Efficient synthesis of 4H-benzo[d][1,3]oxazin-4-ones from anthranilic acids and aryl isoselenocyanates

Article abstract of DOI:10.3184/174751913X13686242406479

A synthesis in good to excellent yields of 23 4H-benzo[d][1,3]oxazin-4- ones, 18 of which are novel, from monosubstituted anthranilic acids and variously substituted phenyl isoselenocyanates without using any harsh reagents has been developed. The Se powder precipitated during the reaction could be efficiently recycled for the preparation of the aryl isoselenocyanates.

Full text of DOI:10.3184/174751913X13686242406479

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 351
JUNE, 351–355
Efficient synthesis of 4H-benzo[d][1,3]oxazin-4-ones from anthranilic
acids and aryl isoselenocyanates
Yuanyuan Xie* and Dongmei Zhu
Key Laboratory for Green PharmaceuticalTechnologies and Related Equipment of Ministry of Education, College of Pharmaceutical
Sciences, Zhejiang University ofTechnology, Hangzhou 310014, P. R. China
A synthesis in good to excellent yields of 23 4H-benzo[d][1,3]oxazin-4-ones, 18 of which are novel, from monosubsti-
tuted anthranilic acids and variously substituted phenyl isoselenocyanates without using any harsh reagents has
been developed. The Se powder precipitated during the reaction could be efficiently recycled for the preparation of
the aryl isoselenocyanates.
Keywords: benzoxazinone, aryl isoselenocyanate, anthranilic acid, cyclisation, selenium powder
4H-Benzo[d][1,3]oxazin-4-ones are alternative substrate
inhibitors of the serine proteinase human leukocyte elastase,1
as well as novel specific PSA (puromycin-sensitive aminopep-
tidase) inhibitors to the invasion of tumour cells that are more
stable than the traditional ones.2 4H-Benzo[d][1,3]oxazin-4-
one derivatives play an important role in the defence of the
human body against infections3 and show anti-cancer effects.4
In addition, 4H-benzo[d][1,3]oxazin-4-ones are widely used
as intermediates to prepare various biologically important
compounds.5–8 Thus, a variety of methods for the synthesis of
4H-benzo[d][1,3]oxazin-4-ones have been reported.
The three ways of synthesising of 2-(arylamino)-4H-
benzo[d][1,3]oxazin-4-ones, are as follows (Scheme 1): (1)
methyl N-aryldithiocarbamates react with 5-substituted potas-
sium anthranilates through a desulfurisation process;9 (2) sub-
stituted methyl 2-aminobenzoates undergo a cyclisation with
isocyanates;1 and (3) a reaction of iminophosphoranes and aryl
isocyanates via tetrabutylammonim fluoride-mediated cyclisa-
tion.10 However, HgO used as a desulfurising reagent in method
(1) is a highly toxic compound which is harmful to the envi-
ronment and methods (2) and (3) often give low yields that
limit their application.
Results and discussion
4-Methoxyphenyl isoselenocyanate and 2-aminobenzoic acid
were chosen as the candidates to optimise the reaction condi-
tions for the cyclisation reaction (Scheme 2), and the results
are summarised in Table 1.
The effects of different solvents, reaction duration and tem-
perature, and the amount of 2-aminobenzoic acid on the effi-
ciency of the cyclisation reaction of 1 equiv. 4-methoxyphenyl
isoselenocyanate were investigated. It was clear that DMF
(Table 1, entry 7) was the optimal solvent while others such as
pyridine, THF, EtOAc and EtOH gave lower yields (Table 1,
entries 1–4). Moreover, toluene and CH2Cl2 gave no desired
product (Table 1, entries 5 and 6). To optimise the duration and
temperature of the reaction, the reaction was carried out at
times ranging from 4.5 to 24h and at temperatures ranging
from 40 to 80 °C. However, in DMF as solvent 4.5h was found
to be sufficient time to attain a 94% yield and an increase of
reaction temperature above 40 °C did not improve the yield,
which was probably due to side reactions. Furthermore, the
effect of the amount of 2-aminobenzoic acid was taken into
consideration and it was found that as little as 1.1 equiv. was
optimal to ensure a high reaction yield.
Isoselenocyanates are widely used in chemistry for prepar-
ing selenium-containing compounds as well as non-selenium-
containing compounds because of their low toxicity, relative
stability and excellent reactivity.11–16 Although there are many
reports of the preparation of selenium-containing deriva-
tives,12,13,15–17 only a few papers focus on the synthesis of non-
selenium-containing compounds.11,18 Thus, inspired by the
reported cyclodeselenization reactions, we have designed a
convenient method to obtain a series of non-selenium-contain-
ing compounds, 2-(arylamino)-4H-benzo[d][1,3]oxazin-4-
ones from various aryl isoselenocyanates and 2-aminobenzoic
acids via a cyclodeselenisation reaction.
On the basis of these results, the optimal conditions for the
efficient (94% yield) cyclisation reaction of 1 equiv. of 4-
methoxyphenyl isoselenocyanate were heating with 1.1 equiv.
2-aminobenzoic acid in DMF at 40 °C for 4.5h (Table 1, entry
10). The scope of this method was then evaluated using vari-
ously substituted phenyl isoselenocyanates 1 in reaction with
2-amino-, 2-amino-4-chloro, and 2-amino-3-methyl-benzoic
acid 2 to obtain 2-(arylamino)-4H-benzo[d][1,3]oxazin-4-ones
3 (Scheme 3). The yields obtained for all 23 cyclisations,
which were good to excellent, are shown in Table 2.
The five known compounds 3l–p were characterised by
comparison of their physical and spectral properties with
Scheme 1 Three synthetic routes to 4H-benzo[d][1,3]oxazin-4-ones.
* Correspondent. E-mail: pharmlab@zjut.edu.cn

352 JOURNAL OF CHEMICAL RESEARCH 2013
Scheme 2
Scheme 3
Table 1 Optimisation of reaction conditions for the cyclisation
reaction of 1 equiv. 4-methoxyphenyl isoselenocyanate and
2-aminobenzoic acid (see Scheme 2)
Table 2 Synthesis of 2-(arylamino)-4H-benzo[d][1,3]oxazin-4-
ones (see Scheme 3)
Entry
1 (R1)
2 (R2)
Product
Yield/%a
Entry 2-Aminobenzoic Solvent Temp
Time
/ha
Yield
/%b
acid/equiv.
/°C
1
2
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-EtOC6H4
C6H5
3-MeC6H4
4-MeC6H4
2-EtC6H4
3,5-MeC6H3
1-Naphthyl
C6H5
2-MeC6H4
3-MeC6H4
4-MeOC6H4
2,5-ClC6H3
1-Naphthyl
4-MeOC6H4
4-EtOC6H4
C6H5
2-EtC6H4
3-MeC6H4
4-MeC6H4
C4H9
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
96
98,97b
95
1
2
1
Pyridine
THF
EtOAc
EtOH
Toluene
60
60
60
60
60
6
75
71
3
1
6
4
89
3
1
6
6
62
5
84
4
1
83
6
80
5
1
12
24
4.5
4.5
4.5
4.5
4.5
None
None
93
7
72
6
1
CH2Cl2 Reflux
8
79,78b
74
7
1
DMF
DMF
DMF
DMF
DMF
40
60
80
40
40
9
8
1
91
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
52
9
1
86
84
10
11
1.1
1.3
94
87
94
H
83
a Reactions were monitored by TLC(petroleum ether/ethyl
acetate, 10:1).
H
80
H
94
b Isolated yield based on isoselenocyanate.
H
75
H
90
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
80
literature data.9,19 The 18 new compounds 3a–k, q–w, which
3s
3t
3u
3v
3w
None
75
1
72
all had similar structures to 3l–p showed very similar IR, H
NMR and 13C NMR spectral properties and, together with
HRMS data, were easily characterised.
64
63
69
From Table 2, it is clear that the nature of R1 group on the
isoselenocyanates greatly affected the reaction yields. Aryl
isoselenocyanates containing electron-withdrawing groups
reacted with 2-amino-3-methylbenzoic acid gave higher yields
than those containing electron-donating groups (Table 2,
entries 1–9). Also, the position of the substituent on the R1
group had an impact on the yields. The para- and ortho-substi-
tuted aryl isoselenocyanates gave higher yields than the
corresponding meta-substituted analogues when they reacted
with the same 2-aminobenzoic acid (Table 2, entries 7, 8,
13 and 14). In order to widen the scope of the reaction,
2-aminobenzoic acid and 2-amino-4-chlorobenzoic acid were
also investigated. Unsubstituted 2-aminobenzoic acid gave a
slightly better yield than 2-amino-3-methylbenzoic acid and
2-amino-4-chlorobenzoic acid (Table 2, entries 6, 12 and 20).
From the results in Table 2, it was also clear that 1-naphthyl
isoselenocyanate had good reactivity either with 2-amino-3-
methylbenzoic acid (entry 11) or with 2-aminobenzoic acid
(entry 17). An alkyl isoselenocyanate was treated with 2-
amino-4-chlorobenzoic acid (entry 24), but no product resulted.
It should be noted that the Se powder formed during the
reaction could be filtered off and used to prepare aryl iso-
selenocyanates without any loss in reactivity.11 For example,
2-(4-chlorophenylamino)-8-methyl-4H-benzo[d][1,3]oxazin-
4-one (3b) and 8-methyl-2-(4-tolylamino)-4H-benzo[d][1,3]-
oxazin-4-one (3h) were obtained in yields of 97 and 78%
(Table 2, entries 2 and 8, respectively) by using the aryl isose-
lenocyanates, 1b and 1h, prepared from recovered selenium.
A plausible mechanism is proposed for the formation of 4H-
benzo[d][1,3]oxazin-4-ones (Scheme 4). Firstly, 2-selenoure-
idobenzoic acid 3–1 was generated from aryl isoselenocyanate
1 and 2-aminobenzoic acid 2, which then underwent an
intramolecular cyclisation and produced the intermediate 3–2.
Finally, with the help of oxygen, the intermediate 3–2
converted to 4H-benzo[d][1,3]oxazin-4-one 3 via cyclodesele-
nisation.
none
a Isolated yields based on aryl isoselenocyanates.
b Using aryl isoselenocyanates prepared from recycled selenium
powder.
In conclusion, an efficient, mild and environmentally
friendly synthesis of 4H-benzo[d][1,3]oxazin-ones was
developed via cyclodeselenization of readily available aryl
isoselenocyanates and 2-aminobenzoic acids. A series of 4H-
benzo[d][1,3]oxazin-ones was obtained in good to excellent
yields. In addition, the Se powder formed during the reaction
could be recycled for preparation of the aryl isoselenocya-
nates.
Experimental
NMR spectra were obtained on a Varian 400 spectrometer (1H NMR
at 400MHz, and 13C NMR at 100 MHz) in CDCl3 or DMSO-d6 using
Scheme 4 Plausible mechanism for the formation of
2-(arylamino)-4H-benzo[d] [1,3]oxazin-4-ones.

JOURNAL OF CHEMICAL RESEARCH 2013 353
TMS as internal standard. Mass spectra (ESI-MS) were determined on
a Thermo Finigan LCQ-Advantage. High resolution electrospray
mass spectra (ESI-HRMS) were determined on an Agilent 6210 TOF
instrument. Electron impact (EI)-mass spectra (MS) were determined
on a Thermo Finnigan Trace DSQ instrument. High resolution
EI-mass spectra (EI-HRMS) were recorded on a Waters GCT Premier
instrument. Melting points were measured on a Büchi B-540 capillary
melting point apparatus. IR spectra were recorded in KBr discs on a
Nicolet Avatar-370 spectrometer. The three 2-aminobenzoic acids and
all solvents were available commercially. Formanilides were prepared
from phenylamine,20 and aryl isoselenocyanate were prepared by
Fernández-Bolaños’s method.11
2923, 1743, 1656, 1567, 1510, 1483, 1322, 1269, 1213, 1161, 1102,
1
1063, 1028, 868, 825, 793, 756, 694 cm−1; H NMR (DMSO-d6):
δ 10.34 (s, 1H), 7.84–7.81 (m, 2H), 7.79–7.76 (m, 1H), 7.62–7.59 (m,
1H), 7.22–7.18 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H), 2.42 (s, 3H) ppm; 13
C
NMR (DMSO-d6): δ 159.1 (C=O), 157.5 (1JCF = 237 Hz), 149.4,
147.4, 136.7, 134.4, 132.2, 125.3, 123.3, 120.4 (3JCF = 7 Hz), 115.1
(2JCF = 22 Hz), 113.3, 17.1 ppm; MS (ESI): m/z (%) = 269 (M− -1,100);
HRMS-ESI: Calcd for C15H10FN2O2 (M-H)− 269.0732; found: 269.0733.
2-(4-Chlorophenylamino)-8-methyl-4H-benzo[d][1,3]oxazin-4-
one (3b): White solid; m.p. 262.5–263.7 °C; IR: νmax = 3281, 3086,
2955, 1742, 1651, 1602, 1555, 1495, 1483, 1463, 1323, 1269, 1233,
1
1099, 1063, 1029, 1011, 818, 758, 695 cm−1; H NMR (DMSO-d6):
δ 10.45 (s, 1H), 7.86–7.84 (m, 2H), 7.82–7.80 (m, 1H), 7.66–7.64 (m,
Synthesis of aryl isoselenocyanates
1H), 7.44–7.42 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 2.46 (s, 3H) ppm; 13
C
A solution of 2-ethylaniline (25 mmol) and HCOOH (25 mmol) in
toluene (50 mL) was heated to reflux for 3h. Then the reaction mixture
was cooled to 0 °C and reacted with Et3N (75 mmol), Se powder
(35 mmol) and toluene containing triphosgene (25 mmol) for 30 min,
then the reaction was heated to reflux for 18h. After completion, the
reaction mixture was filtered and the combined filtrates were concen-
trated in vacuo to give a residue which was purified by column
chromatography (petroleum ether/ethyl acetate, 10:1) to afford 1u a
transparent liquid (3.78 g, 83%).
NMR (DMSO-d6): δ 159.0 (C=O), 149.2, 147.2, 137.0, 136.7, 132.3,
128.3, 126.2, 125.3, 123.6, 120.2, 113.4, 17.1 ppm; MS (ESI): m/z
(%) = 285 (M−-1,100), 287 (M−+1, 33); HRMS-ESI: Calcd for
C15H10ClN2O2 (M-H)− 285.0436; found: 285.0438.
2-(4-Bromophenylamino)-8-methyl-4H-benzo[d][1,3]oxazin-4-
one (3c): White solid; m.p. 281.0–281.9 °C; IR: νmax = 3280, 3084,
1741, 1652, 1602, 1554, 1491, 1463, 1323, 1269, 1234, 1062, 1028,
815, 758, 499, 491 cm−1; 1H NMR (DMSO-d6): δ 10.46 (s, 1H), 7.81–
7.78 (m, 3H), 7.65 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H,), 7.20
(t, J = 7.6 Hz, 1H), 2.45 (s, 3H,) ppm; 13C NMR(DMSO-d6): δ 159.0
(C=O), 149.2, 147.2, 137.4, 136.8, 132.4, 131.3, 125.4, 123.7, 120.7,
114.3, 113.5, 17.1 ppm; MS (ESI): m/z (%) = 329 (M−-1,100), 331
(M−+1, 100); HRMS-ESI: Calcd for C15H10BrN2O2 (M-H)− 328.9931;
found: 323.9938.
1-Isoselenocyanato-2-methylbenzene (1m): White solid; m.p. 31.4–
32.7 °C (lit.21 31–32 °C); IR: νmax = 3021, 2885, 2119, 2071, 1606,
1589, 1484, 1458, 1380, 1114, 1038, 754 cm−1; H NMR (CDCl3):
1
δ 7.21–7.15 (m, 4H), 2.38 (s, 3H) ppm.
1-Isoselenocyanato-4-methylbenzene (1h): White solid; m.p. 59.8–
61.9 °C (lit.21 66–68 °C); IR: νmax = 3026, 2913, 2154, 2068, 1897,
2-(4-Methoxyphenylamino)-8-methyl-4H-benzo[d][1,3]oxazin-4-
one (3d): White solid; m.p. 206.9–207.5 °C; IR: νmax = 3292, 3141,
2969, 1741, 1653, 1602, 1562, 1512, 1463, 1321, 1248, 1174, 1066,
1641, 1574, 1499, 1442, 1376, 1208, 856 cm−1; H NMR (CDCl3):
1
δ 7.15 (d, J=2.4 Hz, 4H), 2.35 (s, 3H) ppm.
1-Ethyl-2-isoselenocyanatobenzene (1u): Transparent liquid; IR:
νmax = 3069, 2967, 2931, 2872, 2111, 2061, 1597, 1574, 1482, 1449,
1375, 857, 788, 752, 625 cm−1; 1H NMR (CDCl3): δ 7.27–7.21
(m, 3H), 7.19–7.15 (m, 1H), 2.74 (q, 2H, J = 7.6 Hz), 1.26 (t,3H,
J = 7.6 Hz) ppm.
1
1029, 817, 758, 701 cm−1; H NMR (DMSO-d6): δ 10.13 (s, 1H),
7.77–7.75 (m, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 7.6 Hz, 1H),
7.12 (t, J = 7.6 Hz, 1H), 6.95–6.93 (m, 2H), 3.74 (s, 3H), 2.41 (s, 3H)
ppm; 13C NMR(DMSO-d6): δ 159.2 (C=O), 154.8, 149.6, 147.8,
136.6, 132.1, 131.0, 125.3, 123.0, 120.4, 113.7, 113.0, 55.1, 17.0
ppm; MS(ESI): m/z(%) = 281 (M−-1,100); HRMS-ESI: Calcd for
C16H13N2O3(M-H)− 281.0932; found: 281.0929.
1-Isoselenocyanato-4-methoxybenzene (1d): White solid; m.p. 48–
51 °C (lit.21 43–44 °C); IR: νmax = 2993, 2956, 2834, 2128, 2059, 1877,
1598, 1579, 1504, 1453, 1422, 1251, 1033, 853, 823 cm−1; H NMR
1
2-(4-Ethoxyphenylamino)-8-methyl-4H-benzo[d][1,3]oxazin-4-
one (3e): White solid; m.p. 240.6–242.2 °C; IR: νmax = 3292, 1759,
1738, 1637, 1598, 1513, 1461, 1324, 1293, 1222, 1182, 1053, 1029,
(CDCl3): δ 7.21 (d, J = 7.2 Hz, 2H), 6.84 (d, J = 7.2 Hz, 2H), 3.81 (s,
3H) ppm.
1-Isoselenocyanato-3,5-dimethylbenzene (1j): White solid; m.p.
1
925, 863, 838, 811, 757, 701 cm−1; H NMR (DMSO-d6): δ 10.15
30.4–31.6 °C; IR: νmax = 2916, 2118, 2087, 1604, 1589, 1467, 1377,
(s, 1H), 7.78 (d, J =7.2 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H) 7.61 (d,
J = 7.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 4.00
(q, J = 6.8 Hz, 2H), 2.42 (s, 3H), 1.32 (t, J = 6.8 Hz, 3H) ppm; 13C
NMR(DMSO-d6): δ 159.3, 154.0, 149.6, 147.9, 136.7, 132.1, 130.9,
125.4, 123.0, 120.3, 114.3, 113.1, 63.0, 17.1, 14.8 ppm; MS (ESI):
m/z (%) = 295 (M−-1,100); HRMS-ESI: Calcd for C17H15N2O3 (M-H)−
295.1088; found: 295.1093.
1
1298, 1037, 844, 701 cm−1; H NMR (CDCl3): δ 6.94 (s, 1H),6.90
(s, 2H), 2.29 (s, 6H) ppm; 13C NMR (CDCl3): δ 139.2, 129.8, 129.0,
128.0, 123.5, 21.1 ppm; MS (EI): m/z (%) = 211 (M+,100), 209 (50);
HRMS-EI: Calcd for C9H9NSe 210.9900; found: 210.9905.
1-Fluoro-4-isoselenocyanatobenzene (1ª): White solid; m.p. 45.8–
47.7 °C; IR: νmax = 3070, 2132, 1887, 1643, 1595, 1501, 1445, 1287,
1227, 1211, 1152, 1093, 1010, 862, 833, 778 cm−1; 1H NMR (CDCl3):
δ 7.28–7.24 (m, 2H), 7.07–7.03 (m, 2H) ppm.
8-Methyl-2-(phenylamino)-4H-benzo[d][1,3]oxazin-4-one (3f): White
solid m.p. 216.4–218.5 °C; IR: νmax = 3284, 3098, 2921, 1761, 1740,
1640, 1595, 1557, 1481, 1448, 1323, 1268, 1234, 1066, 1026, 756,
700 cm−1; 1H NMR (DMSO-d6): δ 10.31 (s, 1H), 7.83–7.79 (m, 3H),
7.63 (d, J = 7.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.17 (t, J = 7.6 Hz,
1H), 7.05 (t, J = 7.2 Hz, 1H), 2.45 (s, 3H) ppm; 13C NMR (DMSO-d6):
δ 159.2 (C=O), 149.4, 147.5, 138.0, 136.7, 132.3, 128.5, 125.4, 123.4,
122.6, 118.8, 113.4, 17.1 ppm; MS (ESI): m/z (%) = 251 (M−-1, 100);
HRMS-ESI: Calcd for C15H11N2O2(M-H)− 251.0826; found: 251.0828.
8-Methyl-2-(3-tolylamino)-4H-benzo[d][1,3]oxazin-4-one (3g):
White solid; m.p. 205.2–206.9 °C; IR: νmax = 3281, 3017, 2958, 1734,
1642, 1595, 1567, 1484, 1460, 1324, 1254, 1214, 1068, 773, 758, 689
cm−1; 1H NMR (DMSO-d6): δ 10.16 (s, 1H), 7.73–7.71 (m, 1H), 7.65
(s, 1H), 7.57–7.53 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.6 Hz,
1H), 6.82 (d, J = 7.6 Hz, 1H), 2.42 (s, 3H), 2.30 (s, 3H) ppm; 13C
NMR(DMSO-d6): δ 159.2 (C=O), 149.4, 147.6, 138.0, 137.6, 136.7,
132.3, 128.3, 125.4, 123.4, 123.3, 119.4, 116.0, 113.3, 21.4, 17.1
ppm; MS (ESI): m/z (%) = 265 (M−-1,100); HRMS-ESI: Calcd for
C16H13N2O2 (M-H)− 265.0983; found: 265.0987.
1-Chloro-4-isoselenocyanatobenzene (1b): White solid; m.p. 70.3–
73.2 °C (lit.21 70.5–71.5 °C); IR: νmax = 3076, 2144, 2059, 1887, 1636,
1482, 1429, 1402, 1290, 1162, 1085, 1011, 849, 824, 469 cm−1; H
1
NMR (CDCl3): δ 7.32 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H)
ppm.
1-Bromo-4-isoselenocyanatobenzene (1c): White solid; m.p. 80.5–
82.0 °C; IR: νmax = 3080, 2525, 2121, 2041, 1887, 1625, 1573, 1478,
1396, 1292, 1214, 1105, 1067, 844, 817, 657, 492 cm−1; H NMR
1
(CDCl3): δ 7.48 (d, J = 8.8 Hz, 2H),7.14 (d, J = 8.8 Hz, 2H) ppm.
1-Ethoxy-4-isoselenocyanatobenzene (1e): White solid; m.p. 95.4–
97.8 °C; IR: νmax = 2923, 2868, 2125, 1877, 1602, 1577, 1501, 1477,
1442, 1386, 1303, 1249, 1165, 1112, 1101, 1042, 923, 834, 821, 798
cm−1; 1H NMR (CDCl3): δ 7.20 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz,
2H), 4.01 (q, J = 6.8 Hz, 2H), 1.41 (t, J = 6.8 Hz, 3H) ppm.
Synthesis of 4H-benzo[d][1,3]oxazin-ones; general procedure
Aryl isoselenocyanate (1 mmol) was added to a solution of a 2-amino-
benzoic acid (1.1 mmol) in DMF (15 mL). The reaction mixture was
heated at 40 °C for 4.5h. After the completion of the reaction, the reac-
tion mixture was filtered and then washed with EtOAc (15 mL×2) to
obtain Se powder. The combined filtrates were concentrated in vacuo
and the residue was purified by column chromatography (petroleum
ether/ethyl acetate, 10:1) to afford a white solid.
8-Methyl-2-(4-tolylamino)-4H-benzo[d][1,3]oxazin-4-one (3h):
White solid; m.p. 213.9–216.5 °C; IR: νmax = 3290, 3086, 2918, 1761,
1738, 1731, 1641, 1613, 1598, 1550, 1456, 1325, 1266, 1235, 1062,
1030, 817, 757, 702 cm−1; 1H NMR (DMSO-d6): δ 10.13 (s, 1H), 7.71
(d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 6.4 Hz, 1H),
7.10–7.05 (m, 3H), 2.39 (s, 3H), 2.25 (s, 3H) ppm; 13C NMR(DMSO-
d6): δ 159.1 (C=O), 149.4, 147.6, 136.5, 135.4, 132.1, 131.5, 128.8,
2-(4-Fluorophenylamino)-8-methyl-4H-benzo[d][1,3]oxazin-4-
one (3a): White solid; m.p. 229.0–230.2 °C; IR: νmax = 3283, 3101,

354 JOURNAL OF CHEMICAL RESEARCH 2013
125.2, 123.1, 118.9, 113.1, 20.3, 17.0 ppm; MS (ESI): m/z (%) = 265
(M−-1,100); HRMS-ESI: Calcd for C16H13N2O2 (M-H)− 265.0983;
found: 265.0988.
137.0, 134.5, 133.5, 129.8, 128.9, 125.7, 125.4, 124.1, 120.7, 120.5,
114.3 ppm; MS (ESI): m/z (%) = 305 (M−-1, 100), 307 (M− +1, 65),
309 (M− +3, 12).
2-(Naphthalen-1-ylamino)-4H-benzo[d][1,3]oxazin-4-one (3q):
White solid; m.p. 208.5–209.7 °C; IR: νmax = 3436, 3272, 3051, 1751,
1645, 1610, 1571, 1478, 1268, 759, 704, 689 cm−1; 1H NMR (DMSO-
d6): δ 10.19 (s, 1H), 8.15–8.13 (m, 1H), 8.00–7.95 (m, 2H), 7.87 (d,
J = 8.0 Hz, 1H,), 7.77 (d, J = 8.0 Hz, 1H,), 7.70–7.66 (m, 1H), 7.60–
7.54 (m, 3H), 7.24 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H) ppm;
13C NMR (DMSO-d6): δ 159.2 (C=O), 150.6, 149.4, 138.0, 136.8,
128.6, 128.1, 124.6, 124.2, 123.8, 120.0, 116.7, 113.9 ppm; MS (ESI):
m/z (%) = 289 (M++1,100); HRMS-ESI: Calcd for C18H13N2O2 (M+H)+
289.0936; found 289.0938.
2-(2-Ethylphenylamino)-8-methyl-4H-benzo[d][1,3]oxazin-4-one
(3i): White solid; m.p. 124.1–125.2 °C; IR: νmax = 3363, 2961, 1767,
1753, 1650, 1594, 1553, 1456, 1322, 1266, 1235, 1205, 1063, 1026,
756, 739, 699 cm−1; 1H NMR (CDCl3): δ 8.25 (d, J = 8.0 Hz, 1H), 7.94
(d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.33–7. 25 (m, 2H),
7.18–7.13 (m, 2H), 6.59 (s, 1H), 2.70 (q, J = 7.6 Hz, 2H), 2.48 (s, 3H),
1.31 (t, J = 7.6 Hz, 3H) ppm; 13C NMR (DMSO-d6): δ 159.5 (C=O),
151.7, 148.2, 138.2, 136.7, 134.6, 132.0, 128.4, 125.9, 125.8, 125.7,
125.4 122.8, 112.8, 23.8, 16.8, 14.3 ppm; MS (ESI): m/z (%) = 281
(M++1,100); HRMS-ESI: Calcd for C17H17N2O2(M+H)+ 281.1285;
found: 281.1287.
2-(3,5-Dimethylphenylamino)-8-methyl-4H-benzo[d][1,3]oxazin-
4-one (3j): White solid; m.p. 244.2–246.3 °C; IR: νmax = 3283, 3123,
2914, 1728, 1641, 1596, 1570, 1484, 1460, 1327, 1280, 1214, 1071,
1015, 844, 760, 688 cm−1; 1H NMR (DMSO-d6): δ 10.18 (s, 1H), 7.79
(d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.48 (s, 2H), 7.17 (t, J =
7.6 Hz, 1H), 6.70 (s, 1H), 2.44 (s, 3H), 2.27 (s, 6H) ppm; 13C NMR
(DMSO-d6): δ 159.1 (C=O), 149.3, 147.5, 137.8, 137.3, 136.6, 132.2,
125.3, 124.0, 123.2, 116.6, 113.2, 21.2, 16.8 ppm; MS (ESI): m/z (%)
=279(M−-1,100);HRMS-ESI:CalcdforC17H15N2O2(M-H)− 279.1139;
found: 279.1148.
8-Methyl-2-(Naphthalen-1-ylamino)-4H-benzo[d][1,3]oxazin-4-
one (3k): White solid; m.p. 201.8–203.0 °C; IR: νmax = 3373, 3052,
1763, 1643, 1608, 1563, 1484, 1458, 1327, 1261, 1206, 1066, 1014,
784, 758, 702 cm−1; 1H NMR (DMSO-d6): δ 10.18 (s, 1H), 8.17 (dd,
1H, J1 = 3.6 Hz, J2 = 6.0 Hz), 7.94 (d, J = 6.8 Hz, 2H), 7.78 (t, J =
6.8 Hz, 2H), 7.56–7.52 (m, 4H), 7.12 (t, J = 7.6 Hz, 1H), 2.22 (s, 3H)
ppm; 13C NMR (DMSO-d6): δ 159.4 (C=O), 151.6, 147.9, 136.6,
133.5, 132.6, 132.1, 127.81, 127.75, 125.8, 125.6, 125.4, 125.3, 125.2,
123.0, 122.7, 121.6, 113.1, 16.8 ppm; MS (ESI): m/z (%) = 301 (M− -
1, 100); HRMS-ESI: Calcd for C19H13N2O2 (M-H)− 301.0983; found:
301.0988.
7-Chloro-2-(4-methoxyphenylamino)-4H-benzo[d][1,3]oxazin-4-
one (3r): White solid; m.p. 195.0–197.5 °C; IR: νmax = 3293, 3100,
1739, 1648, 1604, 1567, 1513, 1461, 1329, 1248, 1231, 1183, 1078,
1040, 933, 862, 821, 768, 723 cm−1; 1H NMR (DMSO-d6): δ 10.24 (s,
1H), 7.89 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H),
7.23 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 6.91(d, J = 8.4 Hz, 2H), 3.73
(s, 3H) ppm; 13C NMR(DMSO-d6): δ = 158.3 (C=O), 155.3, 151.5,
150.8, 141.0, 130.3, 129.7, 123.6, 123.3, 121.4, 113.8, 112.3, 55.2
ppm; MS (ESI): m/z (%) = 301 (M−-1,100), 303 (M−+1,33); HRMS-
ESI: Calcd for C15H10ClN2O3 (M-H)− 301.0385; found: 301.0398.
7-Chloro-2-(4-ethoxyphenylamino)-4H-benzo[d][1,3]oxazin-4-
one (3s): White solid; m.p. 166.6–171.4 °C; IR: νmax = 3445, 3291,
2975, 1738, 1645, 1604, 1566, 1512, 1459, 1443, 1390, 1248, 1229,
1
1179, 1079, 1052, 934, 872, 824, 768 cm−1; H NMR (DMSO-d6):
δ 10.26 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.35
(d, J = 2.0 Hz, 1H), 7.25 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H), 6.92–6.90
(m, 2H), 4.00 (q, J = 6.8 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H) ppm; 13C
NMR(DMSO-d6): δ 158.3 (C=O), 154.5, 151.5, 150.9, 141.0, 130.3,
129.7, 123.6, 123.4, 121.3, 114.3, 112.4, 63.1, 14.8 ppm; MS (ESI):
m/z (%) = 315 (M−-1,100), 317 (M−+1,32); HRMS-ESI: Calcd for
C16H12ClN2O3 (M-H)− 315.0542; found: 315.0542.
7-Chloro-2-(phenylamino)-4H-benzo[d][1,3]oxazin-4-one
(3t):
White solid; m.p. 232.0–233.8 °C; IR: νmax = 3448, 3285, 3147, 1736,
1659, 1592, 1567, 1499, 1459, 1334, 1264, 1232, 1199, 1080, 1057,
932, 870, 856, 770, 746, 700 cm−1; 1H NMR (DMSO-d6): δ = 10.42 (s,
1H), 7.93 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.42 (d, J =
2.0 Hz, 1H), 7.37–7.33 (m, 2H), 7.29 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz,
1H), 7.08 (t, J = 7.2 Hz, 1H) ppm; 13C NMR (DMSO-d6): δ 158.1
(C=O), 151.2, 150.5, 141.0, 137.4, 129.6, 128.5, 124.0, 123.5, 123.1,
119.6, 112.6 ppm; MS (ESI): m/z (%) = 271 (M−-1,100), 273 (M−
+1,34); HRMS-ESI: Calcd for C14H8ClN2O2 (M-H)− 271.0280; found:
271.0301.
2-(Phenylamino)-4H-benzo[d][1,3]oxazin-4-one (3l): White solid;
m.p. 190.9–192.3 °C (lit.9 191–193 °C); IR: νmax = 3273, 3140, 3095,
1
2925, 1741, 1637, 1596, 1474, 1445, 1242, 1021, 769, 706 cm−1; H
NMR (DMSO-d6): δ 10.31 (s, 1H), 7.98 (dd, J1 = 1.6 Hz, J2= 8.0 Hz,
1H), 7.80–7.74 (m, 3H), 7.37 (t, J = 8.0 Hz, 3H), 7.30 (t, J = 7.6 Hz,
1H), 7.08 (t, J = 7.6 Hz, 1H,) ppm; 13C NMR (DMSO-d6): δ 159.3
(C=O), 150.3, 149.2, 136.9, 136.7, 129.2, 128.8, 125.0, 124.8, 124.3,
119.9, 114.0 ppm; MS (ESI): m/z (%) = 239 (M++1,100).
2-(2-Tolylamino)-4H-benzo[d][1,3]oxazin-4-one (3m): White solid;
m.p. 154.6–156.1 °C (lit.9 153–155 °C); IR: νmax = 3281, 3064, 1769,
7-Chloro-2-(2-ethylphenylamino)-4H-benzo[d][1,3]oxazin-4-one
(3u): White solid; m.p. 158.0–160.0 °C; IR: νmax = 3436.64, 3293.14,
2964.49, 1754.92, 1649.95, 1604.65, 1587.20, 1565.40, 1460.25,
1
1681, 1662, 1608, 1541, 1446, 1288, 1242, 1035, 752, 740 cm−1; H
NMR (DMSO-d6): δ 10.23 (s, 1H), 7.98–7.96 (m, 1H), 7.78–7.74 (m,
1H), 7.63 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.39–7.37 (m, 1H), 7.31–
7.23 (m, 2H), 6.91–6.89 (m, 1H,), 2.32 (s, 3H) ppm; 13C NMR
(DMSO-d6): δ 159.2 (C=O), 150.6, 149.4, 138.0, 136.8, 128.6, 128.1,
124.6, 124.2, 123.8, 120.0, 116.7, 113.9, 21.3; MS (ESI): m/z (%) =
253 (M++1,100).
1
1239.24, 1077.61, 878, 765.19, 740 cm−1; H NMR (DMSO-d6): δ
9.81 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.41–7.39 (m, 1H), 7.30–7.28
(m, 1H), 7.25–7.20 (m, 4H), 2.64 (q, J = 7.2 Hz, 2H), 1.14 (t, J =
7.2 Hz, 3H) ppm; 13C NMR(DMSO-d6): δ 158.5 (C=O), 153.6, 151.3,
141.1, 139.3 134.0, 129.8, 128.5, 127.1, 126.5, 126.1, 123.4, 123.0,
112.0, 23.8, 14.4 ppm; MS (ESI): m/z (%) = 301 (M++1,100), 303
(M++3,33); HRMS-ESI: Calcd for C16H14ClN2O2 (M+H)+ 301.0738;
found: 301.0747.
7-Chloro-2-(3-tolylamino)-4H-benzo[d][1,3]oxazin-4-one (3v):
White solid; m.p. 213.6–216.2 °C; IR: νmax = 3437, 3289, 3060, 2920,
1734, 1662, 1607, 1596, 1574, 1495, 1463, 1443, 1334, 1250, 1227,
1061, 937, 895, 871, 777, 713 cm−1; 1H NMR(DMSO-d6): δ 10.35 (s,
1H), 7.92 (d, J = 8.4 Hz, 1H), 7.58–7.55 (m, 2H), 7.41 (d, J = 2.0 Hz,
1H), 7.27 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H), 7.22 (t, J = 8.0 Hz 1H),
6.90 (d, J = 7.2 Hz, 1H), 2.32 (s, 3H) ppm; 13C NMR(DMSO-d6):
δ 158.1 (C=O), 151.1, 150.5, 141.0, 137.7, 137.3, 129.6, 128.3,
123.91, 123.85 123.5, 120.0, 116.7, 112.6, 21.3 ppm; MS (ESI):
m/z (%) = 285 (M−-1,100), 287 (M−+1,33); HRMS-ESI: Calcd for
C15H10ClN2O2 (M-H)− 285.0436; found: 285.0438.
7-Chloro-2-(4-tolylamino)-4H-benzo[d][1,3]oxazin-4-one (3w):
White solid; m.p. 220–221 °C; IR: νmax = 3432, 3289, 3137, 2916,
1728, 1641, 1598, 1550, 1514, 1483, 1456, 1324, 1266, 1234, 1062,
1030, 817, 757, 702 cm−1; 1H NMR (DMSO-d6): δ 10.32 (s, 1H), 7.90
(d, J = 8.4 Hz, 1H), 7.61 (d, J =8.4 Hz, 2H) 7.35 (d, J = 2.0 Hz, 1H),
7.24 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 2.0 Hz, 1H), 7.14 (d, J =8.0 Hz, 2H),
2.28 (s, 3H) ppm; 13C NMR(DMSO-d6): δ 158.2 (C=O), 151.2, 150.6,
141.0, 134.8, 132.1, 129.6, 128.9, 123.8, 123.4, 119.6, 112.4, 20.5
ppm; MS (ESI): m/z (%) = 285 (M−-1,100), 287 (M−+1,43); HRMS-
ESI: Calcd for C15H10ClN2O2 (M-H)− 285.0436; found: 285.0432.
2-(3-Tolylamino)-4H-benzo[d][1,3]oxazin-4-one (3n): White solid;
m.p. 176.4–178.2 °C (lit.19 180–182 °C); IR: νmax = 3277, 3153, 3106,
1735, 1644, 1571, 1477, 1330, 1068, 765, 686 cm−1; 1H NMR (CDCl3):
δ 8.10 (dd, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H), 7.71–7.67 (m, 1H), 7.51
(d, J = 8.0 Hz, 1H,), 7.43–7.41 (m, 2H), 7.30–7. 24 (m, 2H), 6.97 (d,
J = 7.6 Hz, 1H,), 2.39 (s, 3H) ppm; 13C NMR (DMSO-d6): δ 159.6,
150.2, 149.5, 139.1, 136.8, 136.7, 129.0, 128.8, 125.1, 124.7, 120.5,
117.1, 114.0, 21.6 ppm; MS (ESI): m/z (%) = 253(M++1,100).
2-(4-Methoxyphenylamino)-4H-benzo[d][1,3]oxazin-4-one (3o):
White solid; m.p. 192.9–194.4 °C (lit9. 193–195 °C); IR: νmax = 3275,
2827, 1749, 1631, 1601, 1475, 1238, 1171, 1022, 765 cm−1; 1H NMR
(DMSO-d6): δ 10.13 (s, 1H), 7.95 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H),
7.76–7.71 (m, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.0 Hz, 1H),
7.28–7.23 (m, 1H), 6.96–6.94 (m, 2H), 3.75 (s, 3H) ppm; 13C NMR
(DMSO-d6): δ 159.2, 155.3, 150.9, 149.7, 136.7, 130.9, 128.0, 124.3,
123.8, 121.3, 114.0, 113.6, 55.2 ppm; MS (ESI): m/z (%) = 269
(M++1,100).
2-(2,5-Dichlorophenylamino)-4H-benzo[d][1,3]oxazin-4-one (3p):
White solid; m.p. 167.1–168.3 °C (lit.19 179–181 °C); IR: νmax = 3379,
3306, 3093, 1774, 1645, 1588, 1534, 1475, 1410, 1267, 1209, 1048,
1
884, 808, 759 cm−1. H NMR (DMSO-d6): δ 10.02 (s, 1H), 7.96 (d,
J = 7.2 Hz, 1H), 7.76–7.72 (m, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.33–
7.24 (m, 4H) ppm; 13C NMR (DMSO-d6): δ 158.7, 148.9, 148.2,

JOURNAL OF CHEMICAL RESEARCH 2013 355
9
J. Garin, E. Melendez, F.L. Merchan, T. Tejero and E. Villarroya, Synthesis,
1983, 406.
Received 8 February 2013; accepted 24 March 2013
Paper 1301782 doi: 10.3184/174751913X13686242406479
Published online: 12 June 2013
10 P. Molina, E. Aller, M. Ecija and A. Lorenzo, Synthesis, 1996, 690.
11 J.G. Fernández-Bolaños, Ó. López, V. Ulgar, I. Maya and J. Fuentes,
Tetrahedron Lett., 2004, 45, 4081.
12 G.L. Sommen, A. Linden and H. Heimgartner, Eur. J. Org. Chem., 2005,
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