Synthesis of 2-benzylidene and 2-hetarylmethyl derivatives of 2H-1,4-benzoxazin-3-(4H)-ones as neuroprotecting agents

Article abstract of DOI:10.1080/00397910903243823

A wide variety of the title compounds were synthesized by conventional and microwave methods in which the main step is a condensation of an aldehyde with a 1,4-benzoxazin-3-(4H)-one. In all cases, the Z diasteromers were the major products. Of particular importance is the synthesis of novel 2-(3,5-dibromo-4-hydroxy) and 2-(4-acetoxy-3,5-dibromobenzylidene derivatives of 2H-1,4-benzoxazin-3-(4H)-ones, four of which were shown in a previous publication to exhibit potent neuroprotecting properties. The yields of titled compounds ranged from 25 to 83%. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903243823

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Synthesis of 2-Benzylidene and
2-Hetarylmethyl Derivatives of
2H-1,4-Benzoxazin-3-(4H)-ones as
Neuroprotecting Agents
Haribabu Ankati a , Shashidhar Kumar Akubathini a , Santosh R.
D'Mello b & Edward R. Biehl a
a Department of Chemistry , Southern Methodist University , Dallas,
Texas, USA
b Department of Molecular and Cell Biology , University of Texas at
Dallas , Richardson, Texas, USA
Published online: 26 Jul 2010.
To cite this article: Haribabu Ankati , Shashidhar Kumar Akubathini , Santosh R. D'Mello & Edward
R. Biehl (2010) Synthesis of 2-Benzylidene and 2-Hetarylmethyl Derivatives of 2H-1,4-Benzoxazin-3-
(4H)-ones as Neuroprotecting Agents, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:16, 2364-2376, DOI: 10.1080/00397910903243823
To link to this article: http://dx.doi.org/10.1080/00397910903243823
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Synthetic Communications1, 40: 2364–2376, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903243823
SYNTHESIS OF 2-BENZYLIDENE AND
2-HETARYLMETHYL DERIVATIVES OF
2H-1,4-BENZOXAZIN-3-(4H)-ONES AS
NEUROPROTECTING AGENTS
Haribabu Ankati,1 Shashidhar Kumar Akubathini,1
Santosh R. D’Mello,2 and Edward R. Biehl1
1Department of Chemistry, Southern Methodist University, Dallas,
Texas, USA
2Department of Molecular and Cell Biology, University of Texas at Dallas,
Richardson, Texas, USA
A wide variety of the title compounds were synthesized by conventional and microwave
methods in which the main step is a condensation of an aldehyde with a 1,4-benzoxazin-
3-(4H)-one. In all cases, the Z diasteromers were the major products. Of particular
importance is the synthesis of novel 2-(3,5-dibromo-4-hydroxy) and 2-(4-acetoxy-3,5-
dibromobenzylidene derivatives of 2H-1,4-benzoxazin-3-(4H)-ones, four of which were
shown in a previous publication to exhibit potent neuroprotecting properties. The yields
of titled compounds ranged from 25 to 83%.
Keywords: 2-Benzylidene-2H-1,4-benzoxazin-3-(4H)-one derivatives; 2-hetarylmethyl derivatives of 2H-
1,4-benzoxazin-3-(4H)-ones; hydrolysis; neuroprotecting compounds
INTRODUCTION
Recently, we prepared a series of indolin-2-ones,[1,2] some of which proved to
be highly neuroprotecting. We next turned our attention to preparing a variety of
1,4-benzoxazine derivatives and studying their neuroprotecting behavior. We were
attracted to this ring system because its structure contains an active hydrogen at
C-2 (which is adjacent to a ring oxygen and a ring carbonyl group) and thus should
undergo aldehydic condensation reactions similar to those of indolin-2-ones. Indeed,
we were able to prepare 32 novel 1,4-benxoxazine derivatives, several of which were
found to have excellent neuroprotecting properties and to be nontoxic. These bio-
logical properties have been reported,[3] and herein the synthetic procedures, yields,
and spectral properties are presented.
We first attempted to prepare novel 3-(3,5-dibromo-4-hydroxy)benzylidine
derivatives 8–14 by refluxing a mixture of an appropriate benzoxazine and aldehyde
in the presence of acetic anhydride and triethylamine for 7 h. However, as shown in
Received May 18, 2009.
Address correspondence to Edward R. Biehl, Department of Chemistry, Southern Methodist
University, Dallas, TX 75275, USA. E-mail: ebiehl@smu.edu
2364

PREPARATION OF 1,4-BENZOXAZINES
2365
Scheme 1. Synthesis of 2-(3,5-dibromo-4-acetoxybenzylidene) (1–7) and 2-(3,5-dibromo-4-benzylidene)-
2H-benzo[b][1,4]-3-(4H]-ones (8–14).
Scheme 1 and Table 1, the corresponding 4-acetoxy derivatives 1–7 were obtained in
yields ranging from 71 to 80%. The acetoxy compounds were hydrolyzed in the pres-
ence of potassium carbonate to compounds 8–14 in yields ranging from 70–75%. The
6-amino derivative (15) was obtained in 70% yield by successive Raney nickel and
hydrazine hydrate reduction. The 6-amino (15) and 6-chloro (10) derivatives of
Table 1. Preparation of 2-(3,5-dibromo-4-acetoxybenzylidene) (1–7) and 2-(3,5-dibromo-4-benzylidene)-
2H-benzo[b][1,4]-3-(4H]-ones (8–14)
Entry
No.
R
Yield, CH (%)a
Yield, MW (%)b
1
2
1
2
H
NO2
Cl
78
71
82
81
85
82
79
75
81
3
3
80
75
4
4
Me
COCH3
Br
5
5
73
71
6
6
7
7
F
78
8
8
H
75c
75c
71c
70c
71c
70c
70c
70c
9
9
NO2
Cl
10
11
12
13
14
15
10
11
12
13
14
15
Me
COCH3
Br
F
NH2
aCH, conventional heating, 7 h reflux.
bMW, microwave heating, 180 ꢀC for 20 min.
cIsolated yields by recrystallization.

2366
H. ANKATI ET AL.
Scheme 2. Synthesis of 2-(benzylidene)-2H-benzo[b][1,4]-3-(4H]-ones (16–23).
2-(3,5-dibromo-4-hydroxybenzylidene)-2H-1,4-benzoxazin-3-(4H)-one, as well 2-(4-
acetoxy-3,5-benzylidene)-2H-1,4-benzoxazin-3-(4H)-one (1) and 2-(3,5-dibromo-4-
hydroxybenzylidene)-2H-1,4-benzoxazin-3-(4H)-one (8), were found in a previous
study[3] to be highly neuroprotecting and nontoxic.
Anticipating the need to acquire multigram quantities of 1–7 for their conver-
sion to 8–14 and for future toxicity studies, we explored the use of microwave
heating. With our vast background in microwave-assisted synthesis of hetero-
cycles,[4] we were confident that under proper conditions the 7-h reaction times
required for conventional heating could be significantly reduced and the yields of
1–7 could be increased. After much experimentation, compounds 1–7 could be pre-
pared (see Table 1) in yields ranging from 79–85% by subjecting the reaction mixture
to microwave heating at 180 ꢀC for only 20 min. An added benefit was that the pro-
ducts crystallized from the cooled reaction mixture, and thus no chromatographic
workup was required.
Next, a series of benzylidenes lacking a 4-hydroxy group (16–23) were similarly
prepared in yields ranging from 30–83% according to Scheme 2, and the results
are listed in Table 2. A series of hetarylmethyl derivatives (24–32) were prepared
according to Scheme 3. As shown in Table 3, the thiophen-2-yl, thiophen-3-yl, and
pyridin-2-yl derivatives were obtained in good yields; however, the pyrrole-2-yl and
Table 2. Preparation of 2-(benzylidene)-2H-benzo[b][1,4]-3-(4H]-ones (16–23)
Entry
No.
R
Ar
Yield (%)
1
2
3
4
5
6
7
8
16
17
18
19
20
21
22
23
H
H
NMe2
3,4,5-Trimethoxy
3,5-Dibromo
30
79
81
74
83
40
62
72
H
Me
Cl
3,4,5-Trimethoxy
3,4,5-Trimethoxy
NMe2
Cl
NO2
COCH3
3,4,5-Trimethoxy
3,5-Dibromo

PREPARATION OF 1,4-BENZOXAZINES
2367
Scheme 3. Synthesis of 2-(hetaryl)-2H-benzo[b][1,4]-3-(4H]-ones (24–32).
Table 3. Preparation of 2-(hetaryl)-2H-benzo[b][1,4]-3-(4H]-ones (24–32)
Entry
No.
R
Het.
Yield (%)
1
2
3
4
5
6
7
8
9
24
25
26
27
28
29
30
31
32
H
H
Thiophen-2-yl
Thiophen-3-yl
Pyridin-3-yl
55
59
81
21
30
74
25
59
61
H
H
Pyrrole-2-yl
Indolin-3-yl
H
Me
Thiophen-3-yl
Indolin-3-yl
COCH3
COCH3
COCH3
Thiophen-2-yl
Thiophen-3-yl
indolin-3-yl derivatives were produced in poor yields even when the reaction mixture
was refluxed for 24 h. These compounds did not show significant neuroprotection;
however, these compounds are novel benzoxazines and thus are reported here.
In conclusion, we have prepared a variety of novel 3-(4-acetoxy-3,5-dibromo-
phenyl) derivatives of 1,4-benzoxazines (1–7) using conventional (7 h reflux) and
microwave heating (20 min at 180 ꢀC). These compounds were readily hydrolyzed
to novel 3-[(3,5-dibromo-4-hydroxy)benzylidenes]-2H-1,4-benzoxazin-3-(4H)-ones
(8–15). Additionally, novel 3-benzylidene derivatives (17–20, 22, 23) and hetaryl-
methyl derivatives of 1,4-benzoxizines (29–32) were prepared.
EXPERIMENTAL
The 1H and 13C NMR spectra were recorded on a 400-MHz Brucker or
500-MHz Jeol multinuclear NMR spectrometer; chemical shifts were referenced to
tetramethylsilane (TMS) as internal standard. Infrared (IR) spectra were obtained
on a Varian 3100 Fourier transform (FT)–IR Spectrometer. Gas chromatography–
mass spectrometry (GC=MS) data was recorded on a Agilent G1701DA GC=MS
ChemStation. Microwave experiments were carried out in a CEM-Driver Discover

2368
H. ANKATI ET AL.
200-W, 250-psi microwave oven. Melting points were taken on a Meltemp apparatus
and are uncorrected. All chemicals and reagents were purchased from commercial
sources. Silica get (230- to 400-mesh size) for column chromatography was pur-
chased from SiliCycle. Elemental analyses were within 0.3% of calculated values.
Conventional Procedure for the Preparation of Compounds[5–7] 1–7,
17–20, 22–26, 29, 31, and 32
The appropriate aldehyde (15 mmol) was added to a mixture of appropriate
substituted 2H-1,4-benzoxazin-3-(4H)-one (10 mmol), acetic anhydride (4 ml), and
triethylamine (2 ml). The reaction mixture was refluxed for 7 h, left overnight at rt,
and poured into crushed ice. The obtained solid was collected by filtration and
washed with acetonitrile (55–88% yield). The crude product was purified by recrys-
tallization from ethanol.
Microwave Procedure for the Preparation of Compounds 1–7
The appropriate aldehyde (3.75 mmol) was added to a mixture of appropriate
substituted 2H-1,4-benzoxazin-3-(4H)-one (2.5 mmol), acetic anhydride (2 ml), and
triethylamine (1 ml) and placed in a microwave test tube. The tube was then capped
and charged into a CEM microwave instrument. The mixture was irradiated with
250 psi of pressure at a temperature of 180 ꢀC for 20 min. Then the reaction mixture
was left overnight at rt and poured into crushed ice. The obtained solid was collected
by filtration and washed with acetonitrile (75–85% yield).
Procedure for the Preparation of Compound 15[5]
A catalytic amount of Raney nickel was added portionwise with stirring to a
mixture of compound 1 (2 mmol) and hydrazine hydrate (1 ml) in ethanol (20 ml).
The reaction mixture was refluxed for 3 h and then filtered. The filtrate was evapo-
rated to dryness under reduced pressure. The crude product was purified by recrys-
tallization from ethanol to give 15 in 70% yield.
Procedure for the Preparation of Compounds 8–14
The respective ester of these compounds (1–7) (1 mmol) was treated with pot-
assium carbonate (3 mmol) at 0 ꢀC in methanol (10 ml) and stirred for 3 h at rt to give
the respective alcohols 8–14 in 70–75% yields.
Procedure for the Preparation of Compound 27[5]
Sodium methoxide was added in one portion to a mixture of 2H-1,4-
benzoxazin-3-(4H)-one (10 mmol) and pyrrole-2-carboxaldehyde (16 mmol) in dry
DMF (10 ml). The reaction mixture was refluxed for 48 h, cooled to rt, poured onto
crushed ice, and left overnight at 4 ꢀC. The precipitated solid was collected by fil-
tration, washed with water, and dried. The precipitate was boiled with ethanol
(150 ml) and filtered while hot to remove impurities. The filtrate was evaporated

PREPARATION OF 1,4-BENZOXAZINES
2369
to dryness under reduced pressure, and the residue was chromatographed on a
silica-gel column using (95:5) toluene–ethyl acetate as the mobile phase to yield 27
in 21% yield.
Procedure for the Preparation of Compounds 16 and 21[5]
Sodium methoxide was added in one portion to a mixture of appropriate
substituted 2H-1,4-benzoxazin-3-(4H)-one (10 mmol) and 4-dimethylamino benzal-
dehyde (16 mmol) in dry DMF (10 ml). The reaction mixture was refluxed overnight,
cooled to rt, poured onto crushed ice, and left overnight in the refrigerator. The pre-
cipitated solid was collected by filtration, washed with water, and dried. The crude
products were recrystallized from ethanol to yield 16 in 30% yield or from DMF–
ethanol to yield 21 in 40% yield.
Procedure for the Preparation of Compounds 28 and 30[5]
Sodium methoxide was added in one portion to a mixture of appropriate sub-
stituted 2H-1,4-benzoxazin-3-(4H)-one (10 mmol) and indole-3-carboxaldehyde
(16 mmol) in dry DMF (10 ml). The reaction mixture was refluxed for 24 h, cooled
to rt, poured onto crushed ice, and left overnight in the refrigerator. The precipitated
solid was collected by filtration, washed with water, and dried. The crude product
was chromatographed on a silica-gel column using (9:1) toluene–ethyl acetate to give
28 or 30 in 30% and 25% yields, respectively.
Physical and Spectral Properties of Compounds 1–32
(Z)-2,6-Dibromo-4-{(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ylidene)
methyl}phenyl acetate (1). White solid; mp 306–308 ꢀC; IR (cmꢁ1): 3417.9,
2914.6, 2835.3, 1767.0, 1687.5, 1638.8, 1504.0, 1458.3, 1434.1, 1386.1, 1269.3,
1
1208.2, 1191.8, 1110.5, 903.8, 879.8, 809.2, 742.5. H NMR (500 MHz, DMSO-d6)
d 11.24, (brs, 1H), 8.14 (s, 2H), 7.11 (m, 1H), 7.04–6.98 (m, 2H), 6.98–6.94 (m,
1H), 6.71 (s, 1H), 2.35 (s, 3H); 13C NMR (500 MHz, DMSO-d6) d 167.5 (C), 156.1
(C), 145.2 (C), 144.1 (C), 140.7 (C), 134.9 (C), 133.4 (CH), 125.8 (C), 124.3 (CH),
123.8 (CH), 117.6 (C), 116.3 (CH), 115.8 (CH), 107.4 (CH), 20.6 (CH3). Anal. calcd.
for C17H11Br2NO4: C, 43.13; H, 2.79; Br, 32.79; Cl, 3.64; N, 2.87; O, 14.77. Found:
C, 43.20, H, 2.97, N 2.99.
(Z)-2,6-Dibromo-4-{(6-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-
2-ylidene)methyl}phenyl acetate (2). Light yellow solid; mp 303–306 ꢀC; IR
(cmꢁ1): 3386.3, 2916.4, 2848.2, 1765.8, 1678.2, 1637.4, 1508.2, 1459.4, 1432.6,
1
1385.7, 1263.2, 1116.5, 1032.9, 858.9, 811.7, 745.3. H NMR (500 MHz, DMSO-
d6) d 11.46 (br, 1H, NH), 8.07 (s, 2H), 7.83 (d, J ¼ 8.6 Hz, 1H), 7.69 (s, 1H) 7.24
(d, J ¼ 6.5 Hz, 1H), 6.73 (s, 1H), 2.34 (s, 3H, CH3); 13C NMR (500 MHz, DMSO-
d6) d 167.7 (C), 155.4 (C), 145.4 (C), 145.2 (C), 143.2 (C), 142.7 (C), 134.2 (C),
133.6 (CH), 126.8 (C), 119.5 (CH), 117.8 (C), 116.6 (CH), 111.1 (CH), 108.8 (CH),
20.6 (CH3). Anal. calcd. for C17H10Br2N2O6: C, 40.99; H, 2.02; Br, 32.08; N, 5.62;
O, 19.27. Found: C, 41.02, H, 2.07, N, 5.66.

2370
H. ANKATI ET AL.
(Z)-2,6-Dibromo-4-{(6-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-
2-ylidene)methyl}phenyl acetate (3). Light yellow solid; mp 306–309 ꢀC; IR
(cmꢁ1): 3422.9, 2905.9, 2453.6, 1762.8, 1672.7, 1637.8, 1450.0, 1439.8, 1265.7,
1
1109.9, 1032.7, 861.9, 811.9, 745.4. H NMR (500 MHz, DMSO-d6) d 11.30 (br,
1H, NH), 8.12 (s, 2H), 7.12 (d, J ¼ 8.59 Hz, 1H), 7.0 (d, J ¼ 6.87 Hz, 1H), 6.92 (s,
1H), 6.71 (s, 1H), 2.36 (s, 3H, CH3); 13C NMR (500 MHz, DMSO-d6) d 167.7 (C),
155.8 (C), 145.1 (C), 143.4 (C), 139.4 (C), 134.7 (C), 133.4 (CH), 127.6 (C), 127.2
(C), 123.2 (CH), 117.7 (C), 117.4 (CH), 115.4 (CH), 107.6 (CH), 20.7 (CH3). Anal.
calcd. for C17H10Br2ClNO4: C, 41.88; H, 2.07; Br, 32.78; Cl, 7.27; N, 2.87; O, 13.
Found: C, 41.99; H, 2.15; N 3.03.
(Z)–2,6-Dibromo-4-{(6-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-
2-ylidene)methyl}phenyl acetate (4). Light yellow solid; mp 205–207 ꢀC; IR
(cmꢁ1): 3389.2, 3061.9, 2988.9, 1770.1, 1692.2, 1633.6, 1547.9, 1455.9, 1370.3,
1
1265.0, 1176.0, 1007.4, 979.2, 893.8, 859.7, 748.4. H NMR (500 MHz, DMSO-d6)
d 11.16 (br, 1H, NH), 8.10 (s, 2H), 6.96 (d, J ¼ 8.02 Hz, 1H), 6.77 (d, J ¼ 7.45 Hz,
1H), 6.71 (s, 1H), 6.66 (s, 1H), 2.35 (s, 3H, CH3), 2.15 (s, 3H, CH3); 13C NMR
(500 MHz, DMSO-d6) d 167.7 (C), 156.0 (C), 144.9 (C), 144.0 (C), 138.4 (C), 135.0
(C), 133.4 (C), 133.2 (CH), 125.3 (C), 124.2 (CH), 117.6 (C), 116.3 (CH), 115.5
(CH), 106.8 (CH), 20.9 (CH3) 20.7 (CH3). Anal. calcd. for C18H13Br2NO4: C,
44.04; H, 2.43; Br, 33.48; Cl, 3.71; N, 2.93; O, 13.41. Found: C, 44.27; H, 2.56; N,
3.07.
(Z)-4-{(6-Acetyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ylidene)
methyl}-2,6-dibromophenyl acetate (5). Light yellow solid; mp 263–265 ꢀC; IR
(cmꢁ1): 3417.0, 3054.4, 2987.0, 2305.6, 1767.3, 1701.0, 1643.4, 1603.1, 1485.4, 1421.7,
1368.8, 1265.5, 1296.8, 1182.3, 896.0, 738.8, 705.3. 1H NMR (500 MHz, DMSO-d6) d
11.34 (br, 1H, NH), 8.13 (s, 1H), 7.62 (d, J ¼ 8.05 Hz, 1H), 7.47 (s, 1H), 7.18 (d,
J ¼ 8.05 Hz, 1H), 6.75 (s, 1H), 2.48 (s, 3H, CH3), 2.36 (s, 3H, CH3); 13C NMR
(500 MHz, DMSO-d6) d 196.4 (CO), 167.7 (C), 155.7 (C), 145.2 (C), 144.0 (C),
143.3 (C), 134.6 (C), 133.4 (C), 133.5 (CH), 132.9 (C), 126.1 (C), 124.9 (C), 117.7
(C), 115.9 (CH), 115.6 (CH), 108.0 (CH), 26.9 (CH3), 20.7 (CH3). Anal. calcd. for
C17H13Br2NO5: C, 43.34; H, 2.78; Br, 33.92; N, 2.97; O, 16.98. Found: C, 43.49;
H, 2.73; N, 3.07.
(Z)-2,6-Dibromo-4-{(6-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-
2-ylidene)methyl}phenyl acetate (6). Light yellow solid; mp 298–300 ꢀC; IR
(cmꢁ1): 3424.4, 3054.4, 2989.2, 2305.2, 1765.8, 1688.9, 1633.2, 1509.4, 1443.5,
1396.6, 1305.6, 1265.3, 1205.4, 1164.9, 1119.0, 1105.3, 896.5, 845.9, 743.2. 1H
NMR (500MHz, DMSO-d6) d 11.31 (br, 1H, NH), 8.13 (s, 2H), 7.14 (d, J ¼ 8.50Hz,
1H), 7.09 (d, J ¼ 6.85 Hz, 1H), 7.07(s, 1H), 6.73 (s, 1H), 2.36 (s, 3H, CH3); 13C
NMR (500 MHz, DMSO-d6) d 167.6 (C), 155.8 (C), 144.9 (C), 142.4 (C), 139.5
(C), 134.3 (C), 133.4 (CH), 132.3 (C), 127.5 (C), 118.3 (CH), 117.9 (CH), 114.3
(C), 115.4 (CH), 107.6 (CH), 20.7 (CH3). Anal. calcd. for C17H10Br3NO4: C, 43.34;
H, 2.14; Br, 33.92; F, 4.03; N, 2.97; O, 13.59. Found: C, 43.51; H, 2.25; N, 3.15.
(Z)-2,6-Dibromo-4-{(6-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-
2-ylidene)methyl}phenyl acetate (7). White solid; mp 290–292 ꢀC; IR (cmꢁ1):
3425.1, 3051.3, 2987.6, 2311.9, 1766.3, 1690.8, 1638.8, 1580.9, 1455.0, 1382.6,

PREPARATION OF 1,4-BENZOXAZINES
2371
1306.0, 1274.3, 1245.7, 1205.1, 1165.0, 1112.8, 897.0, 849.4, 748.8. 1H NMR
(500 MHz, DMSO-d6) d 11.29 (br, 1H, NH), 8.11 (s, 2H), 7.11–7.13 (m, 1H),
6.69–6.72 (m, 1H), 2.36 (s, 3H, CH3); 13C NMR (500 MHz, DMSO-d6) d 167.7
(C), 159.2 (C), 157.3 (C), 155.9 (C), 145.1 (C), 143.5 (C), 136.9 (C), 134.8 (C),
133.4 (CH), 127.0 (CH), 117.7 (C), 117.1 (CH), 119.9 (CH), 107.3 (CH), 103.0
(CH), 20.7 (CH3). Anal. calcd. for C17H10Br2FNO4: C, 42.97; H, 2.44; Br, 33.63;
Cl, 1.87; F, 1.00; N, 2.95; O, 15.15. Found: C, 43.14; H, 2.57; N, 3.02.
(Z)-2-(3,5-Dibromo-4-hydroxybenzylidene)-2H-benzo[b][1,4]oxazin-3-(4H)-
one (8). Light yellow solid; mp >300 ꢀC; IR (cmꢁ1): 3417.2, 2989.8, 2846.7, 2301.3,
1
1676.6, 1641.4, 1508.0, 1477.8, 1396.9, 1265.6, 1120.7, 892.2, 738.1, 704.7. H NMR
(500 MHz, DMSO-d6) d 10.63, (brs, 1H), 7.71 (s, 2H), 6.92 (m, 3H), 6.84 (m, 1H),
6.42 (s, 1H); 13C NMR (500 MHz, DMSO-d6) d 163.5 (C), 158.0 (C), 141.6 (C),
135.9 (C), 133.8 (CH), 126.6 (C), 123.3 (CH), 115.7 (CH), 115.5 (C), 115.3 (CH),
113.8 (C), 113.0 (CH). Anal. calcd. for C15H9Br2NO3: C, 43.83; H, 2.21; Br,
38.88; N, 3.41; O, 11.68. Found: C, 43.99; H, 2.30; N, 3.45.
(Z)-2-(3,5-Dibromo-4-hydroxybenzylidine)-6-nitro-2H-benzo[b][1,4]
oxazin-3-(4H)-one (9). Orange red solid; mp >300 ꢀC; IR (cmꢁ1): 3485.6, 2943.9,
2832.9, 2522.8, 2226.1, 2044.5, 1660.1, 1449.6, 1404.6, 1265.8, 1114.5, 1027.4,
1
893.2, 737.6, 704.8. H NMR (500 MHz, DMSO-d6) d 11.15 (br, 1H, NH), 7.83
(dd, J ¼ 8.6 Hz, 2.3 Hz, 1H), 7.78 (d, J ¼ 2.85 Hz, 1H), 7.74 (s, 2H), 7.15 (d,
J ¼ 8.6 Hz, 1H), 6.54 (s, 1H); 13C NMR (500 MHz, DMSO-d6) d 164.5 (C), 156.9
(C), 146.2 (C), 142.7 (C), 135.1 (C), 134.2 (CH), 119.4 (CH), 116.0 (CH), 115.6
(C), 114.6 (CH), 114.2 (C), 110.7 (CH). Anal. calcd. for C15H8Br2N2O5: C, 43.83;
H, 2.21; Br, 38.88; N, 3.41; O, 11.68. Found: C, 43.98; H, 2.30; N 3.46.
(Z)-6-Chloro-2-(3,5-dibromo-4-hydroxybenzylidine)-2H-benzo[b][1,4]-
oxazin-3-(4H)-one (10). Light yellow solid; mp 307–309 ꢀC; IR (cmꢁ1): 3361.3,
2945.6, 2833.5, 2524.4, 2225.8, 2043.2, 1660.3, 1449.8, 1404.8, 1233.3, 1200.7,
1114.5, 1028.1, 893.8, 739.9, 704.3. 1H NMR (500 MHz, DMSO-d6) d 10.9 (br,
1H, NH), 7.71 (s, 2H), 6.88–6.95 (m, 3H), 6.44 (s, 1H); 13C NMR (500 MHz,
DMSO-d6) d 163.6 (C), 158.0 (C), 140.6 (C), 135.6 (C), 133.9 (CH), 128.9 (C),
126.5 (C), 122.4 (CH), 116.7 (CH), 115.6 (CH), 115.3 (C), 113.9 (C), 113.1 (CH).
Anal. calcd. for C15H8Br2ClNO3: C, 40.44; H, 1.81; Br, 35.87; Cl, 7.96; N, 3.14;
O, 10.77. Found: C, 40.57; H, 1.88; N, 3.27.
(Z)-2-(3,5-Dibromo-4-hydroxybenzylidine)-6-methyl-2H-benzo[b][1,4]-
oxazin-3-(4H)-one (11). Yellow solid; mp 305–307 ꢀC; IR (cmꢁ1): 3419.0, 3054.7,
2986.9, 2306.3, 2045.9, 1639.2, 1478.3, 1422.1, 1265.4, 1195.9, 1140.2, 895.9, 736.5.
1H NMR (500 MHz, DMSO-d6) d 10.93 (br, 1H, NH), 7.94 (s, 2H), 6.95 (d,
J ¼ 8.0 Hz, 1H), 6.78 (d, J ¼ 8.45 Hz, 1H), 6.71 (s, 1H), 6.58 (s, 1H), 2.20 (s, 3H);
13C NMR (500 MHz, DMSO-d6) d 157.5 (C), 139.8 (C), 139.0 (C), 133.7 (CH),
132.8 (C), 125.8 (C), 123.9 (CH), 116.1 (CH), 115.3 (CH), 113.8 (C), 109.7 (CH),
20.9 (CH3). Anal. calcd. for C16H11Br2NO3: C, 48.89; H, 2.82; Br, 40.66; N, 3.56;
O, 4.07. Found: C, 49.02; H, 2.75; N 3.70.
(Z)-6-Acetyl-2-(3,5-dibromo-4-hydroxybenzylidine)-2H-benzo[b][1,4]-
oxazin-3-(4H)-one (12). Orange red solid; mp >300 ꢀC; IR (cmꢁ1): 3376.2, 2946.7,

2372
H. ANKATI ET AL.
1
2834.0, 2524.0, 2221.7, 1708.3, 1658.7, 1449.8. H NMR (500 MHz, DMSO-d6) d
11.07 (br, 1H, NH), 7.93 (s, 2H), 7.62 (dd, J ¼ 8.6 Hz, 2.3 Hz, 1H), 7.47 (d,
J ¼ 2.3 Hz, 1H), 7.15 (d, J ¼ 8.6 Hz, 1H), 6.64 (s, 1H), 2.36 (s, 3H); 13C NMR
(500 MHz, DMSO-d6) d 166.6 (CO), 155.5 (C), 143.8 (C), 142.8 (C), 133.6 (CH),
126.9 (C), 119.5 (CH), 118.2 (C), 117.8 (CH), 115.5 (C), 111.1 (CH), 108.7 (CH),
20.7 (CH3). Anal. calcd. for C17H11Br2NO4: C, 45.07; H, 2.45; Br, 35.27; N, 3.09;
O, 14.12. Found: C, 45.13; H, 2.55; N, 3.16.
(Z)-6-Bromo-2-(3,5-dibromo-4-hydroxybenzylidine)-2H-benzo[b][1,4]
oxazin-3-(4H)-one (13). Light yellow solid; mp >300 ꢀC; IR (cmꢁ1): 3424.4,
3054.4, 2987.0, 2359.4, 1631.3, 1421.7, 1265.0, 1119.8, 1026.1, 896.2, 736.8, 703.6.
1H NMR (500 MHz, DMSO-d6) d 10.8 (br, 1H, NH), 7.71 (s, 2H), 6.88–6.95 (m,
3H), 6.44 (s, 1H); 13C NMR (500 MHz, DMSO-d6) d 163.6 (C), 157.9 (C), 140.9
(C), 135.5 (C), 133.9 (CH), 128.6 (C), 125.6 (CH), 117.9 (CH), 117.3 (CH), 115.5
(C), 114.1 (C), 113.4 (CH). Anal. calcd. for C15H8Br3NO3: C, 36.77; H, 1.65; Br,
48.93; N, 2.86; O, 9.80. Found: C,36.80, H, 1.78, N 2.99.
(Z)-2-(3,5-Dibromo-4-hydroxybenzylidine)-6-fluoro-2H-benzo[b][1,4]-
oxazin-3-(4H)-one (14). Light yellow solid; mp >300 ꢀC; IR (cmꢁ1): 3388.9,
3054.5, 2987.0, 2305.5, 1671.5, 1636.6, 1508.7, 1421.3, 1383.1, 1265.6, 1174.4,
1
1119.4. H NMR (500 MHz, DMSO-d6) d 10.96 (br, 1H, NH), 7.87 (s, 2H), 7.05
(dd, J ¼ 9.15 Hz, 4.9 Hz, 1H), 6.77 (dt, J ¼ 5.75 Hz, 2.85 Hz, 1H), 6.69 (dd,
J ¼ 9.15 Hz, 2.85 Hz, 1H), 6.55 (s, 1H); 13C NMR (500 MHz, DMSO-d6) d 163.6
(C), 157.9 (C), 140.8 (C), 142.5 (C), 133.8 (CH), 128.9 (C), 116.7 (CH), 110.9 (CH),
109.5 (CH), 108.6 (C), 107.2 (C), 102.8 (CH). Anal. calcd. for C15H8Br2FNO3: C,
41.99; H, 1.88; Br, 37.25; F, 4.43; N, 3.26; O, 11.19. Found: C, 42.06; H, 1.78; N 3.30.
(Z)-6-Amino-2-(3,5-Dibromo-4-hydroxybenzylidine)-2H-benzo[b][1,4]-
oxazin-3-(4H)-one (15). Light yellow solid; mp 254–256 ꢀC; IR (cmꢁ1): 3388.9,
3054.5, 2987.0, 2305.5, 1671.5, 1636.6, 1508.7, 1421.3, 1383.1, 1265.6, 1174.4,
1
1119.4, 895.6, 738.9, 705.7. H NMR (500 MHz, DMSO-d6) d 10.73 (br, 1H, NH),
9.71 (brs, 1H, OH), 7.66 (s, 2H), 6.94 (m, 2H), 6.78 (d, J ¼ 8.0 Hz, 1H), 6.58 (s,
1H), 6.16 (s, 2H, NH2); 13C NMR (500 MHz, DMSO-d6) d 157.6 (C), 157.1 (C),
144.9 (C), 140.9 (C), 132.1 (C), 131.8 (CH), 125.9 (C), 126.5 (C), 116.0 (CH),
110.9 (CH), 106.8 (CH), 100.1 (CH). Anal. calcd. for C15H10Br2N2O3: C, 42.29;
H, 2.37; Br, 37.51; N, 6.57; O, 11.2. Found: C, 42.40; H, 2.44; N, 6.67.
(Z)-2-(4-Dimethylamino)benzylidene)-2H-benzo[b][1,4]oxazin-3-(4H)-one
(16). Yellow solid; mp 245–247 ꢀC (lit.[5] mp 245–247 ꢀC); IR (cmꢁ1): 3417.8, 3054.2,
2986.6, 2685.7, 2305.5, 1682.3, 1634.0, 1604.4, 1503.5, 1421.7, 1389.3, 1353.5, 1265.2,
1
1188.5, 896.0, 741.5, 704.5. H NMR (500 MHz, DMSO-d6) d 10.83 (br, 1H, NH),
7.69 (d, J ¼ 8.59 Hz, 2H), 7.16 (d, J ¼ 8.59 Hz, 1H), 6.90–6.96 (m, 3H), 6.72 (d,
J ¼ 8.59 Hz, 2H), 6.64 (s, 1H), 2.92 (s, 6H, N(CH3)2); 13C NMR (500 MHz,
DMSO-d6) d 157.5 (C), 150.5 (C), 141.3 (C), 139.1 (C), 131.7 (CH), 126.2 (C),
123.6 (CH), 123.5 (CH), 121.4 (C), 115.9 (CH), 115.8 (CH), 112.5 (CH), 112.4
(CH), 40.2 [N(CH3)2]. Anal. calcd. for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99; O,
11.42. Found: C, 72.98, H 5.87, N, 10.06.

PREPARATION OF 1,4-BENZOXAZINES
2373
(Z)-2-(3,4,5-Trimethoxybenzylidene)-2H-benzo[b][1,4]oxazin-3-(4H)-one
(17). White solid; mp 262–265 ꢀC; IR (cmꢁ1): 3332.6, 2944.6, 2832.4, 2520.9, 2227.3,
1685.9, 1637.9, 1449.7, 1265.1, 1115.6, 1031.4, 895.6, 738.9, 703.8. 1H NMR
(500 MHz, DMSO-d6) d 11.03 (br, 1H, NH), 7.14–7.17 (m, 3H), 6.97–6.99 (m,
3H), 6.70 (s, 1H), 3.81 (s, 6H, 2xOCH3), 3.67 (s, 3H, OCH3); 13C NMR
(500 MHz, DMSO-d6) d 156.8 (C), 153.2 (C), 144.6 (C), 140.8 (C), 138.1 (C), 129.2
(C), 125.9 (C), 123.9 (CH) 123.6 (CH), 116.0 (CH), 115.9 (CH), 116.4 (C), 111.4
(CH), 107.6 (CH), 60.5 (OCH3), 56.2 (OCH3). Anal. calcd. for C18H17NO5: C,
66.05; H, 5.23; N, 4.28; O, 24.44. Found: C, 65.98; H, 5.30; N, 4.50.
(Z)-2-(3,5-Dibromobenzylidene)-2H-benzo[b][1,4]oxazin-3-(4H)-one (18).
White solid; mp >300 ꢀC; IR (cmꢁ1): 3421.9, 3059.0, 2987.9, 2305.5, 2087.5,
1700.4, 1655.6, 1449.1, 1402.7, 1264.9, 1119.5, 1020.9, 893.1, 740.4, 704.1. 1H
NMR (500 MHz, DMSO-d6) d 11.00, (brs, 1H), 7.99 (s, 2H), 7.68 (s, 1H), 7.10 (d,
J ¼ 11.46 Hz, 1H), 7.03–7.01 (m, 3H), 6.71 (m, 1H), 6.71 (s, 1H); 13C NMR
(500 MHz, DMSO-d6) d 156.3 (CO), 144.5 (C), 140.8 (C), 138.2 (C), 132.9 (CH),
131.3 (CH), 124.4 (CH), 123.9 (CH), 123.1 (C), 116.3 (CH), 115.9 (CH), 107.7
(CH). Anal. calcd. for C15H9Br2NO2: C, 45.61; H, 2.30; Br, 40.45; N, 3.55; O,
8.10. Found: C, 45.69; H, 2.41; N, 3.67.
(Z)-2-Methyl-(3,4,5-trimethoxybenzylidene)-2H-benzo[b][1,4]oxazin-3-(4H)-
one (19). White solid; mp 245–247 ꢀC; IR (cmꢁ1): 3442.4, 3054.2, 2958.6, 2305.0,
1685.1, 1633.4, 1545.3, 1494.5, 1421.4, 1402.9, 1265.8, 1132.5, 1004.7, 894.9, 740.2,
1
703.8. H NMR (500 MHz, DMSO-d6) 11.01 (br, 1H, NH), 7.18 (s, 2H), 7.04 (d,
J ¼ 7.45 Hz, 1H), 6.78 (d, J ¼ 7.45 Hz, 1H), 6.73 (s, 1H), 6.69 (s, 1H), 3.81 (s, 6H,
2xOCH3), 3.66 (s, 3H, OCH3), 2.21 (s, 3H, CH3); 13C NMR (500 MHz, DMSO-
d6) d 156.9 (C), 153.2 (C), 141.7 (C), 138.8 (C), 138.1 (C), 133.1 (C), 129.3 (C),
125.5 (C) 124.1 (CH), 116.2 (CH), 115.7 (CH), 111.1 (CH), 107.6 (CH), 60.6
(OCH3), 56.3 (OCH3), 20.9 (CH3). Anal. calcd. for C19H19NO5: C, 66.85; H, 5.61;
N, 4.10; O, 23.43. Found: C, 66.93; H, 5.69; N, 4.26.
(Z)-6-Chloro-2-(3,4,5-trimethoxybenzylidene)-2H-benzo[b][1,4]oxazin-
3-(4H)-one (20). White solid; mp 261–263 ꢀC; IR (cmꢁ1): 3440.9, 3055.2, 2905.5,
1
2305.7, 1683.9, 1658.8, 1537.6, 1493.1, 1449.7, 1395.4, 1338.8, 1265.4, 1114.3. H
NMR (500 MHz, DMSO-d6) d 11.14 (br, 1H, NH), 7.20 (d, J ¼ 4.59 Hz, 1H), 7.17
(s, 2H), 7.01 (d, J ¼ 8.59 Hz, 1H), 6.93 (s, 1H), 6.72 (s, 1H), 3.81 (s, 6H, 2xOCH3),
3.67 (s, 3H, OCH3); 13C NMR (500 MHz, DMSO-d6) d 156.6 (C), 153.2 (C), 141.7
(C), 140.0 (C), 138.2 (C), 129.0 (C), 128.6 (C), 127.5 (C), 126.8 (C), 123.0 (CH),
117.7 (CH), 117.6 (CH), 115.3 (CH), 112.0 (CH), 107.7 (CH), 60.7 (OCH3), 56.3
(OCH3). Anal. calcd. for C18H16Br2ClNO5: C, 41.45; H, 3.09; Br, 30.64; Cl, 6.80;
N, 2.69; O, 15.34. Found: C, 41.55; H, 3.18; N, 2.89.
(Z)-6-Chloro-2-(4-dimethylamino)benzylidene)-2H-benzo[b][1,4]oxazin-
3-(4H)-one (21). Yellow solid; mp 306–309 ꢀC (lit.[5] mp 307–309 ꢀC; IR (cmꢁ1):
3417.1, 3054.4, 2986.9, 2685.5, 2305.6, 1676.5, 1629.5, 1603.6, 1495.0, 1422.0,
1382.4, 1265.5, 1189.1, 1108.0, 1078.0, 896.1, 849.8, 734.3, 704.8. 1H NMR
(500 MHz, DMSO-d6) d 10.89 (br, 1H, NH), 7.67 (d, J ¼ 8.59 Hz, 2H), 7.19 (d,
J ¼ 8.59 Hz, 1H), 6.85–6.98 (m, 2H), 6.71 (d, J ¼ 8.59 Hz, 2H), 6.65 (s, 1H), 2.92
[s, 6H, N(CH3)2]; 13C NMR (500 MHz, DMSO-d6) d 157.3 (C), 150.6 (C), 140.3

2374
H. ANKATI ET AL.
(C), 138.5 (C), 131.8 (CH), 127.8 (C), 126.9 (C), 122.8 (CH), 121.1 (C), 117.3 (CH),
115.1 (CH), 113.1 (CH), 112.3 (CH), 40.2 [N(CH3)2].
(Z)-6-Nitro-2-(3,4,5-trimethoxybenzylidene)-2H-benzo[b][1,4]oxazin-3-(4H)-
one (22). Yellow solid; mp 269–271 ꢀC; IR (cmꢁ1): 3443.8, 3054.8, 2946.7, 2305.2,
1684.2, 1637.7, 1533.6, 1494.8, 1420.6, 1395.9, 1338.3, 1321.2, 1265.0, 1137.3,
1
1005.0, 895.1, 738.9, 704.5. H NMR (500 MHz, DMSO-d6) d 11.22 (br, 1H, NH),
7.76 (d, J ¼ 9.20 Hz, 1H), 7.62 (s, 1H), 7.19 (d, J ¼ 9.20 Hz, 1H), 7.04 (s, 2H), 6.66
(s, 1H), 3.80 (s, 6H, 2xOCH3), 3.66 (s, 3H, OCH3); 13C NMR (500 MHz, DMSO-
d6) d 153.1 (C), 144.1 (C), 142.9 (C), 140.2 (C), 139.2 (C), 132.3 (C), 131.9 (C),
130.5 (C) 128.4 (C), 126.9 (CH), 119.3 (CH), 116.4 (CH), 113.1 (CH), 110.9 (CH),
107.8 (CH), 60.5 (OCH3), 56.2 (OCH3).
(Z)-6-Acetyl-2-(3,5-dibromobenzylidine)-2H-benzo[b][1,4]oxazin-3-(4H)-
one (23). Light yellow solid; mp 318–321 ꢀC; IR (cmꢁ1): 3382.6, 2945.2, 2832.7,
2305.8, 2227.2, 1705.6, 1656.9, 1449.5, 1404.1, 1265.8, 1115.0, 1028.1, 890.2, 735.2,
1
703.8. H NMR (500 MHz, DMSO-d6) d 11.32 (br, 1H, NH), 7.97 (s, 2H), 7.70 (s,
1H), 7.62 (d, J ¼ 8.05 Hz, 1H), 7.46 (s, 1H), 7.15 (d, J ¼ 8.05 Hz, 1H), 6.71 (s, 1H),
2.48 (s, 3H); 13C NMR (500 MHz, DMSO-d6) d 196.4 (CO), 155.7 (C), 144.0 (C),
143.5 (C), 137.4 (C), 133.1 (CH), 132.9 (C), 131.5 (CH), 126.1 (C), 124.9 (CH),
123.1 (C), 115.8 (CH), 115.6 (CH), 108.6 (CH), 26.9 (CH3).
(Z)-2-(Thiophen-2-ylmethylene)-2H-benzo[b][1,4]oxazin-3-(4H)-one (24).
Light green solid; mp 243–245 ꢀC; 1H NMR (500 MHz, DMSO-d6) IR (cmꢁ1):
3415.3, 3054.3, 2986.9, 2305.8, 1681.8, 1632.6, 1503.2, 1391.7, 1356.0, 1265.3,
1102.9, 896.2, 742.8, 705.2. d 11.07 (br, 1H, NH), 7.68 (d, J ¼ 5.15 Hz, 1H), 7.46
(d, J ¼ 3.44 Hz, 1H), 7.17–7.19 (m, 1H), 7.11–7.13 (m, 1H), 7.10 (s, 1H), 6.96–7.02
(m, 3H); 13C NMR (500 MHz, DMSO-d6) d 156.5 (C), 141.0 (C), 139.9 (C), 136.1
(C), 130.6 (CH), 129.5 (CH), 127.8 (CH), 126.0 (C), 124.1 (CH), 123.7 (CH), 116.2
(CH), 115.8 (CH), 106.3 (CH).
(Z)-2-(Thiophen-3-ylmethylene)-2H-benzo[b][1,4]oxazin-3-(4H)-one (25).
Light green solid; mp 255–257 ꢀC (lit.[5] mp 256–257 ꢀC); IR (cmꢁ1): 3416.9, 3054.9,
2985.6, 2305.0, 1689.5, 1640.1, 1502.5, 1392.9, 1265.8, 1109.2, 894.5, 744.7, 704.6. 1H
NMR (500 MHz, DMSO-d6) d 11.02 (br, 1H, NH), 8.05 (s, 1H), 7.55–7.57 (m, 2H),
7.29–7.31 (m, 1H), 6.98–7.11 (m, 3H), 6.84 (s, 1H); 13C NMR (500 MHz, DMSO-d6)
d 156.5 (C), 144.5 (C), 140.5 (C), 135.1 (C), 132.6 (C), 129.5 (CH), 128.1 (CH), 126.7
(CH), 124.8 (CH), 116.2 (CH), 115.6 (CH), 107.3 (CH).
(Z)-2-(Pyridin-3-ylmethylene)-2H-benzo[b][1,4]oxazin-3-(4H)-one (26).
Light brown solid; mp 256–258 ꢀC (lit.[5] mp 257–258 ꢀC); IR (cmꢁ1): 3425.7,
3053.9, 2986.5, 2305.6, 1681.9, 1644.2, 1500.6, 1420.7, 1384.5, 1264.3, 1110.3,
1
896.0, 741.5, 700.8. H NMR (500 MHz, DMSO-d6) d 11.18 (br, 1H, NH), 8.90 (s,
1H), 8.45 (d, J ¼ 4.0 Hz, 1H), 8.30 (d, J ¼ 8.0 Hz, 1H), 7.41 (dd, J ¼ 4.60, 7.25 Hz,
1H), 7.25 (d, J ¼ 7.4 Hz, 1H), 6.95–6.99 (m, 3H), 6.76 (s, 1H); 13C NMR
(500 MHz, DMSO-d6) d 156.2 (C), 151.0 (CH), 148.9 (CH), 143.9 (C), 140.7 (C),
136.5 (CH), 129.9 (C), 125.8 (C), 124.2 (CH), 124.1 (CH), 123.7 (CH), 116.1 (CH),
107.4 (CH).

PREPARATION OF 1,4-BENZOXAZINES
2375
(Z)-2-{(1H-Pyrrol-2-yl)methylene}-2H-benzo[b][1,4]oxazin-3-(4H)-one
(27). Light brown solid; mp 263–265 ꢀC (lit.[5] mp 263–265 ꢀC); IR (cmꢁ1): 3424.9,
3054.1, 2945.8, 2305.9, 1685.9, 1634.5, 1449.7, 1420.8, 1379.8, 1265.1, 1115.0,
1
895.7, 743.2, 703.4. H NMR (500 MHz, DMSO-d6) d 11.04 (br, 1H, NH), 10.80
(s, 1H, NH), 7.31–7.33 (m, 1H), 6.93–6.96 (m, 4H), 6.72 (s, 1H), 6.67–6.69 (m,
1H), 6.16–6.18 (m, 1H); 13C NMR (500 MHz, DMSO-d6) d 157.3 (C), 141.5 (C),
137.5 (C), 126.2 (C), 126.1 (C), 123.6 (CH), 123.4 (CH), 121.4 (CH), 116.2 (CH),
115.9 (CH), 113.2 (CH), 110.2 (CH), 104.1 (CH).
(Z)-2-(1H-Indol-3-yl)methylene)-2H-benzo[b][1,4]oxazin-3-(4H)-one (28).
Light brown solid; mp >300 ꢀC (lit.[5] mp > 300 ꢀC); IR (cmꢁ1): 3423.5, 3054.3,
2986.9, 2685.5, 2305.6, 1728.4, 1690.1, 1504.2, 1449.7, 1421.7, 1379.4, 1265.4,
1
1214.3, 1147.2, 896.0, 739.2, 705.4. H NMR (500 MHz, DMSO-d6) d 11.16 (br,
1H, NH), 10.84 (br, 1H, NH), 8.17–8.34 (m, 2H), 7.72–7.84 (m, 3H), 7.12–7.57
(m, 4H), 6.93 (s, 1H); 13C NMR (500 MHz, DMSO-d6) d 156.7 (C), 144.2 (C),
140.9 (C), 134.1 (C), 133.6 (C), 129.3 (C), 127.1 (C), 126.7 (C), 125.7 (CH), 125.1
(CH), 124.6 (CH), 119.5 (CH), 116.5 (CH), 115.9 (CH), 115.7 (CH), 102.4 (CH).
(Z)-6-Methyl-2-(thiophen-2-ylmethylene)-2H-benzo[b][1,4]oxazin-3-(4H)-
one (29). Light green solid; mp 272–275 ꢀC; IR (cmꢁ1): 3414.8, 3054.4, 2989.3,
1
2305.9, 1686.2, 1633.2, 1499.8, 1389.4, 1265.0, 1119.4, 896.4. H NMR (500 MHz,
DMSO-d6) d 10.98 (br, 1H, NH), 8.03 (s, 1H), 7.53–7.56 (m, 2H), 7.18 (d,
J ¼ 7.45 Hz, 1H), 6.72–6.81 (m, 3H), 2.20 (s, 3H, CH3); 13C NMR (500 MHz,
DMSO-d6) d 157.0 (C), 141.2 (C), 139.1 (C), 134.7 (C), 133.0 (C), 129.5 (CH),
127.2 (CH), 126.6 (CH), 125.6 (C), 124.0 (CH), 116.2 (CH), 115.9 (CH), 105.9
(CH), 20.9 (CH3). Anal. calcd. for C14H11NO2S: C, 65.35; H, 4.31; N, 5.44; O,
12.44; S, 12.46. Found: C, 65.44; H, 4.40; N, 5.67.
(Z)-2-(1H-Indol-3-yl)methylene)-7-acetyl-2H-benzo[b][1,4]oxazin-3-(4H)-
one (30). Light brown solid; mp 298–300 ꢀC; IR (cmꢁ1): 3421.9, 3054.4, 2987.1,
2686.7, 2359.8, 1706.8, 1688.4, 1638.1, 1546.1, 1494.1, 1421.8, 1349.9, 1265.5,
1215.2, 1012.2, 896.1, 744.4, 704.9. 1H NMR (500 MHz, CDCl3 þ DMSO-d6) d
11.17 (br, 1H, NH), 10.82 (br, 1H, NH), 8.24–8.45 (m, 2H), 7.70–7.91 (m, 3H),
7.33–7.42 (m, 3H), 7.09 (s, 1H); 13C NMR (500 MHz, DMSO-d6) 196.4 (CO),
156.0 (C), 144.4 (C), 141.8 (C), 134.9 (C), 132.7 (C), 129.4 (C), 127.5 (C), 126.2
(C), 125.8 (CH), 124.6 (CH), 124.2 (CH), 119.2 (CH), 116.4 (CH), 116.2 (CH),
115.5 (CH), 102.1 (CH), 26.8 (CH3). Anal. calcd. for C19H14N2O3: C, 71.69; H,
4.43; N, 8.80; O, 15.08. Found: C, 71.75; H, 4.60; N 8.95.
(Z)-6-Acetyl-2-(thiophen-2-ylmethylene)-2H-benzo[b][1,4]oxazin-3-(4H)-
one (31). Light yellow solid; mp 230–232 ꢀC; IR (cmꢁ1): 3415.8, 3054.4, 2986.9,
2305.8, 1686.9, 1633.0, 1606.8, 1493.2, 1422.3, 1378.5, 1354.1, 1265.6, 1216.1,
1
1101.4, 1019.0, 896.0, 745.5, 704.6. H NMR (500 MHz, DMSO-d6) d 11.17 (br,
1H, NH), 7.70 (s, 1H), 7.63 (d, J ¼ 8.0 Hz, 1H), 7.45–7.48 (m, 2H), 7.24 (d,
J ¼ 8.0 Hz, 1H), 7.13 (s, 2H), 2.48 (s, 3H, CH3); 13C NMR (500 MHz, DMSO-d6)
d 196.4 (CO), 156.2 (C), 144.6 (C), 139.3 (C), 135.7 (C), 132.7 (C), 131.1 (CH),
129.9 (CH), 127.9 (C), 126.4 (C), 124.9 (CH), 115.8 (CH), 115.6 (CH), 107.2 (CH),
26.9 (CH3). Anal. calcd. for C15H11NO3S: C, 63.14; H, 3.89; N, 4.91; O, 16.82; S,
11.24. Found: C, 63.20; H, 3.97; N, 5.04.

2376
H. ANKATI ET AL.
(Z)-6-Acetyl-2-(thiophen-3-ylmethylene)-2H-benzo[b][1,4]oxazin-3-(4H)-
one (32). Light yellow solid; mp 246–248 ꢀC; IR (cmꢁ1): 3416.7, 3054.3, 2987.0, 2305.6,
1
1700.7, 1641.2, 1598.1, 1421.8, 1362.6, 1265.5, 1224.4, 1099.4, 896.0, 738.9, 705.4. H
NMR (500 MHz, DMSO-d6) d 11.14 (br, 1H, NH), 8.08 (s, 1H), 7.63 (d, J ¼ 8.60Hz,
1H), 7.55–7.59 (m, 3H), 7.47 (s,1H), 7.40 (d, J ¼ 8.0 Hz, 1H), 6.88 (s,1H), 2.48 (s, 3H,
CH3); 13C NMR (500MHz, DMSO-d6) d 196.5 (CO), 156.6 (C), 144.8 (C), 144.0 (C),
134.3 (C), 132.6 (C), 129.6 (CH), 128.0 (CH), 126.8 (CH), 126.4 (CH), 124.9 (CH),
116.1 (CH), 115.4 (CH), 107.1 (CH), 26.9 (CH3). Anal. calcd. for C15H11NO3S: C,
63.14; H, 3.89; N, 4.91; O, 16.82; S, 11.24. Found: C, 63.29; H, 4.02; N, 5.06.
ACKNOWLEDGMENTS
This work was supported in part by grants from the Welch Foundation (N-118,
to E. R. B.), Defense Advanced Research Projects Agency (HR0011-06-1-0032, to
E. R. B.), and the National Institutes of Health (NS047201, to S. R. D.).
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