (d, J = 8.7 Hz, 2H, H-3″ and
H-5″), 8.52 (s, 1H, H-5′), 10.02 (s, 1H, OH); 13C NMR
(100.5 MHz, DMSO-d6): δ 36.40 (C-4a), 67.15 (C-2),
115.83 (C-8), 116.16 (C-3″ and C-5″), 117.95 (C-7),
121.75 (C-5′), 122.02 (C-2″ and C-6″), 123.20 (C-5),
126.37 (C-6), 128.66 (C-1″), 129.91 (C-10), 142.92 (C-4′),
143.91 (C-9), 157.89 (C-4″), 164.17 (C-3); HRMS (m/z):
Calculated for C17H13ClN4O3 [M+Na]+ 379.0574, found
55.64 (OCH3), 67.48 (C-2), 106.32 (C-8), 112.35 (C-2″),
112.64 (C-4″), 114.92 (C-6), 116.03 (C-5′), 119.07 (C-6″),
121.95 (C-5), 130.59 (C-1′), 134.15 (C-4′), 137.70
(C-10), 142.84 (C-5″), 143.89 (C-7), 144.73 (C-9),
160.75 (C-3″), 164.52 (C-3); HRMS (m/z): Calculated
for C18H15N5O5 [M+ Na]+ 404.0971, found 404.0967
[M + Na]+.
4-[(1-(2-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl]-7-
nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (39). Light yellow
solid; Yield: 82%; Melting point: 218–220°C; UV
(MeOH) λmax: 242, 291, and 340nm; IR (KBr) νmax
(cmÀ1): 2983, 1690, 1507, 1389, 1250; 1H NMR
(400 MHz, CDCl3): δ 3.87 (s, 3H, OCH3), 4.72 (s, 2H, H-
4a), 5.32 (s, 2H, H-2), 7.07–7.12 (m, 2H, H-4″ and H-5″),
7.42 (t, J= 8. Hz, 1H, H-8), 7.77–8.01 (m, 4H, H-5, H-6, H-
3″ and H-6″), 8.58 (s, 1H, H-5′); 13C NMR (100.5MHz,
CDCl3): δ 37.63 (C-4a), 55.96 (OCH3), 67.46 (C-2), 112.19
379.0560 [M+Na]+.
6-Chloro-4-[(1-(3-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)methyl]-
2H-benzo[b][1,4]oxazin-3(4H)-one (36). Light brown solid;
Yield: 79%; Melting point: 242–243°C; UV (MeOH) λmax
:
254 and 293nm; IR (KBr) νmax (cmÀ1): 3321, 2372, 1693,
1488, 1363, 1245; 1H NMR (400 MHz, DMSO-d6): δ 4.73
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Khan, S. Prasad, V. S. Parmar, and S. K. Sharma
Vol 000
7-Nitro-4-[(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl]-
2H-benzo[b][1,4]oxazin-3(4H)-one (43). Light yellow solid;
(C-6), 112.53 (C-4′), 116.20 (C-8), 119.03 (C-5), 121.22
(C-5″), 125.34 (C-6″), 125.95 (C-4″), 130.34 (C-4′),
134.18 (C-10), 143.69 (C-9), 144.83 (C-7), 150.96 (C-2″),
164.05 (C-3); HRMS (m/z): Calculated for C18H15N5O5
Yield: 95%; Melting point: 193–194°C; UV (MeOH) λmax
:
251, 295 and 337nm; IR (KBr) νmax (cmÀ1): 3083, 1701,
1521, 1342, 1240; 1H NMR (400MHz, DMSO-d6): δ
4.84 (s, 2H, H-4a), 5.23 (s, 2H, H-2), 5.72 (s, 2H, H-1′a),
7.47 (d, J =8.7 Hz, 2H, H-3″ and H-5″), 7.52 (d,
J = 9.5 Hz, 1H, H-5), 7.77 (d, J =2.9 Hz, 1H, H-8), 7.93
(dd, J =8.7 and 2.2 Hz, 1H, H-6), 8.18 (s, 1H, H-5′), 8.20
(d, J= 3.6 Hz, 2H, H-2″ and H-6″); 13C NMR
[M+Na]+ 404.0971, found 404.0974 [M+Na]+.
4-[(1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl]-7-nitro-
2H-benzo[b][1,4]oxazin-3(4H)-one (40). Light yellow solid;
Yield: 88%; Melting point: 201–203°C; UV (MeOH) λmax
:
251 and 338nm; IR (KBr) νmax (cmÀ1): 3090, 2936, 1686,
1519, 1341, 1258; 1H NMR (400 MHz, CDCl3): δ 3.85 (s,
3H, OCH3), 4.71 (s, 2H, H-4a), 5.28 (s, 2H, H-2), 7.00 (d,
J =8.7 Hz, 2H, H-2″ and H-6″), 7.59 (d, J= 8.7 Hz, 2H, H-
3″ and H-5″), 7.83–7.85 (m, 2H, H-5 and H-6), 7.98 (d,
J =2.2 Hz, 1H, H-8), 7.99 (s, 1H, H-5′); 13C NMR
(100.5 MHz, CDCl3): δ 37.65 (C-4a), 55.62 (OCH3),
67.47 (C-2), 112.60 (C-6), 114.80 (C-3″ and C-5″),
116.06 (C-5′), 119.07 (C-8), 121.99 (C-2″ and C-6″),
122.12 (C-5), 130.11 (C-1″), 134.12 (C-4′), 142.62 (C-
10), 143.68 (C-7), 144.74 (C-9), 160.01 (C-4″), 164.39
(C-3); HRMS (m/z): Calculated for C18H15N5O5 [M+Na]+
(100.5 MHz, DMSO-d6):
δ 36.64 (C-4a),52.07(C-2),
67.05 (C-1′a), 11.79 (C-6), 116.18 (C-8), 118.62 (C-
5′), 124.00 (C-3″, C-5″ and C-5), 124.57 (C-5′),
129.14 (C-2″ and C-6″), 134.55 (C-4′), 142.22 (C-10),
142.78 (C-1″), 143.36 (C-7), 144.77 (C-4″), 147.34
(C-9), 164.10 (C-3); HRMS (m/z): Calculated for
C18H14N6O6 [M+ Na]+ 433.0873, found 433.0866 [M
+ Na]+.
4-[(1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl]-7-nitro-
2H-benzo[b][1,4]oxazin-3(4H)-one (44). Light yellow solid;
Yield: 95%; Melting point: 233–235°C; UV (MeOH) λmax:
404.0971, found 404.0954 [M+Na]+.
4-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-7-nitro-2H-benzo
[b][1,4]oxazin-3(4H)-one (41). Light yellow solid; Yield:
248 and 339 nm; IR (KBr) νmax (cmÀ1): 3101, 1691, 1501,
1340, 1246; 1H NMR (400MHz, CDCl3): δ 4.71 (s, 2H, H-
4a), 5.28 (s, 2H, H-2), 7.49 (d, J =8.7 Hz, 2H, H-2″ and H-
6″), 7.66 (d, J = 8.7 Hz, 2H, H-3″ and H-5″), 7.81 (d,
J = 8.7 Hz, 1H, H-5), 7.85 (d, J =2.9 Hz, 1H, H-8), 7.99
(dd, J = 8.7 and 2.2 Hz, 1H, H-6), 8.06 (s, 1H, H-5′); 13C
NMR (100.5MHz, CDCl3): δ 37.55 (C-4a), 67.44 (C-2),
112.65 (C-6), 115.93 (C-8), 119.08 (C-5), 121.63 (C-2″
and C-6″), 121.84 (C-5′), 130.01 (C-3″ and C-5″), 134.04
(C-4′), 134.92 (C-4″), 135.13 (C-1″), 143.04 (C-10),
143.76 (C-9), 144.78 (C-7), 164.33 (C-3); HRMS (m/z):
Calculated for C17H12ClN5O4 [M + Na]+ 408.0476, found
95%; Melting point: 199–201°C; UV (MeOH) λmax: 238,
304 and 338 nm; IR (KBr) νmax (cmÀ1): 3083, 1701,
1
1521, 1342, 1240; H NMR (400 MHz, CDCl3): δ 4.67
(s, 2H, H-4a), 5.18 (s, 2H, H-2), 5.49 (s, 2H, H-1′a),
7.27–7.28 (m, 2H, H-2″ and H-6″), 7.36–7.37 (m, 3H, H-
3″, H-4″ and H-5″), 7.54 (s, 1H, H-5′), 7.77 (d,
J = 9.5 Hz, 1H, H-5), 7.82 (d, J = 2.2 Hz, 1H, H-8), 7.96
(dd, J = 9.5 and 2.2 Hz, 1H, H-6); 13C NMR (100.5 MHz,
CDCl3): δ 37.53 (C-4a), 54.28 (C-1′a), 67.33 (C-2), 112.41
(C-6), 115.95 (C-8), 118.89 (C-5), 123.38 (C-5′), 128.16 (C-
2″ and C-6″), 128.86 (C-4″), 129.09 (C-3″ and C-5″),
134.03 (C-4′), 134.17 (C-1″), 142.41 (C-10), 143.54 (C-7),
144.68 (C-9), 164.03 (C-3); HRMS (m/z): Calculated for
408.0458 [M + Na]+.
4-[(1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl)methyl]-7-nitro-
2H-benzo[b][1,4]oxazin-3(4H)-one (45). Light yellow solid;
C18H15N5O4 [M+Na]+ 388.1122, found 388.1116 [M+Na]+.
4-[(1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl]-7-nitro-
2H-benzo[b][1,4]oxazin-3(4H)-one (42). Light yellow solid;
Yield: 93%; Melting point: 233–234°C; UV (MeOH) λmax
:
251 and 339nm; IR (KBr) νmax (cmÀ1): 3101, 2928, 1690,
1510, 1340, 1244; 1H NMR (400 MHz, CDCl3): δ 4.71 (s,
2H, H-4a), 5.28 (s, 2H, H-2), 7.60 (d, J = 9.5 Hz, 2H, H-2″
and H-6″), 7.65 (d, J= 9.5 Hz, 2H, H-3″ and H-5″), 7.81
(d, J = 9.5 Hz, 1H, H-5), 7.84 (d, J =2.2 Hz, 1H, H-8),
7.99 (dd, J = 8.7 and 2.2 Hz, 1H, H-6), 8.06 (s, 1H, H-5′);
13C NMR (100.5 MHz, CDCl3): δ 37.55 (C-4a), 67.44 (C-
2), 112.65 (C-6), 115.93 (C-8), 119.08 (C-4″), 121.77 (C-
5), 121.85 (C-2″ and C-6″), 122.80 (C-5′), 132.97 (C-3″
and C-5″), 134.13 (C-4′), 135.60 (C-10), 143.08 (C-1″),
143.77 (C-9), 144.80 (C-7), 164.33 (C-3); HRMS (m/z):
Yield: 92%; Melting point: 150–152°C; UV (MeOH) λmax
:
246, 301, and 337nm; IR (KBr) νmax (cmÀ1): 3088, 2957,
1
1689, 1508, 1344, 1221; H NMR (400 MHz, CDCl3): δ
4.65 (s, 2H, H-4a), 5.15 (s, 2H, H-2), 5.43 (s, 2H, H-1′
3
a), 7.03 (t, JHF = 8.7 Hz, 2H, H-2″ and H-6″), 7.22–7.26
(m, 2H, H-3″ and H-5″), 7.52 (s, 1H, H-5′), 7.73 (d,
J =8.7 Hz, 1H, H-5), 7.79 (d, J= 2.2 Hz, 1H, H-8), 7.93
(dd, J= 8.7 and 2.2 Hz, 1H, H-6); 13C NMR
(100.5 MHz, CDCl3): δ 37.55 (C-4a), 53.56 (C-2), 67.36
(C-1′a), 112.47 (C-6), 115.95 (C-8), 116.15 (d,
JCF = 21.09 Hz, C-3″ and C-5″), 118.94 (C-5), 123.32
(C-5′), 129.92 (d, JCF =2.88 Hz, C-1″), 130.11 (d,
JCF = 7.67Hz, H-2″ and H-6″), 134.16 (C-4′), 142.55
(C-10), 143.60 (C-9), 144.71 (C-7), 161.62 (C-4″),
164.09 (C-3); HRMS (m/z): Calculated for C18H14FN5O4
[M + Na]+ 406.0928, found 406.0928 [M+ Na]+.
Calculated for C17H12BrN5O4 [M+ Na]+ 451.9970, found
451.9970 [M + Na]+.
4-[(1-(3-Hydroxyphenyl)-1H-1,2,3-triazol-4-yl)methyl]-7-nitro-
2H-benzo[b][1,4]oxazin-3(4H)-one (46).
Light yellow
solid; Yield: 77%; Melting point: 268–270°C; UV
(MeOH) λmax: 247, 296, and 337nm; IR (KBr) νmax
1
(cmÀ1): 3377, 3096, 1673, 1500, 1342, 1212; H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Design and Synthesis of Novel Triazolyl Benzoxazine Derivatives and Evaluation of
Their Antiproliferative and Antibacterial Activity
Month 2015
(400 MHz, DMSO-d6): δ 4.89 (s, 2H, H-4a), 5.31 (s, 2H,
H-2), 6.85 (d, J = 7.3 Hz, 1H, H-6″), 7.25 (s, 2H, H-6 and
H-8), 7.34 (t, J = 8.2 Hz, 1H, H-5″), 7.52 (d, J= 9.1 Hz,
1H, H-5), 7.81 (s, 1H, H-2″), 7.94 (d, J = 8.2 Hz, 1H, H-
4″), 8.69 (s, 1H, H-5′),10.02 (s, 1H, –OH); 13C NMR
(100.5 MHz, DMSO-d6): δ 36.58 (C-4a), 66.94 (C-2),
106.89 (C-6), 110.33 (C-8), 111.61 (C-5), 115.67 (C-4″),
116.01 (C-6″), 118.53 (C-1″), 121.77 (C-5′), 130.72
(C-4′), 134.37 (C-10), 137.40 (C-5″), 142.66 (C-7),
142.79 (C-9), 144.62 (C-7), 158.43 (C-3″), 163.96 (C-3);
HRMS (m/z): Calculated for C17H13N5O5 [M + Na]+
66.95 (C-2), 111.65 (C-6), 116.05 (C-8), 116.72
(d, JCF =23.00Hz, C-3″ and C-5″), 118.57 (C-5′), 122.16
(C-5), 122.39 (d, JCF =8.63Hz, C-2″ and C-6″), 132.98
(C-4′), 134.42 (C-1″), 142.69 (C-9), 142.96 (C-10),
144.64 (C-7), 161.66 (d, JCF =244.41Hz, C-4″), 163.98
(C-3); HRMS (m/z): Calculated for C17H12FN5O4
[M+Na]+ 392.0771, found 392.0726 [M+Na]+.
7-Nitro-4-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-2H-benzo
[b][1,4]oxazin-3(4H)-one (50). Light yellow solid; Yield:
88%; Melting point: 210–211°C; UV (MeOH) λmax: 245,
309, 339nm; IR (KBr) νmax (cmÀ1): 3091, 1689, 1502,
1
390.0814, found 390.0816 [M + Na]+.
1341, 1257; H NMR (400MHz, CDCl3): δ 4.72 (s, 2H,
7-Nitro-4-[(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl]-
H-4a), 5.29 (s, 2H, H-2), 7.45–7. 54 (m, 3H, H-3″, H-4″
and H-5″), 7.70 (d, J=8.05Hz, 2H, H-2″ and H-6″), 7.83
(s, 1H, H-5), 7.85 (d, J=2.20 Hz, 1H, H-8), 8.00 (dd,
J=8.79 and 2.93 Hz, 1H, H-6), 8.08 (s, 1H, H-5′); 13C NMR
(100.5 MHz, CDCl3): δ 37.55 (C-4a), 67.44 (C-2), 112.65
(C-6), 115.93 (C-8), 119.09 (C-5), 121.85 (C-5′), 122.80 (C-
2″ and C-6″), 132.97 (C-3″, C-4″ and C-5″), 134.13 (C-4′),
135.66 (C-10), 143.08 (C-1″), 143.77 (C-9), 144.80 (C-7),
164.33 (C-3); HRMS (m/z): Calculated for C17H13N5O4
[M+Na]+ 374.0865, found 374.0862 [M+Na]+.
2H-benzo[b][1,4]oxazin-3(4H)-one (47).
Light yellow
solid; Yield: 91%; Melting point: 229–231°C; UV
(MeOH) λmax: 294 and 339 nm; IR (KBr) νmax (cmÀ1):
3153, 1695, 1521, 1342, 1257; 1H NMR (400 MHz,
DMSO-d6): δ 4.89 (s, 2H, H-4a), 5.35 (s, 2H, H-2), 7.53
(d, J = 9.5 Hz, 1H, H-5), 7.82 (d, J = 2.9 Hz, 1H, H-8),
7.94 (dd, J = 8.7 and 2.2 Hz, 1H, H-6), 8.16 (d,
J = 8.7 Hz, 2H, H-2″ and H-6″), 8.42 (d, J = 9.5 Hz, 2H,
H-3″ and H-5″), 8.94 (s, 1H, H-5′); 13C NMR
(100.5 MHz, DMSO-d6): δ 36.38 (C-4a), 66.94 (C-2),
111.84 (C-6), 116.15 (C-8), 118.73 (C-5), 120.76 (C-2″
and C-6″), 122.57 (C-5′), 125.71 (C-3″ and C-5″),
134.49 (C-4′), 140.75 (C-10), 142.85 (C-1″), 143.73 (C-
9), 144.86 (C-7), 146.88 (C-4″), 164.17 (C-3); HRMS
(m/z): Calculated for C17H12N6O6 [M +Na]+ 419.0716,
Acknowledgments. Financial assistance from the University of
Delhi and Council of Scientific and Industrial Research (CSIR),
New Delhi, India, is gratefully acknowledged. A. Khan thanks the
CSIR for the award of Junior and Senior Research Fellowships. We
gratefully thank Prof. K. Parang at the School of Pharmacy,
Chapman University, USA, and Dr. H. K. Gautam at CSIR-IGIB
Delhi, India, for carrying out the biological screening of a few
representative compounds.
found 419.0706 [M+ Na]+.
4-[(1-(2,5-Dimethoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl]-
7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (48). Light yellow
solid; Yield: 95%; Melting point: 229–231°C; UV (MeOH)
λ
max: 304 and 340 nm; IR (KBr) νmax (cmÀ1): 3080, 2964,
1
1690, 1508, 1344, 1285; H NMR (400MHz, CDCl3): δ
3.80 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.71 (s, 2H, H-
4a), 5.30 (s, 2H, H-2), 6.65 (dd, J=8.7 and 2.9Hz, 1H, H-
4″), 7.00 (d, J=9.5Hz, 1H, H-3″), 7.36 (d, J=2.9Hz, 1H,
H-6″), 7.84 (d, J=2.9Hz, 1H, H-8), 7.87 (d, J=8.7Hz,
1H, H-5), 8.00 (dd, J = 9.5 and 2.2 Hz, 1H, H-6), 8.25 (s,
1H, H-5′); 13C NMR (100.5 MHz, CDCl3): δ 37.49 (C-
4a), 55.86 (OCH3), 56.39 (OCH3), 67.38 (C-2), 110.17
(C-6″), 112.43 (C-1″), 113.44 (C-4″), 115.72 (C-3″),
116.08 (C-6), 118.90 (C-8), 125.71 (C-5′), 126.02 (C-5),
134.27 (C-4′), 141.47 (C-10), 143.57 (C-7), 144.67 (C-9),
144.76 (C-2″), 153.73 (C-5″), 164.05 (C-3); HRMS (m/z):
Calculated for C19H17N5O6 [M+H]+ 412.1257, found
REFERENCES AND NOTES
[1] Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; 2nd
ed.; Wiley-VCH: Weinheim, 2003.
[2] (a) La, D. S.; Belzile, J.; Bready, J. V.; Coxon, A.; DeMelfi, T.;
Doerr, N.; Estrada, J.; Flynn, J. C.; Flynn, S. R.; Graceffa, R. F.;
Harriman, S. P.; Larrow, J. F.; Long, A. M.; Martin, M. W.;
Morrison, M. J.; Patel, V. F.; Roveto, P. M.; Wang, L.; Weiss, M. W.;
Whittington, D. A.; Teffera, Y.; Zhao, Z. Y.; Polverino, A. J.;
Harmang, J. C. J Med Chem 2008, 51, 1695; (b) Has, J.; Tomasic, T.;
Kikelj, D. J Med Chem 2008, 51, 2863; (c) Has, J.; Jakopin, Z.;
Bonrstnar, T.; Stegnar, M.; Kikelj, D. J Med Chem 2008, 51, 5617.
[3] Huang, M. Z.; Luo, F. X.; Mo, H. B.; Ren, Y. G.; Wang, X. G.;
Ou, X. M.; Lei, M. X.; Liu, A. P.; Huang, L.; Xu, M. C. J Agric Food
Chem 2009, 57, 9585.
[4] Li, A. R.; Zhang, J.; Greenberg, J.; Lee, T. W.; Liu, J. Bioorg
Med Chem Lett 2011, 21, 2472.
[5] Lanni Jr., T. B.; Greene, K. L.; Kolz, C. N.; Para, K. S.;
Visnick, M.; Mobley, J. L.; Dudley, D. T.; Baginski, T. J.; Liimatta, M. B.
Bioorg Med Chem Lett 2007, 17, 756.
412.1251 [M+H]+.
4-[(1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl]-7-
nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (49).
Light yellow
solid; Yield: 94%; Melting point: 216–217°C; UV (MeOH)
[6] Siddiqui, N.; Ali, R.; Arshad, M. F.; Ahsan, W.; Ahmed, S.;
Alam, M. S. Arch Pharm Chem Life Sci 2010, 10, 657.
[7] Wu, J. H.; Chang, F. R.; Hayashi, K. I.; Shiraki, H.; Liaw, C. C.;
Nakanishi, Y.; Bastow, K. F.; Yu, D.; Chenb, I. S.; Lee, K. H. Bioorg Med
Chem Lett 2003, 13, 2223.
λ
max: 246, 306 and 340nm; IR (KBr) νmax (cmÀ1): 3095,
1
1691, 1517, 1340, 1241; H NMR (400MHz, DMSO-d6):
δ 4.89 (s, 2H, H-4a), 5.32 (s, 2H, H-2), 7.42-7.90 (m, 7H,
H-5, H-6, H-8, H-2″, H-3″, H-5″ and H-6″), 8.74 (s, 1H,
H-5′); 13C NMR (100.5MHz, DMSO-d6): δ 36.53 (C-4a),
[8] Smid, P.; Coolen, H. K. A. C.; Keizer, H. G.; van Hes, R.; de
Moes, J.-P.; den Hartog, A. P.; Stork, B.; Plekkenpol, R. H.; Niemann, L. C.;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Khan, S. Prasad, V. S. Parmar, and S. K. Sharma
Vol 000
[16] Junior, C. V.; Danuello, A.; Bolzani, V. D. S.; Barreiro, E. J.;
Fraga, C. A. M. Curr Med Chem 2007, 14, 1829.
[17] El-Far, M.; Elmegeed, G. A.; Eskander, E. F.; Rady, H. M.;
Tantawy, M. A. Eur J Med Chem 2009, 44, 3936.
[18] Francis, W.; Muregi, A. I. Drug Dev Res 2010, 71, 20.
[19] Kolb, H. C.; Sharpless, K. B. Drug Discov Today 2009, 8, 1128.
[20] Kallander, L. S.; Lu, Q.; Chen, W.; Tomaszek, T.; Yang, G.;
Tew, D.; Meek, T. D.; Hofmann, G. A.; Pritchard, C. K. S.; Smith, W. W.;
Ho, T. F.; Fisher, P. W.; Mattern, M. R.; Johnson, R. K.; Hansbury, M. J.;
Winkler, J. D.; Ward, K. W.; Veber, D. F.; Thompson, S. K. J Med Chem
2005, 48, 5644.
[21] Zieringer, M.; Wyszogrodzka, M.; Biskupa, K.; Haag, R. New
J Chemistry 2012, 36, 402.
[22] Wilkening, I.; Signore, G.; Hackenberger, C. P. R. Chem
Commun 2011, 47, 349.
[23] Bauer, A. W.; Kirby, W. M. M.; Sherris, J. C.; Turck, M. Am J
Clin Path 1966, 36, 41.
[24] Rao, P.; Vara, K. Indian J Chem, Sect B 1985, 24B, 1120.
[25] Walser, A.; Flynn, T.; Mason, C.; Crowley, H.; Maresca, C.;
Yaremko, B.; O’Donnell, M. J Med Chem 1991, 34, 1209.
Stroomer, C. N. J.; Tulp, M. T. M.; van Stuivenberg, H. H.; McCreary, A. C.;
Hesselink, M. B.; Herremans, A. H. J.; Kruse, C. G. J Med Chem 2005,
48, 6855.
[9] Fringuelli, R.; Pietrella, D.; Schiaffella, F.; Guarraci, A.;
Perito, S.; Bistoni, F.; Vecchiarelli, A. Bioorg Med Chem 2002,
10, 1681.
[10] Macchiarulo, A.; Costantino, G.; Fringuelli, D.; Vecchiarelli, A.;
Schiaffella, F.; Fringuelli, R. Bioorg Med Chem 2002, 10, 3415.
[11] Lanni, T. B., Jr.; Greene, K. L.; Kolz, C. N.; Para, K. S.;
Visnick, M.; Mobley, J. L.; Dudley, D. T.; Baginski, T. J.; Liimatta, M. B.
Bioorg Med Chem Lett 2007, 17, 756.
[12] Huang, M.-Z.; Huang, K.-L.; Ren, Y.-G.; Lei, M.-X.; Huang, L.;
Hou, Z.-K.; Liu, A.-P.; Qu, X.-M. J Agric Food Chem 2005, 53, 7908.
[13] Anderluh, M.; Cesar, J.; Stefanic, P.; Kikelj, D.; Janes, D.;
Murn, J.; Nadrah, K.; Tominc, M.; Addicks, E.; Giannis, A.; Stegnar, M.;
Dolenc, M. S. Eur J Med Chem 2005, 40, 25.
[14] Scheunemann, M.; Sorger, D.; Kouznetsova, E.; Sabri, O.;
Schliebs, R.; Wenzel, B.; Steinbach, J. Tetrahedron Lett 2007,
48, 5497.
[15] Niemeyer, H. M. Phytochemistry 1988, 27, 3349.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet