Synthesis of novel 1,4-benzoxazine-2,3-dicarboximides from maleic anhydride and substituted aromatic amines

Article abstract of DOI:10.1080/00397910802369638

A series of novel 1,4-benzoxazine-2,3-dicarboximides starting from maleic anhydride and substituted aromatic amines were synthesized. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802369638

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Synthesis of Novel
1,4-Benzoxazine-2,3-
Dicarboximides from Maleic
Anhydride and Substituted
Aromatic Amines
Peng Wu a & Yongzhou Hu a
a ZJU-ENS Joint Laboratory of Medicinal Chemistry,
College of Pharmaceutical Sciences, Zhejiang
University, Hangzhou, China
Version of record first published: 15 Feb 2011.
To cite this article: Peng Wu & Yongzhou Hu (2008): Synthesis of Novel 1,4-
Benzoxazine-2,3-Dicarboximides from Maleic Anhydride and Substituted
Aromatic Amines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:1, 70-84
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Synthetic Communications1, 39: 70–84, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802369638
Synthesis of Novel 1,4-Benzoxazine-2,3-
Dicarboximides from Maleic Anhydride
and Substituted Aromatic Amines
Peng Wu and Yongzhou Hu
ZJU-ENS Joint Laboratory of Medicinal Chemistry,
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
Abstract: A series of novel 1,4-benzoxazine-2,3-dicarboximides starting from
maleic anhydride and substituted aromatic amines were synthesized.
Keywords: 1,4-Benzoxazine-2,3-dicarboximide, maleic anhydride, synthesis
INTRODUCTION
Various kinds of 1,4-benzoxazine derivatives show interesting biological
activities,[1–5] such as antifungal[6] and antimicrobial[7,8] properties.
They are also found in herbicides[9] and dyes.[10] Moreover, a number
of 1,4-benzoxazine derivatives are developed as antipyretic, analgesic,
anti-inflammatory, and neuroprotective agents.[11–13] Consequently,
many efforts have been devoted to the synthesis of them.[2–5,14]
The maleic anhydride is present in several natural products,[15] and it
is an important intermediate in the chemical and pharmaceutical indus-
tries.[16,17] A variety of methods have been developed for the preparation
of some biologically active compounds using maleic anhydride as one of
the starting materials.[18,19]
Herein, we report a three-step procedure to synthesize a series of
1,4-benzoxazine-2,3-dicarboximides starting from maleic anhydride and
Received May 8, 2008.
Address correspondence to Yongzhou Hu, ZJU-ENS Joint Laboratory of
Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University,
Hangzhou 310058, China. E-mail: huyz@zju.edu.cn
70

1,4-Benzoxazine-2,3-Dicarboximides
71
substituted aromatic amines in moderate to good yield. Our attempt was
to synthesize this novel kind of 1,4-benzoxazine-2,3-dicarboximides and
provide more options for pharmaceutical uses.
RESULTS AND DISCUSSION
N-Phenyldichloromaleimide derivatives 3 were synthesized according
to an improved procedure based on reported methods[20,21] using
commercially available maleic anhydride 1 and substituted aromatic
amines 2 as the starting materials (Scheme 1). The results are summarized
in Table 1.
The condensation reactions of 3 with 2-aminophenol derivatives 4
were studied under different conditions. Initially, reaction of 3a with 4a
was carried out in methanol or dimethylformamide (DMF) in the pre-
sence of CH3COONa or potassium hydride (KOH).[22–24] However, the
reaction was very complex, and we could not isolate the expected product
5a. After several trials, we found that reaction of 3a with 2-aminophenol
4a in ethanol afforded the desired compound 5a in 71% yield after reflux-
ing for 10 h. Use of dichloromethane as the solvent in the reaction gave
5a in lower yield (Table 2).
To explore the scope of our method, a variety of N-phenyldichloro-
maleimide derivatives 3 were investigated to react with 2-aminophenol
4a, 4-chloro-2-amino-phenol 4b, and 4-tert-butyl-2-aminophenol 4c,
respectively, under the optimized reaction condition (Scheme 2).
Most of the N-phenyldichloromaleimide derivatives 3 can provide
the corresponding products in moderate to good yields. However, reac-
tion of 3 with 4-tert-butyl-2-aminophenol 4c can lead to slightly higher
yield than reaction with 2-aminophenol 4a or 4-chloro-2-aminophenol
4b. We deduced that the present of the electron-donating group, tert-
butyl on the benzene ring, may increase the nucleophilicity of 4c, which
makes the attack of the electrophilic N-phenyldichloromaleimide 3 easier.
Scheme 1. a, R1 ¼ phenyl; b, R1 ¼ p-F-phenyl; c, R1 ¼ p-Cl-phenyl; d, R1 ¼ p-
CH3-phenyl; e, R1 ¼ m-CH3-phenyl; f, R1 ¼ p-NO2-phenyl; g, R1 ¼ m-NO2-
phenyl; h, R1 ¼ 3,4-dimethoxyphenyl; i, R1 ¼ naphthyl; and j, R1 ¼ benzyl.

72
P. Wu and Y. Hu
Table 1. Synthesis of N-phenyldichloromaleimide derivatives 3
Substituted aromatic
amines 2
Yield MP (ꢀC) MP (ꢀC)
Compound 3 (%) (reported) (found)
Entry
1
2
3
4
5
6
7
8
9
10
Aniline 2a
3a
3b
3c
3d
3e
3f
66 204–206[20] 205–206
86 161–163[21] 162–164
75 214–215[25] 213–215
p-Fluorobenzenamine 2b
p-Chlorobenzenamine 2c
p-Toluidine 2d
79 196–198[25] 198–199
a
m-Touidine 2e
75
—
147–148
p-Nitrobenzenamine 2f
m-Nitrobenzenamine 2g
3,4-Dimethoxybenzenamine 2h
1-Naphthylamine 2i
Benzylamine 2j
88 188–190[21] 193–195
a
3g
3h
3i
86
61
81
—
—
—
179–180
165–167
199–201
a
a
3j
59 109–110[25] 111–112
aNo data available.
In summary, a series of novel 1,4-benzoxazine-2,3-dicarboximides,
which may have potential antimicrobial activities, were synthesized start-
ing from maleic anhydride and substituted aromatic amines in moderate
Table 2. Procedure optimization of the cyclization between N-phenyldichloroma-
leimide 3a and 2-aminophenol 4a
Temperatureb Time Yield
Entry
Solvent
Catalysta
(ꢀC )
(h)
(%)c
1
2
3
4
5
6
7
8
9
10
Methanol
Methanol
CH3COONa
KOH
60
60
160
160
60
60
60
90
3
—
13
d
d
—
—
e
Dimethylformamide (DMF) CH3COONa
Dimethylformamide (DMF) KOH
Dichloromethane
Dichloromethane
Ethanol
Ethanol
Ethanol
Ethanol
3
d
d
—
—
CH3COONa
—
CH3COONa
—
—
—
3
19
32
36
61
21
71
2.5
2.5
2.5
24
r.t.
90
10
a0.2 eq of KOH or CH3COONa was used as catalyst.
bRefers to temperature of oil baths.
cRefers to isolated yield.
dThe reaction mixture turned to be dark in minutes after KOH was added to
the reaction system.
eComplex mixtures were observed on TLC, and the desired product was not
isolated.

1,4-Benzoxazine-2,3-Dicarboximides
73
Scheme 2. Synthesis of 1,4-benzoxazine-2,3-dicarboximide derivatives of 5–7.
to good yield. To the best of our knowledge, this kind of 1,4-benzoxazine-
2,3-dicarboximide derivative was synthesized for the first time.
EXPERIMENTAL
Melting points were recorded on a B-540 Buchi melting-point apparatus
and are uncorrected. 1H NMR spectra were recorded on a 400 MHz Bru-
ker instrument at 400 MHz using CDCl3 or DMSO-d6 as the solvent with
TMS as an internal standard. IR spectra were recorded using KBr pellets
on a Bruker Vector-22 FTIR spectrophotometer. Mass spectra (MS) and
ESI (negative) were recorded on an Esquire-LC-00075 spectrometer.
Other regents and solvents are commercially available and used without
further purification unless otherwise noted.
Preparation of 3,4-Dichloro-1-phenyl-1H-pyrrole-2,5-dione (3a)
A solution of aniline 2a (1.9 mL, 20 mmol) in 10 ml acetone was added to a
suspension of maleic anhydride 1 (1.96 g, 20 mmol) in 10 ml acetone. After
warming it in an oil bath at 55 ꢀC for 1 h, Et3N (2.5 mL), acetic anhydride
(1 mL), and 15% NiSO4 (0.2 mL) were added. After refluxing in 80 ꢀC for
another 2 h, the reaction mixture was poured into ice-cold water. The pre-
cipitated product was filtered, washed with ice-cold water, and dried
under vacuum to give a yellow residue. The obtained residue was dissolved
in 15 mL thionyl chloride, then 2 mL pyridine was added dropwise at less
than 0 ꢀC over 15 min. The reaction mixture was allowed to stir for addi-
tional 15 min at less than 0 ꢀC and 30 min at ambient temperature. Then
the reaction mixture was refluxed at 85 ꢀC for 2 h. After removing the sol-
vent under vacuum, the residue of the reaction mixture was reconstituted
and diluted with ice-cold water. The resulting mixture was then neutra-
lized (pH about 7.0) using sodium bicarbonate solution and extracted
with dichloromethane (3 ꢁ 10 mL). The organic layers were combined,
washed with water (2 ꢁ 5 mL), and dried over anhydrous sodium sulfate.

74
P. Wu and Y. Hu
The solvent was removed to give the crude product and then purified by
silica-gel column chromatography, eluting with petroleum=ethyl acetate
(4:1 v=v) to afford compound 3a (3.18 g, 66%) as a solid.
In the same manner, compounds 3b–j were synthesized by reaction of the
corresponding substituted aromatic amines 2b–j with maleic anhydride 1.
Preparation of 2-Phenyl-pyrrolo[3,4-b][1,4]benzoxazine-1,3(2H,9H)-
dione (5a)
A solution of 3,4-dichloro-1-phenyl-1H-pyrrole-2,5-dione 3a (240 mg,
1 mmol) and 2-aminophenol 4a (109 mg, 1 mmol) in ethanol (5 mL) was
refluxed in an oil bath at 85–95 ꢀC for 10 h. After cooling to room tempera-
ture, the solvent was removed under vacuum to give the crude product and
then purified by silica-gel column chromatography, eluting with petro-
leum=ethyl acetate=dichloromethane (8:2:1 v=v=v) to afford compound
5a (196 mg, 71%) as yellow powder. Mp 201–203 ꢀC. 1H NMR
(400 MHz, CDCl3): d 7.47 (t, 2H, J ¼ 8.0 Hz), 7.43–7.37 (m, 3H), 7.28
(dd, 1H, J ¼ 8.0 and 1.6 Hz), 6.99 (t, 1H, J ¼ 8.0 Hz), 7.00 (t, 1H,
J ¼ 8.0 Hz), 6.92 (dd, 1H, J ¼ 8.0 and 1.6 Hz), 5.45 (s, 1H). IR (KBr):
n (cmꢂ1) 3204, 3035, 1770, 1702, 1678, 1653, 1597, 1502, 1456, 1415, 1299,
1243, 1200. MS (ESI): m=s¼ 277 [M ꢂ 1]. Anal. calcd. for C16H10N2O3:
C, 69.06; H, 3.62; N, 10.07. Found: C, 69.11; H, 3.59; N, 10.02.
In the same manner, compounds 5b–j were synthesized by reaction
of the corresponding N-phenyldichloromaleimide derivatives 3b–j with
2-aminophenol 4a.
Data
2-(4-Fluorophenyl)-pyrrolo[3,4-b][1,4]benzoxazine-1,3(2H,9H)-dione (5b)
Orange powder, yield 78%, mp 197–198 ꢀC. 1H NMR (400 MHz, CDCl3):
d 7.34–7.30 (m, 2H), 7.21–7.14 (m, 3H), 7.07–6.96 (m, 2H), 6.90 (d, 1H,
J ¼ 8.0 Hz), 6.81 (s, 1H). IR (KBr): n (cmꢂ1) 3412, 3097, 1768, 1717, 1663,
1601, 1512, 1460, 1402, 1346, 1285, 1234. MS (ESI): m=s ¼ 295 [M ꢂ 1].
Anal. calcd. for C16H9FN2O3: C, 64.87; H, 3.06; N, 9.46. Found: C,
64.79; H, 3.11; N, 9.51.
2-(4-Chlorophenyl)-pyrrolo[3,4-b][1,4]benzoxazine-1,3(2H,9H)-dione
(5c)
Yellow powder, yield 70%, mp 188–190 ꢀC. 1H NMR (400 MHz, CDCl3):
d 7.44 (d, 2H, J ¼ 9.2 Hz), 7.38 (d, 2H, J ¼ 9.2 Hz), 7.25 (d, 2H,

1,4-Benzoxazine-2,3-Dicarboximides
75
J ¼ 7.6 Hz), 7.16 (t, 1H, J ¼ 7.2 Hz), 6.98 (t, 1H, J ¼ 7.2 Hz), 6.91 (d, 1H,
J ¼ 7.6 Hz), 5.56 (s, 1H). IR (KBr): n (cmꢂ1) 3330, 3112, 3060, 2800, 2385,
1779, 1712, 1646, 1593, 1528, 1496, 1400, 1347, 1280, 1245, 1218. MS
(ESI): m=s ¼ 311 [M ꢂ 1]. Anal. calcd. for C16H9ClN2O3: C, 61.45; H,
2.90; N, 8.96. Found: C, 61.34; H, 2.98; N, 8.92.
2-(4-Methylphenyl)-pyrrolo[3,4-b][1,4]benzoxazine-1,3(2H,9H)-dione
(5d)
1
Orange yellow powder, yield 72%, mp 212–213ꢀC. H NMR (400 MHz,
DMSO-d6): d 7.28 (d, 2H, J ¼ 8.8 Hz), 7.23 (d, 2H, J ¼ 8.8 Hz), 7.10 (t,
2 H, J ¼ 8.0 Hz), 6.88 (d, 1H, J ¼ 7.6 Hz), 6.79 (t, 1H, J ¼ 7.6 Hz), 5.58
(s, 1H), 2.39 (s, 3H). IR (KBr): n (cmꢂ1) 3336, 3098, 2921, 1777, 1712,
1650, 1596, 1518, 1458, 1403, 1351, 1281, 1240, 1214. MS (ESI):
m=s ¼ 291 [M ꢂ l]. Anal. calcd. for C17H12N2O3: C, 69.86; H, 4.14; N,
9.58. Found: C, 69.78; H, 4.08; N, 9.49.
2-(3-Methylphenyl)-pyrrolo[3,4-b][1,4]benzoxazine-1,3(2H,9H)-dione
(5e)
Yellow powder, yield 67%, mp 158–160 ꢀC. 1H NMR (400 MHz, CDCl3):
d 7.33 (t, 1H, J ¼ 8.0 Hz), 7.26–7.10 (m, 5H), 6.96 (t, 1H, J ¼ 7.6 Hz), 6.89
(d, 1H, J ¼ 8.0 Hz), 5.76 (s, 1H), 2.39 (s, 3H). IR (KBr): n (cmꢂ1) 3342,
3048, 2955, 1770, 1727, 1668, 1600, 1522, 1492, 1460, 1396, 1344, 1291,
1244. MS (ESI): m=s ¼ 291 [M ꢂ 1]. Anal. calcd. for C17H12N2O3: C,
69.86; H, 4.14; N, 9.58. Found: C, 69.76; H, 4.13; N, 9.49.
2-(4-Nitrophenyl)-pyrrolo[3,4-b][1,4]benzoxazine-1,3(2H,9H)-dione (5f)
Yellow powder, yield 71%, mp 205–207 ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.34 (d, 2H, J ¼ 9.2 Hz), 7.77 (d, 2H, J ¼ 9.2 Hz), 7.21–6.94 (m, 3H),
6.63 (d, 1H, J ¼ 9.2 Hz), 5.63 (s, 1H). IR (KBr): n (cmꢂ1) 3352, 3126,
3022, 1768, 1735, 1672, 1594, 1516, 1500, 1461, 1420, 1387, 1339, 1248,
1219. MS (ESI): m=s ¼ 322 [M ꢂ 1]. Anal. calcd. for C16H9N3O5: C,
59.45; H, 2.81; N, 13.00. Found: C, 59.41; H, 2.74; N, 12.97.
2-(3-Nitrophenyl)-pyrrolo[3,4-b][1,4]benzoxazine-1,3(2H,9H)-dione (5g)
Yellow powder, yield 66%, mp 192–194ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.42 (s, 1H), 8.22 (d, 1H, J ¼ 8.0 Hz), 7.87–7.83 (m, 1H), 7.60 (t, 1H,

76
P. Wu and Y. Hu
J ¼ 8.4 Hz), 7.21–7.17 (m, 2H), 7.00 (t, 1H, J ¼ 8.0 Hz), 6.92 (d, 1H,
J ¼ 8.8 Hz), 5.54 (s, 1H). IR (KBr): n (cmꢂ1) 3326, 3103, 3018, 1768,
1710, 1651, 1601, 1526, 1484, 1449, 1395, 1348, 1303, 1226. MS (ESI):
m=s ¼ 322 [M ꢂ 1]. Anal. calcd. for C16H9N3O5: C, 59.45; H, 2.81; N,
13.00. Found: C, 59.36; H, 2.78; N, 12.97.
2-(3,4-Dimethoxyphenyl)-pyrrolo[3,4-b][1,4]-benzoxazine-1,3(2H,9H)-
dione (5h)
Orange powder, yield 76%, mp 182–184 ꢀC. 1H NMR (400 MHz, CDCl3):
d 7.23–7.13 (m, 2H), 7.03–6.89 (m, 4H), 6.79 (s, 1H), 5.63 (s, 1H), 3.89 (s,
3H), 3.86 (S, 3H). IR (KBr): n (cmꢂ1) 3394, 3331, 3007, 2967, 2839, 1773,
1720, 1664, 1598, 1514, 1425, 1372, 1335, 1267, 1218. MS (ESI):
m=s ¼ 337 [M ꢂ 1]. Anal. calcd. for C18H14N2O5: C, 63.90; H, 4.17; N,
8.28. Found: C, 62.86; H, 4.14; N, 8.29.
2-Naphthyl-pyrrolo[3,4-b][1,4]benzoxazine-1,3(2H,9H)-dione (5i)
Yellow powder, yield 75%, mp 181–183 ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.00–7.95 (m, 2H), 7.71–7.68 (m, 1H), 7.61–7.56 (m, 3H), 7.44 (d, 1H,
J ¼ 7.6 Hz), 7.17 (t, 2H, J ¼ 7.6 Hz), 7.02 (t, 1H, J ¼ 7.6 Hz), 6.93 (t, 1H,
J ¼ 8.4 Hz), 5.78 (s, 1H). IR (KBr): n (cmꢂ1) 3308, 3051, 1932, 1772, 1707,
1666, 1598, 1510, 1462, 1418, 1380, 1281, 1231. MS (ESI): m=s ¼ 327
[M ꢂ 1]. Anal. calcd. for C20H12N2O3: C, 73.16; H, 3.68; N, 8.53. Found:
C, 73.09; H, 3.62; N, 8.48.
2-Benzyl-pyrrolo[3,4-b][1,4]benzoxazine-1,3(2H,9H)-dione (5j)
1
Orange red powder, yield 68%, mp 176–178 ꢀC. H NMR (400 MHz,
CDCl3): d 7.37 (d, 2H, J ¼ 8.0 Hz), 7.35–7.29 (m, 3H), 7.15 (dd, 1H,
J ¼ 8.0 and 1.6 Hz), 7.09 (t, 1H, J ¼ 8.0 Hz), 6.91 (t, 1H, J ¼ 8.0 Hz),
6.93 (dd, 1H, J ¼ 8.0 and 0.8 Hz), 5.78 (s, 1H), 4.71 (s, 2H). IR (KBr):
n (cmꢂ1) 3330, 3056, 2962, 2849, 1766, 1709, 1657, 1600, 1520, 1449,
1411, 1345. MS (ESI): m=s ¼ 291 [M ꢂ 1]. Anal. calcd. for C17H12N2O3:
C, 69.86; H, 4.14; N, 9.58. Found: C, 69.78; H, 4.18; N, 9.56.
Preparation of 2-Phenyl-7-chloro-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (6a)
A solution of 3,4-dichloro-1-phenyl-1H-pyrrole-2,5-dione 3a (240 mg,
0.1 mmol) and 2-amino-4-chlorophenol 4b (143 mg, 0.1 mmol) in ethanol

1,4-Benzoxazine-2,3-Dicarboximides
77
(5 ml) were refluxed in an oil bath at 85–95 ꢀC for 10 h. After cooling to
room temperature, the solvent was removed under vacuum to give the
crude product, and then purified by silica gel column chromatography
eluting with petroleum=ethyl acetate=dichloromethane (6:2:1 v=v=v) to
afford compound 6a (215 mg, 69%) as yellow powder. Mp 209–211ꢀC.
1H NMR (400 MHz, CDCl3): d 7.46 (t, 2H, J ¼ 7.6 Hz), 7.38 (m, 3H),
7.27 (s, 1H), 7.11 (dd, 1H, J ¼ 8.4 and 2.0 Hz), 6.84 (d, 1H, J ¼ 8.4 Hz),
5.44 (s, 1H). IR (KBr): n (cmꢂ1) 3202, 3030, 2808, 2712, 1770, 1702,
1677, 1652, 1597, 1501, 1455, 1408, 1298, 1264, 1244. MS (ESI):
m=s ¼ 311 [M ꢂ 1]. Anal. calcd. for C16H9ClN2O3: C, 61.45; H, 2.90; N,
8.96. Found: C, 61.37; H, 2.88; N, 9.01.
In the same manner, compounds 6b–j were synthesized by reaction
of the corresponding N-phenyldichloromaleimide derivatives 3b–j with
2-amino-4-chloro-phenol 4b, respectively.
Data
2-(4-Fluorophenyl)-7-chloro-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (6b)
Yellow powder, yield 73%, mp 199–202 ꢀC. 1H NMR (400 MHz, CDCl3): d
7.33–7.30 (m, 2H), 7.21–7.17 (m, 3H), 6.87 (m, 1H), 6.71 (s, 1H), 6.62 (m,
1H). IR (KBr): n (cmꢂ1) 3197, 2938, 1769, 1709, 1654, 1603, 1511, 1411,
1236. MS (ESI): m=s ¼ 329 [M ꢂ 1]. Anal. calcd. for C16H8ClFN2O3: C,
58.11; H, 2.44; N, 8.47. Found: C, 58.03; H, 2.41; N, 8.44.
2-(4-Chlorophenyl)-7-choloro-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (6c)
1
Orange yellow powder, yield 66%, mp 234–235 ꢀC. H NMR (400 MHz,
CDCl3): d 7.56 (d, 2H, J ¼ 8.8 Hz), 7.42 (d, 2H, J ¼ 8.8 Hz), 7.19–7.16 (m,
2H), 6.90 (d, 1H, J ¼ 8.8 Hz), 5.82 (s, 1H). IR (KBr): n (cmꢂ1) 3332, 3095,
2982, 2815, 1781, 1714, 1651, 1594, 1522, 1495, 1428, 1395, 1276, 1194.
MS (ESI): m=s ¼ 345 [M ꢂ 1]. Anal. calcd. for C16H8Cl2N2O3: C, 69.06;
H, 3.62; N, 10.07. Found: C, 69.00; H, 3.58; N, 10.03.
2-(4-Methylphenyl)-7-chloro-pyrrolo[3,4-b][1,4]benzoxazine-1,3
(2H,9H)-dione (6d)
Yellow powder, yield 71%, mp 236–238 ꢀC. 1H NMR (400 MHz, DMSO-
d6): d 7.28 (d, 2H, J ¼ 8.4 Hz), 7.23 (d, 2H, J ¼ 8.4 Hz), 7.19–7.15 (m, 2H),

78
P. Wu and Y. Hu
6.89 (d, 1H, J ¼ 8.0 Hz), 5.59 (s, 1H), 2.35 (s, 3H). IR (KBr): n (cmꢂ1
)
3308, 3025, 2923, 1777, 1711, 1652, 1595, 1517, 1495, 1428, 1399, 1275,
1234, 1211. MS (ESI): m=s ¼ 325 [M ꢂ 1]. Anal. calcd. for C17H11ClN2O3:
C, 62.49; H, 3.39; N, 8.57. Found: C, 62.39; H, 3.35; N, 8.55.
2-(3-Methylphenyl)-7-chloro-pyrrolo[3,4-b][1,4]benzoxazine-
1,3 (2H,9H)-dione (6e)
1
Orange yellow powder, yield 67%, mp 187–188ꢀC. H NMR (400MHz,
CDCl3): d 7.40–7.35 (m, 2H), 7.26–7.10 (m, 2H), 7.09 (d, 1 H, J ¼ 8.4 Hz),
7.07–6.96 (m, 1H), 6.85 (d, 1H, J ¼ 8.4 Hz), 5.67 (s, 1H), 2.39 (s, 3H). IR
(KBr): n (cmꢂ1) 3204, 2918, 1769, 1702, 1652, 1595, 1519, 1500, 1450,
1406, 1299, 1248, 1199. MS (ESI): m=s¼ 325 [M ꢂ 1]. Anal. calcd. for
C17H11ClN2O3: C, 62.49; H, 3.39; N, 8.57. Found: C, 62.46; H, 3.33; N, 8.56.
2-(4-Nitrophenyl)-7-chloro-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (6f)
Orange powder, yield 70%, mp 231–233ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.35 (d, 2H, J ¼ 9.2 Hz), 7.76 (d, 2H, J ¼ 9.2 Hz), 7.17–6.87 (m, 2H),
6.63 (d, 1H, J ¼ 9.2 Hz), 5.75 (s, 1H). IR (KBr): n (cmꢂ1) 3330, 3081,
1777, 1727, 1670, 1593, 1526, 1425, 1389, 1348, 1275, 1247, 1218. MS
(ESI): m=s ¼ 356 [M ꢂ 1]. Anal. calcd. for C16H8ClN3O5: C, 53.72; H,
2.25; N, 11.75. Found: C, 53.68; H, 2.24; N, 11.69.
2-(3-Nitrophenyl)-7-chloro-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (6g)
Yellow powder, yield 64%, mp 208–209ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.41–7.49 (m, 4H), 7.22–6.47 (m, 2H), 6.47–6.27 (m, 2H), 6.47–6.27 (m,
1H), 5.65 (s, 1H). IR (KBr): n (cmꢂ1) 3205, 3024, 1770, 1707, 1676, 1653,
1597, 1540, 1500, 1444, 1405, 1351, 1307, 1263, 1228, 1191. MS (ESI):
m=s ¼ 356 [M ꢂ 1]. Anal. calcd. for C16H8ClN3O5: C, 53.72; H, 2.25; N,
11.75. Found: C, 53.67; H, 2.23; N, 11.67.
2-(3,4-Dimethoxyphenyl)-7-chloro-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (6h)
1
Orange yellow powder, yield 71%, mp 201–203ꢀC. H NMR (400 MHz,
CDCl3): d 7.24 (d, 1H, J ¼ 2.4 Hz), 7.10 (m, 2H), 6.98 (m, 1H),

1,4-Benzoxazine-2,3-Dicarboximides
79
6.85–6.83 (d, 1H, J ¼ 8.4 Hz), 6.77 (m, 1H), 6.56 (s, 1H), 3.88 (s, 3H), 3.86
(s, 3H). IR (KBr): n (cmꢂ1) 3394, 3331, 3007, 2967, 2839, 1773, 1721,
1665, 1598, 1515, 1443, 1335, 1268, 1187. MS (ESI): m=s ¼ 371 [M ꢂ 1].
Anal. calcd. for C18H13ClN2O5: C, 58.00; H, 3.52; N, 7.52. Found: C,
58.01; H, 3.50; N, 7.47.
2-Naphthyl-7-chloro-pyrrolo[3,4-b][1,4]benzoxazine-1,3(2H,9H)-dione
(6i)
Yellow powder, yield 72%, mp 222–224 ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.00–7.93 (m, 2H), 7.66–7.64 (m, 1H), 7.59–7.52 (m, 3H), 7.43–7.41 (d,
J ¼ 6.8 Hz, 1H), 7.13–7.09 (m, 2H), 6.85–6.83 (d, J ¼ 8.0 Hz, 1H), 5.82 (s,
1H). IR (KBr): n (cmꢂ1) 3431, 3332, 2925, 2851, 1772, 1710, 1653, 1597,
1526, 1500, 1468, 1417, 1347, 1228. MS (ESI): m=s ¼ 361 [M ꢂ 1]. Anal.
calcd. for C20H11ClN2O3: C, 66.22; H, 3.06; N, 7.72. Found: C, 66.15;
H, 3.09; N, 7.68.
2-Benzyl-7-chloro-pyrrolo[3,4-b][1,4]benzoxazine-1,3(2H,9H)-dione (6j)
Orange red powder, yield 67%, mp 161–163ꢀC. 1H NMR (400MHz,
CDCl3): d 7.39–7.32 (m, 5H), 7.16 (d, 1H, J¼ 2.4 Hz), 7.05 (dd, 1H,
J¼ 8.4 and 2.0 Hz), 6.80 (d, 1H, J ¼ 8.4Hz), 5.78 (s, 1H), 4.72 (s, 1H). IR
(KBr): n (cmꢂ1) 3440, 3253, 3051, 2929, 1772, 1707, 1651, 1595, 1502,
1406, 1350, 1281, 1193. MS (ESI): m=s¼ 325 [M ꢂ 1]. Anal. calcd. for
C17H11ClN2O3: C, 62.49; H, 3.39; N, 8.57. Found: C, 62.47; H, 3.36; N, 8.49.
Preparation of 2-phenyl-7-tert-butyl-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (7a)
A solution of 3,4-dichloro-1-phenyl-1H-pyrrole-2,5-dione 3a (240 mg,
1 mmol) and 2-amino-4-tert-butylphenol 4c (165 mg, 1 mmol) in ethanol
(5 ml) were refluxed in an oil bath at 85–95ꢀC for 10 h. After cooling to
room temperature, the solvent was removed under vacuum to give the
crude product, and then purified by silica gel column chromatography
eluting with petroleum=ethyl acetate=dichloromethane (8:2:1 v=v=v) to
afford compound 7a (243 mg, 73%) as orange powder. Mp 169–171 ꢀC.
1H NMR (400 MHz, CDCl3): d 7.46 (t, 2H, J ¼ 8.0 Hz), 7.42–7.37 (m,
3H), 7.24 (d, 1H, J ¼ 2.0 Hz), 7.14 (dd, 1H, J ¼ 8.0 Hz), 6.82 (d, 1H,
J ¼ 8.0 and 2.0 Hz), 5.43 (s, 1H), 1.32 (s, 9H).IR (KBr): n (cmꢂ1) 3273,
3050, 2953, 2908, 2850, 1778, 1708, 1668, 1645, 1597, 1502, 1405, 1353,

80
P. Wu and Y. Hu
1269, 1212. MS (ESI): m=s ¼ 333 [M ꢂ 1]. Anal. calcd. for C20H18N2O3:
C, 71.84; H, 5.43; N, 8.38. Found: C, 71.79; H, 5.39; N, 8.35.
In the same manner, compounds 7b–j were synthesized by reaction
of the corresponding N-phenyldichloromaleimide derivatives 3b–j with
2-amino-4-tert-butyl-phenol 4c, respectively.
Data
2-(4-Fluorophenyl)-7-tert-butyl-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (7b)
1
Orange red powder, yield 84%, mp 173–175 ꢀC. H NMR (400 MHz,
CDCl3): d 7.40–7.37 (m, 2H), 7.18–7.15 (m, 4H), 6.82 (d, 1H, J ¼ 8.4 Hz),
5.49 (s, 1H), 1.32 (s, 9H). IR (KBr): n (cmꢂ1) 3283, 2960, 1774, 1712,
1653, 1602, 1513, 1414, 1354, 1231. MS (ESI): m=s ¼ 351 [M ꢂ 1]. Anal.
calcd. for C20H17FN2O3: C, 68.17; H, 4.86; N, 7.95. Found: C, 68.11;
H, 4.82; N, 7.90.
2-(4-Chlorophenyl)-7-tert-butyl-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (7c)
Yellow powder, yield 72%, mp 171–173 ꢀC. 1H NMR (400 MHz, CDCl3):
d 7.41 (d, 2H, J ¼ 8.8 Hz), 7.35 (d, 2H, J ¼ 8.8 Hz), 7.21 (d, 1H,
J ¼ 2.4 Hz), 7.12 (dd, 1H, J ¼ 8.8 and 2.0 Hz), 6.80 (d, 1H, J ¼ 8.8 Hz),
6.2 (s, 1H), 1.31 (s, 9H). IR (KBr): n (cmꢂ1) 3327, 2961, 2878, 2846,
1785, 1716, 1659, 1600, 1497, 1397, 1211. MS (ESI): m=s ¼ 367 [M ꢂ 1].
Anal. calcd. for C20H17ClN2O3: C, 65.13; H, 4.65; N, 7.60. Found: C,
65.09; H, 4.62; N, 7.56.
2-(4-Methylphenyl)-7-tert-butyl-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (7d)
1
Yellow powder, yield 72%, mp 90–93 ꢀC. H NMR (400 MHz, CDCl3):
d 7.27 (m, 3H), 7.23 (d, 1H, J ¼ 2.0 Hz), 7.13 (dd, 2H, J ¼ 8.8 and
2.0 Hz), 6.81 (d, 1H, J ¼ 8.8 Hz), 5.44 (s, 1H), 2.40 (s, 3H), 1.32 (s, 9H).
IR (KBr): n (cmꢂ1) 3332, 3050, 2960, 2918, 2856, 1786, 1716, 1659,
1602, 1513, 1401, 1279, 1211. MS (ESI): m=s ¼ 347 [M ꢂ 1]. Anal. calcd.
for C21H20N2O3: C, 72.40; H, 5.79; N, 8.04. Found: C, 72.34; H, 5.76;
N, 7.99.

1,4-Benzoxazine-2,3-Dicarboximides
81
2-(3-methylphenyl)-7-tert-butyl-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (7e)
Orange powder, yield 73%, mp 173–175 ꢀC. 1H NMR (400 MHz, CDCl3):
d 7.33 (t, 1H, J ¼ 8.0 Hz), 7.23–7.14 (m, 5H), 6.81 (d, 1H, J ¼ 8.8 Hz), 5.51
(s, 1H), 2.39 (s, 3H), 1.32 (s, 9H). IR (KBr): n (cmꢂ1) 3389, 3333, 3028,
2958, 2912, 2853, 1782, 1719, 1650, 1602, 1500, 1436, 1395, 1276, 1238.
MS (ESI): m=s ¼ 347 [M ꢂ 1]. Anal. calcd. for C21H20N2O3: C, 72.40;
H, 5.79; N, 8.04. Found: C, 72.37; H, 5.72; N, 8.07.
2-(4-Nitrophenyl)-7-tert-butyl-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (7f)
Orange powder, yield 83%, mp 195–197 ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.33 (d, 2H, J ¼ 9.2 Hz), 7.76 (d, 2H, J ¼ 9.2 Hz), 7.24–7.17 (m, 2H),
6.83 (d, 1H, J ¼ 8.4 Hz), 5.33 (s, 1H), 1.32 (s, 9H). IR (KBr): n (cmꢂ1
)
3394, 3100, 2961, 2916, 2857, 1782, 1718, 1649, 1600, 1533, 1501, 1399,
1348, 1219. MS (ESI): m=s ¼ 378 [M ꢂ 1]. Anal. calcd. for C20H17N3O5:
C, 63.32; H, 4.52; N, 11.08. Found: C, 63.28; H, 4.49; N, 11.06.
2-(3-Nitrophenyl)-7-tert-butyl-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (7g)
Yellow powder, yield 73%, mp 191–193 ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.41 (d, 1H, J ¼ 2 Hz), 8.21 (d, 1H, J ¼ 7.6 Hz), 7.85 (d, 1H, J ¼ 8.0 Hz),
7.64 (t, 1H, J ¼ 8.0 Hz), 7.24 (m, 1H), 7.16 (d, 1H, J ¼ 8.4 Hz), 6.84 (d,
1H, J ¼ 8.0 Hz), 5.66 (s, 1H), 1.32 (s, 9H). IR (KBr): n (cmꢂ1) 3458,
332, 3098, 2964, 2865, 1788, 1773, 1725, 1662, 1602, 1504, 1399, 1340,
1214. MS (ESI): m=s ¼ 378 [M ꢂ 1]. Anal. calcd. for C20H17N3O5: C,
63.32; H, 4.52; N, 11.08. Found: C, 63.36; H, 4.49; N, 11.07.
2-(3,4-Dimethoxyphenyl)-7-tert-butyl-pyrrolo[3,4-b][1,4]benzoxazine-
1,3(2H,9H)-dione (7h)
1
Light brown powder, yield 83%, mp 144–146 ꢀC. H NMR (400 MHz,
CDCl3): d 7.23–7.21 (m, 2H), 7.12 (dd, 1H, J ¼ 8.4 and 1.6 Hz), 6.94
(d, 1H, J ¼ 2.0 Hz), 6.78 (t, 2H, J ¼ 8.4 Hz), 5.99 (s, 1H), 3.90 (s, 3H),
3.87 (s, 3H), 1.31 (s, 9H). IR (KBr): n (cmꢂ1) 3444, 2960, 1770, 1719,
1658, 1603, 1513, 1452, 1333, 1262. MS (ESI): m=s ¼ 393 [M ꢂ 1]. Anal.
calcd. for C22H22N2O5: C, 66.99; H, 5.62; N, 7.10. Found: C, 66.96; H,
5.62; N, 7.08.

82
P. Wu and Y. Hu
2-Naphthyl-7-tert-butyl-pyrrolo[3,4-b] [1,4]benzoxazine-1,3(2H,9H)-dione
(7i)
Orange powder, yield 81%, mp 98–101 ꢀC. 1H NMR (400 MHz, CDCl3):
d 7.92 (d, 1H, J ¼ 8.4 Hz), 7.91–7.89 (m, 1H), 7.68–7.66 (m, 1H), 7.54–
7.50 (m, 3H), 7.39 (d, 1H, J ¼ 7.6 Hz), 7.24 (m, 1H), 7.02 (dd, 1H,
J ¼ 8.4 and 1.6 Hz), 6.45 (d, 1H, J ¼ 8.4 Hz), 6.27 (s, 1H), 1.32 (s, 9H).
IR (KBr): n (cmꢂ1) 3440, 3333, 3058, 2959, 2849, 1788, 1717, 1657,
1601, 1506, 1412, 1373, 1373, 275, 1227. MS (ESI): m=s ¼ 383 [M ꢂ 1].
Anal. calcd. for C24H20N2O3: C, 74.98; H, 5.24; N, 7.29. Found: C,
74.91; H, 5.22; N, 7.27.
2-Benzyl-7-tert-butyl-pyrrolo[3,4-b][1,4]benzoxazine-1,3(2H,9H)-dione
(7j)
Yellow powder, yield 72%, mp 141–144 ꢀC. 1H NMR (400 MHz, CDCl3):
d 7.39 (d, 2H, J ¼ 7.2 Hz), 7.35–7.29 (m, 3H), 7.15 (s, 1H), 7.10 (d, 1H,
J ¼ 8.4 Hz), 6.79 (d, 1H, J ¼ 8.4 Hz), 5.45 (s, 1H), 4.72 (s, 2H), 1.29 (s,
9H). IR (KBr): n (cmꢂ1) 3282, 3060, 2956, 2912, 2867, 1768, 1706,
1649, 1600, 1508, 1437, 1352, 1225. MS (ESI): m=s ¼ 347 [M ꢂ 1]. Anal.
calcd. for C21H20N2O3: C, 72.40; H, 5.79; N, 8.04. Found: C, 72.35; H,
5.72; N, 8.04.
ACKNOWLEDGMENTS
We are grateful to the Department of Chemistry and Pharmaceutical of
1
Informatics Institute of Zhejiang University for H NMR data, ESI-MS
spectra and elemental analyses. We are also grateful to other staff of
ZJU-ENS Joint Medicinal Chemistry Laboratory.
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