A simple one-pot synthesis of benzoxazine-2,4-diones and benzothiazine-2,4-diones

Article abstract of DOI:10.3987/com-02-s2

A simple and efficient procedure has been developed for a one-pot synthesis of substituted benzoxazine-2,4-diones and benzothiazine-2,4-diones directly from salicylic acid (or thiosalicylic acid) and amines.

Full text of DOI:10.3987/com-02-s2

HETEROCYCLES, Vol. 59, No. 1, 2003, pp. 115 - 128, Received, 12th February, 2002
A SIMPLE ONE-POT SYNTHESIS OF
BENZOXAZINE- 2,4-DIONES AND
BENZOTHIAZINE-2,4-DIONES †
Xiaoxiang Zhu,a Qian-sheng Yu,a Nigel H. Greig,a* , Judith L. Flippen-
Anderson,b and Arnold Brossi c
aDrug Design & Development Section, Laboratory of Neurosciences,
Gerontology Research Center (4E02), National Institute on Aging Intramural
Program, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore,
Maryland 21224-6825, USA
bLaboratory for the Structure of Matter, Naval Research Laboratory, 4555
Overlook Ave, SW Washington, D.C. 20375, USA
cSchool of Pharmacy, University of North Carolina at Chapel Hill, North Carolina
27599-7361, USA
Abstract  A simple and efficient procedure has been developed for a one-pot
synthesis of substituted benzoxazine-2,4-diones and benzothiazine-2,4-diones
directly from salicylic acid (or thiosalicylic acid) and amines.
Synthetic chemists are becoming increasingly interested in the synthesis of substituted benzoxazine-2,4-
diones due to their utility in pharmacology1-4 and photography.5 Hence, considerable effort has been
devoted to the preparation of benzoxazine-2,4-diones by using a wide variety of synthetic approaches,
including palladium-catalyzed cyclocarbonylation of o-iodophenols with heterocumulenes,6 reaction of
phenyl salicylate with isocyanates,7 cyclization of salicylic acid with isothiocyanate in the presence of
silver trifluoroacetate,8 preparation from salicylamide9 and other methods.10 In this paper, we describe a
new and efficient process for the synthesis of substituted benzoxazine-2,4-diones in one pot directly from
salicylic acid and amines.
Initially, compound (4a) was prepared by cyclization of salicylamide with ethyl chloroformate according
to the known procedure,11 which took three steps from commercially available acetylsalicyloyl chloride.
Scheme 1 illustrates this synthetic approach. Reaction of acetylsalicyloyl chloride with 3,4-

*Corresponding Author. Fax: 410-558-8278; e-mail: greign@vax.grc.nia.nih.gov
†This paper is dedicated to Professor Y. Kanaoka, Toyama Women’s College, 444 Gankaiji, Toyama,
Japan, on the occasion of his 75th birthday

dimethoxyphenethylamine was carried out to give acetylsalicylamide (2a), and then compound (2a) was
deacetylated with triethylamine/methanol to afford salicylamide (3a). Compound (3a) was cyclized with
ethyl chloroformate to give compound (4a).
We realized that the existing methods include multi-step procedures, use of expensive catalyst or
conversion of amine to isocyanates for synthesis of benzoxazine-2,4-dione derivatives, which provided us
impetus to develop a simple and practical method to synthesize benzoxazine-2,4-dione derivatives. We
found that benzoxazine-2,4-dione derivatives could be prepared in a one-pot reaction directly from
salicylic acid and amines (Scheme 1). Salicylic acid was treated with ethyl chloroformate and the reaction
mixture was evaporated at reduced pressure to remove unreacted ethyl chloroformate. Stirring the
resulting residue with amines in the presence of triethylamine afforded the substituted benzoxazine-2,4-
diones (4a-4f), whose structures have been confirmed by NMR and MS spectrometries.
O
O
COCl
R
R
RNH2
N
H
N
Et3N/MeOH
H
OCOMe
OCOMe
OH
3a
1
2a
ClCOOEt
O
O
1) ClCOOEt
2) H2NR
R
N
OH
OH
O
O
4a-4f
a, R = 3,4-dimethoxyphenethyl b, R = benzyl c, R = 3,4-dimethylphenyl
d, R = 3-indolylethyl e, R = 2,6-dimethoxypyridin-3-yl f, R = 4-imidazolylethyl
Scheme 1
The mechanistic scheme for the one-pot synthesis of benzoxazine-2,4-dione is proposed in Scheme 2.
Initially, we attempted to characterize the structures of intermediates produced by the reaction of salicylic
acid with ethyl chloroformate. In this regard, salicylic acid was stirred with ethyl chloroformate in the
presence of triethylamine at 0°C, the solvent then was evaporated under vacuum and the residue was
extracted with ether and concentrated to obtain crude intermediate. The resulting liquid intermediate,
however, proved hard to handle and we failed to acquire pure intermediate for further structure
identification. We therefore modified the procedure to use 5-nitrosalicylic acid as the starting material for
reaction with ethyl chloroformate in a dry ice-acetone bath. The resulting intermediate could be
recrystallized from ether, and X-Ray crystallographic analysis (Figure 1) confirmed it to be anhydride (6).
The results of the X-Ray study are illustrated in Figure 1. Most of the molecule is essentially planar.
Excluding the 6 atoms in the O1 to C9 chain, the remainder of the molecule is planar (rms deviation of
0.21 Å for the 17 atoms). The O1 to C9 chain itself is planar (rms deviation of 0.05 Å) and is

approximately perpendicular to the plane through the rest of the molecule (the dihedral angle between the
two planes is ~97 °). Both chains (O1 to C9 and C10 to C13) extend away from the aromatic ring with a
dihedral angle of ~120 ° between the best planes through the two chains. There is one close
intermolecular approach of 3.05 Å between C4 and O6 in a neighboring molecule (Tables 2, 3, 4, 5 and 6).
Figure 1, X-Ray structure of anhydride (6), drawn using experimentally determined coordinates with the
thermal ellipsoids at the 20% probability level.
Depending on the nucleophilicity of the specific amines and reaction temperature, the reaction of
anhydride (6) with amines may produce benzoxazine-2,4-diones (7) and/or salicylic amide (8) (Scheme 2
and Table 1). This results from nucleophilic attack on the anhydride or ethoxycarbonyl group in the
intermediate (6) by amines.
O
O
O
O
O
O2N
O
O
R
R
O2N
O2N
O2N
N
H
OH
N
OH
OH
O
+
O
O
O
O
8a-8c
7a-7c
5
6
a R = 3,4-dimethylphenyl, b R = 3,4-dimethoxyphenethyl, c R = n-butyl
Scheme 2
Table 1. Reaction of anhydride (6) with amines
Amine
Reaction temperature
0°C to rt
7
8
3,4-Dimethylaniline
3,4-Dimethoxyphenethylamine
n-Butylamine
69%
9%
0%
63%
0%
0°C to rt
0°C
79%

Table 2. Crystal data and structure refinement for Molecule (6).
Empirical formula
Formula weight
Temperature
C13 H13 N O9
327.24
273(2) K
Wavelength
1.54178 Å
Crystal system
Space group
Monoclinic
P2(1)/c
α= 90°.
Unit cell dimensions
a = 12.394(5) Å
b = 7.873(3) Å
c = 15.588(5) Å
1459.0(9) Å3
4
β= 106.43(3)°.
γ = 90°.
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
1.490 Mg/m3
1.120 mm-1
680
Crystal size
0.09 x 0.22 x 0.50 mm3
3.72 to 66.83°.
Theta range for data collection
Index ranges
-13<=h<=14, -8<=k<=9, -14<=l<=17
6860
Reflections collected
Independent reflections
Completeness to theta = 66.83°
Absorption correction
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
Extinction coefficient
Largest diff. peak and hole
2449 [R(int) = 0.0427]
94.0 %
None
Full-matrix least-squares on F2
2449 / 53 / 417
1.030
R1 = 0.0476, wR2 = 0.1298
R1 = 0.0560, wR2 = 0.1443
0.0168(11)
0.168 and -0.201 e.Å-3

4
2
3
Table 3. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters (Å x 10 )
ij
for Molecule (6). U(eq) is defined as one third of the trace of the orthogonalized U tensor.
x
y
z
U(eq)
O(1)
5722(1)
4809(1)
1791(1)
4352(1)
6949(1)
7480(1)
3356(1)
2861(1)
4286(1)
5885(1)
3330(1)
6435(1)
4314(1)
6758(1)
7337(1)
1354(1)
8643(1)
1396(1)
9288(2)
4804(1)
6540(1)
8168(2)
8665(2)
5727(2)
4816(2)
1793(3)
4352(3)
6954(3)
7482(2)
3349(3)
2861(3)
4291(3)
5881(2)
3323(3)
6447(5)
4312(4)
6765(2)
7331(3)
1294(4)
713(1)
449(1)
9462(1)
8717(1)
6671(1)
8498(1)
8652(1)
10149(1)
7816(1)
7380(1)
8854(1)
9490(1)
7576(1)
9329(1)
8260(1)
9349(1)
10455(1)
6522(1)
10188(1)
6253(1)
11151(1)
8945(1)
9730(1)
10802(1)
11762(1)
9466(2)
8718(3)
6674(3)
8495(3)
8656(2)
10154(2)
7819(3)
7387(3)
8838(4)
9489(3)
7603(4)
9314(3)
8282(4)
9348(2)
10458(2)
6569(5)
54(1)
51(1)
70(1)
49(1)
71(1)
64(1)
54(1)
57(1)
75(1)
63(1)
62(1)
69(1)
60(1)
55(1)
71(1)
94(1)
76(1)
98(1)
92(1)
55(1)
58(1)
83(1)
92(1)
82(2)
69(2)
97(4)
61(2)
113(3)
90(2)
69(2)
85(4)
103(2)
87(2)
81(3)
98(3)
86(3)
90(3)
98(2)
100(3)
C(1)
N(1)
-40(2)
C(2)
-1165(2)
256(2)
O(2)
O(3)
665(2)
C(3)
-1312(2)
134(2)
C(4)
O(4)
-4081(1)
-2645(1)
1736(2)
-5365(2)
1883(2)
524(2)
O(5)
C(5)
O(6)
C(6)
C(7)
O(7)
-3661(1)
-1411(2)
376(3)
O(8)
C(8)
O(9)
1236(2)
310(4)
C(9)
C(10)
C(11)
C(12)
C(13)
O(1A)
C(1A)
N(1A)
C(2A)
O(2A)
O(3A)
C(3A)
C(4A)
O(4A)
O(5A)
C(5A)
O(6A)
C(6A)
C(7A)
O(7A)
O(8A)
-2802(2)
-4074(2)
-4996(2)
-4730(3)
-685(5)
-437(2)
-2(3)
1172(2)
-224(12)
-618(9)
1301(3)
-153(3)
4096(4)
2653(3)
-1756(3)
5356(4)
-1884(3)
-548(12)
3681(4)
1324(4)

C(8A)
8648(2)
1389(6)
9299(4)
4809(2)
6534(3)
8152(4)
8728(9)
-378(18)
-1306(5)
-360(30)
2817(3)
4085(4)
5035(7)
4694(15)
10192(2)
6288(6)
11154(3)
8928(3)
9731(3)
10799(3)
11740(4)
115(5)
177(6)
159(9)
79(2)
O(9A)
C(9A)
C(10A)
C(11A)
C(12A)
C(13A)
81(3)
155(6)
176(10)
Table 4. Bond lengths [Å] and angles [°] for Molecule (6)
O(1)-C(7)
O(1)-C(1)
C(1)-C(6)
C(1)-C(2)
N(1)-O(8)
N(1)-O(9)
N(1)-C(4)
C(2)-C(3)
C(2)-C(10)
O(2)-C(7)
O(3)-C(7)
O(3)-C(8)
C(3)-C(4)
C(4)-C(5)
O(4)-C(10)
O(5)-C(10)
O(5)-C(11)
C(5)-C(6)
O(6)-C(11)
O(7)-C(11)
O(7)-C(12)
C(8)-C(9)
C(12)-C(13)
1.3524(16)
1.3886(16)
1.3819(18)
1.3941(17)
1.2004(18)
1.2224(18)
1.4727(18)
1.3874(18)
1.4960(17)
1.1944(18)
1.3181(15)
1.4433(19)
1.3780(19)
1.386(2)
O(1A)-C(7A)
1.353(2)
1.389(2)
1.382(2)
1.394(2)
1.201(3)
1.223(3)
1.473(2)
1.388(2)
1.496(2)
1.195(2)
1.319(2)
1.443(3)
1.378(2)
1.387(3)
1.181(2)
1.375(2)
1.377(2)
1.379(3)
1.182(3)
1.315(2)
1.466(3)
1.489(3)
1.464(3)
O(1A)-C(1A)
C(1A)-C(6A)
C(1A)-C(2A)
N(1A)-O(8A)
N(1A)-O(9A)
N(1A)-C(4A)
C(2A)-C(3A)
C(2A)-C(10A)
O(2A)-C(7A)
O(3A)-C(7A)
O(3A)-C(8A)
C(3A)-C(4A)
C(4A)-C(5A)
O(4A)-C(10A)
O(5A)-C(10A)
O(5A)-C(11A)
C(5A)-C(6A)
O(6A)-C(11A)
O(7A)-C(11A)
O(7A)-C(12A)
C(8A)-C(9A)
C(12A)-C(13A)
1.1813(16)
1.3739(16)
1.3763(16)
1.379(2)
1.1808(18)
1.3149(17)
1.464(2)
1.489(2)
1.464(3)
C(7)-O(1)-C(1)
C(6)-C(1)-O(1)
C(6)-C(1)-C(2)
O(1)-C(1)-C(2)
O(8)-N(1)-O(9)
116.96(11)
116.50(11)
121.90(12)
121.30(11)
123.00(14)
C(1)-C(2)-C(10)
C(7)-O(3)-C(8)
C(4)-C(3)-C(2)
C(3)-C(4)-C(5)
C(3)-C(4)-N(1)
126.78(11)
115.46(12)
119.00(13)
122.86(13)
118.28(12)

O(8)-N(1)-C(4)
119.37(12)
117.63(13)
118.36(11)
114.83(11)
128.24(13)
125.30(12)
106.45(11)
114.76(12)
107.07(15)
123.60(11)
123.98(12)
112.41(10)
127.70(14)
126.29(13)
105.86(11)
108.87(17)
117.0(2)
C(5)-C(4)-N(1)
118.86(12)
119.42(10)
118.07(13)
119.77(13)
126.7(2)
115.5(2)
119.0(2)
122.9(2)
118.5(2)
118.5(2)
119.0(2)
118.0(2)
119.8(2)
128.1(3)
125.2(3)
106.2(2)
114.3(3)
107.1(3)
123.4(3)
124.1(2)
112.32(19)
127.5(3)
126.0(3)
106.2(2)
108.8(3)
O(9)-N(1)-C(4)
C(10)-O(5)-C(11)
C(3)-C(2)-C(1)
C(6)-C(5)-C(4)
C(3)-C(2)-C(10)
O(2)-C(7)-O(3)
C(5)-C(6)-C(1)
C(1A)-C(2A)-C(10A)
C(7A)-O(3A)-C(8A)
C(4A)-C(3A)-C(2A)
C(3A)-C(4A)-C(5A)
C(3A)-C(4A)-N(1A)
C(5A)-C(4A)-N(1A)
C(10A)-O(5A)-C(11A)
C(6A)-C(5A)-C(4A)
C(5A)-C(6A)-C(1A)
O(2A)-C(7A)-O(3A)
O(2A)-C(7A)-O(1A)
O(3A)-C(7A)-O(1A)
C(11A)-O(7A)-C(12A)
O(3A)-C(8A)-C(9A)
O(4A)-C(10A)-O(5A)
O(4A)-C(10A)-C(2A)
O(5A)-C(10A)-C(2A)
O(6A)-C(11A)-O(7A)
O(6A)-C(11A)-O(5A)
O(7A)-C(11A)-O(5A)
C(13A)-C(12A)-O(7A)
O(2)-C(7)-O(1)
O(3)-C(7)-O(1)
C(11)-O(7)-C(12)
O(3)-C(8)-C(9)
O(4)-C(10)-O(5)
O(4)-C(10)-C(2)
O(5)-C(10)-C(2)
O(6)-C(11)-O(7)
O(6)-C(11)-O(5)
O(7)-C(11)-O(5)
O(7)-C(12)-C(13)
C(7A)-O(1A)-C(1A)
C(6A)-C(1A)-O(1A)
C(6A)-C(1A)-C(2A)
O(1A)-C(1A)-C(2A)
O(8A)-N(1A)-O(9A)
O(8A)-N(1A)-C(4A)
O(9A)-N(1A)-C(4A)
C(3A)-C(2A)-C(1A)
C(3A)-C(2A)-C(10A)
116.4(2)
122.0(2)
121.1(2)
122.7(3)
119.4(3)
117.3(3)
118.24(18)
115.04(18)
Table 5. Anisotropic displacement parameters (Å2x 103)for Molecule (6). The anisotropic
displacement factor exponent takes the form: -2p2[ h2a*2U11 + ... + 2 h k a* b* U12
]
U11
U22
U33
U23
U13
U12
O(1)
C(1)
N(1)
C(2)
O(2)
O(3)
C(3)
56(1)
56(1)
58(1)
55(1)
72(1)
57(1)
57(1)
58(1)
53(1)
87(1)
49(1)
88(1)
77(1)
54(1)
49(1)
47(1)
61(1)
46(1)
60(1)
58(1)
53(1)
-8(1)
-3(1)
3(1)
17(1)
19(1)
7(1)
-6(1)
0(1)
5(1)
1(1)
18(1)
29(1)
15(1)
16(1)
0(1)
-8(1)
-6(1)
-2(1)
-6(1)
-2(1)
-3(1)

C(4)
56(1)
65(1)
59(1)
74(1)
73(1)
73(1)
58(1)
65(1)
68(1)
58(1)
92(1)
66(1)
56(1)
62(1)
64(1)
82(1)
75(3)
83(5)
110(8)
70(5)
108(6)
72(4)
75(5)
81(7)
77(4)
77(3)
87(6)
96(5)
100(6)
67(5)
81(4)
86(5)
75(7)
184(12)
84(10)
77(5)
79(5)
67(1)
57(1)
48(1)
96(1)
67(1)
57(1)
65(1)
63(1)
58(1)
69(1)
103(1)
78(1)
82(1)
84(2)
53(1)
56(1)
87(2)
82(1)
69(3)
61(4)
104(9)
61(4)
87(6)
74(4)
67(5)
81(7)
137(5)
91(4)
70(6)
112(6)
101(7)
100(7)
93(4)
77(5)
118(9)
143(9)
126(13)
83(5)
69(5)
91(7)
150(16)
0(1)
11(1)
5(1)
15(1)
10(1)
5(1)
9(1)
-9(1)
-2(1)
10(1)
5(1)
O(4)
O(5)
53(1)
C(5)
55(1)
8(1)
20(1)
15(1)
23(1)
22(1)
2(1)
O(6)
66(1)
-4(1)
0(1)
C(6)
48(1)
53(1)
-1(1)
-5(1)
5(1)
C(7)
-4(1)
-5(1)
-5(1)
-1(1)
17(1)
-3(1)
1(1)
O(7)
68(1)
O(8)
92(1)
-7(1)
22(1)
0(1)
-5(1)
2(1)
C(8)
96(1)
O(9)
103(1)
121(2)
54(1)
23(1)
5(1)
C(9)
10(1)
15(1)
19(1)
2(1)
C(10)
C(11)
C(12)
C(13)
O(1A)
C(1A)
N(1A)
C(2A)
O(2A)
O(3A)
C(3A)
C(4A)
O(4A)
O(5A)
C(5A)
O(6A)
C(6A)
C(7A)
O(7A)
O(8A)
C(8A)
O(9A)
C(9A)
C(10A)
C(11A)
-4(1)
0(1)
57(1)
5(1)
86(1)
8(1)
7(1)
98(1)
3(1)
-2(1)
14(3)
22(4)
45(7)
20(3)
44(4)
16(3)
27(4)
24(6)
13(4)
1(3)
16(1)
-3(3)
10(4)
39(6)
-15(4)
14(5)
4(3)
97(4)
13(3)
1(4)
65(5)
87(7)
-2(6)
-15(3)
17(5)
19(3)
21(4)
-18(5)
-25(4)
-4(3)
5(4)
52(4)
154(8)
122(5)
68(5)
15(4)
-46(5)
3(3)
94(7)
86(4)
81(3)
6(3)
80(6)
11(4)
47(4)
40(5)
22(5)
1(3)
-19(5)
13(4)
-4(5)
8(5)
95(6)
24(4)
0(4)
64(5)
102(7)
106(4)
127(6)
155(13)
182(11)
240(20)
75(5)
-3(5)
-4(3)
2(4)
1(3)
5(4)
-4(4)
-4(7)
-29(9)
-13(10)
-5(4)
-2(5)
122(8)
-9(14)
-5(7)
-83(7)
-7(12)
-10(4)
-5(4)
-74(6)
-14(12)
33(6)
10(8)
-10(9)
20(4)
12(4)
-21(7)
50(14)
88(6)
C(12A) 170(11)
C(13A) 190(20)
169(9)
190(20)

Table 6. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103)
for Molecule (6).
x
y
z
U(eq)
H(3A)
3027
-2370
7656
65
74
H(5A)
2991
4644
8920
8721
10068
9002
9211
8750
7809
9215
8086
9020
3011
2975
4640
8746
8905
10083
9197
9037
8694
7773
9300
9067
8194
2685
2942
1290
-686
7256
8414
H(6A)
72
H(8A)
9890
92
H(8B)
9896
92
H(9A)
108
11204
11439
11431
10497
10698
11995
12061
11861
7659
139
139
139
100
100
139
139
139
83
H(9B)
-592
H(9C)
1371
-4959
-6101
-5596
-4783
-3635
2353
-2714
-2942
685
H(12A)
H(12B)
H(13A)
H(13B)
H(13C)
H(3AA)
H(5AA)
H(6AA)
H(8AA)
H(8AB)
H(9AA)
H(9AB)
H(9AC)
H(12C)
H(12D)
H(13D)
H(13E)
H(13F)
7298
98
8446
103
138
138
239
239
239
186
186
264
264
264
9908
-1298
-195
9884
11206
11426
11450
10456
10741
11960
11796
12082
-1415
558
5073
6124
5536
3589
4736
3,4-Dimethylaniline was reacted with intermediate (6), from 0°C to rt, to give the single product (7a).
However, compound (8b), in addition to 7b, was obtained as a major product when reaction of anhydride
(6) with 3,4-dimethoxyphenethylamine was performed under the same conditions. Compared to 3,4-
dimethoxyphenethylamine, butylamine, that possesses less steric hindrance and more nucleophilicity,
when reacted with 6 at 0°C afforded only benzoxazine-2,4-dione (7c). The one-pot reactions shown in
Scheme 1, gave benzoxazine-2,4-diones as a single product when the reaction was carried out from 0°C

to rt. If, however, the reaction was performed at rt or above, a small amount of salicylamide (3a), in
addition to major product (4a), also was obtained. Hence, the substituted group on the salicylic acid, the
nucleophilicity of the amine and reaction temperature all play a key role in this reaction.
When this method was applied to thiosalicylic acid, benzothiazine-2,4-diones (9) was produced with
benzylamine. However, thiosalicylamide ester (10) was obtained with 3,4-dimethylaniline (Scheme 3).
O
O
1) ClCOOEt
2) H2NCH2C6H5
OH
N
SH
O
S
O
9
Me
Me
O
1) ClCOOEt
2) 3,4-dimethylaniline
N
H
OH
SH
SCOOEt
10
Scheme 3
In summary, the present procedure provides a simple, efficient and convenient one-pot synthesis for
different kinds of benzoxazine-2,4-dione derivatives and benzyl substituted benzothiazine-2,4-dione
derivatives. We believe that the described procedure will provide a better and more practical alternative to
existing methods for synthesis of such derivatives.
EXPERIMENTAL
1
13
Melting points were determined with a Fisher-Johns apparatus and are uncorrected. H NMR and C
NMR spectra were recorded on a Bruker AC-300 spectrometer. MS spectra and HRMS were recorded on
a VG 7070 mass spectrometer and Finnigan-1015D mass spectrometer. All exact mass measurements
showed an error of less than 5 ppm. Elemental analyses were performed by Atlantic Microlab, Inc.,
Norcross, GA.
N-(3,4-Dimethoxyphenethyl)-2-acetoxybenzamide (2a): To an ice cold solution of 3,4-
dimethoxyphenethylamine (0.26 mL, 1.5 mmol) and triethylamine (0.21 mL, 3.0 mmol) in CHCl3 (20
mL), acetylsalicyloyl chloride (1) (300 mg, 1.5 mmol) was added, and the reaction mixture then was
stirred at rt overnight. Thereafter, the solvent was removed, the residue was dissolved in EtOAc, washed
with saturated NaHCO3 solution and water, and dried over Na2SO4. Purification by column
chromatography, using CH2Cl2/EtOAc (50:1) as an eluent, gave semi-solid compound (2a), which was
1
recrystallized from ether to afford compound (2a) as white crystals (303 mg, 59%). mp 129°C; H NMR
(CDCl3) δ 7.73 (dd, J = 1.7 Hz, J = 7.7 Hz, 1H), 7.50-7.45 (m, 1H), 7.33 (dd, J = 1.1 Hz, J = 7.6 Hz, 1H),
7.09 (dd, J = 1.0 Hz, J = 8.1 Hz, 1H), 6.86-6.78 (m, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.69-3.63 (m, 2H),
2.88 (t, J = 6.8 Hz, 2H), 2.15 (s, 3H); MS (CI/CH4) 343 [M]+; HRMS m/z calcd for C19H21NO5 343.1420,

found 343.1431. Anal. Calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08. Found: C, 66.34; H, 6.17; N,
4.03.
N-(3,4-Dimethoxyphenethyl)-2-hydroxybenzamide (3a): A solution of compound (2a) (32 mg, 0.093
mmol) in Et3N/MeOH (1:1, 1 mL) was stirred at rt for one day. The solvent was evaporated under
vacuum and recrystallized from ether to give compound (3a) (27 mg, 96%) as white crystals. mp 108°C;
1H NMR (CDCl3) δ 12.35 (s, 1H), 7.33-7.28 (m, 1H), 7.11 (dd, J = 1.5 Hz, J = 8.0 Hz, 1H), 6.90 (dd, J =
1.1 Hz, J = 8.4 Hz, 1H), 6.78-6.66 (m, 4H), 3.80 (s, 3H), 3.77 (s, 3H), 3.65-3.53 (m, 2H), 2.81 (t, J = 6.9
Hz, 2H); MS (CI/CH4) 301 [M]+; HRMS m/z calcd for C17H19NO4 301.1314, found 301.1321. Anal.
Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.78; H, 6.44; N, 4.61.
3-(3,4-Dimethoxyphenethyl)benzoxazine-2,4-dione (4a): To an ice/salt cold solution of compound
(3a) (27 mg, 0.090 mmol) and triethylamine (50 µL) in CHCl3 (1 mL) was added ethyl chloroformate (17
µL, 0.18 mmol ). The reaction mixture was allowed to rise to rt and stirring was continued at rt for one
day. The solvent was removed under vacuum and the residue was applied to column chromatography
(eluent: CH2Cl2) for purification and was recrystallized from ether to give compound (4a) (24 mg, 83%)
as white crystals. mp 178°C; 1H NMR (CDCl3) δ 8.10 (dd, J = 1.5 Hz, J = 7.8 Hz, 1H), 7.90-7.70 (m, 1H),
7.43-7.34 (m, 1H), 7.31 (dd, J = 0.5 Hz, J = 8.3 Hz, 1H), 6.89-6.76 (m, 3H), 4.26 (t, J = 8.0 Hz, 2H), 3.89
(s, 3H), 3.88 (s, 3H), 2.98 (t, J = 8.0 Hz, 2H). MS (CI/CH4) m/z 327 [M]+. Anal. Calcd for C18H17NO5: C,
66.05; H, 5.23; N, 4.28. Found: C, 65.84; H, 5.40; N, 4.30.
General procedure for one-pot synthesis of compounds (4): To an ice/salt cold solution of salicylic
acid 1 (139 mg, 1 mmol) and triethylamine (0.42 mL, 3 mmol) in chloroform (10 mL) was added ethyl
chloroformate (0.22 mL, 2.2 mmol). The reaction mixture was allowed to rise to rt and was stirred for 3 h.
The solvent was removed under vacuum to eliminate extra ethyl chloroformate, and the residue then was
dissolved in CHCl3 and cooled with ice. To the ice cold solution was added triethylamine (0.28 mL,
2mmol) and amine (1 mmol). The ice bath was removed and the reaction mixture was stirred at rt
overnight. Thereafter, solvent was evaporated and the residue was applied to column chromatography
(eluent: CH2Cl2/petroleum ether = 2) for purification and recrystallized from ether to give white crystals
except indicated specifically.
3-Benzylbenzoxazine-2,4-dione (4b): yield 61%; mp 125°C (lit.,12 134°C); 1H NMR (CDCl3) δ 8.07 (dd,
J = 1.5 Hz, J = 7.8 Hz, 1H), 7.68-7.67 (m, 1H), 7.53-7.50 (m, 2H), 7.37-7.26 (m, 5H), 5.19 (s, 2H); MS
(CI/CH4) m/z 253 [M]+.
1
3-(3,4-Dimethylphenyl)benzoxazine-2,4-dione (4c): yield 63%; mp 209°C; H NMR (CDCl3) δ 8.15
(dd, J = 1.6 Hz, J = 7.9 Hz, 1H), 7.80-7.74 (m, 1H), 7.45-7.33 (m, 3H), 7.10-7.05 (m, 2H), 2.34 (s, 3H),
2.33 (s, 3H); MS (CI/CH4) m/z 267 [M]+; HRMS m/z calcd for C16H13NO3 267.0895, found 267.0885.
Anal. Calcd for C16H13NO3: C, 71.90; H, 4.90; N, 5.24. Found: C, 71.61; H, 4.96; N, 5.22.

3-(3-Indolylethyl)benzoxazine-2,4-dione (4d): The precipitate was collected by filtration, washed with
cold CHCl3 and recrystallized from EtOAc to give 4d as white crystals in the yield of 63%; mp 222°C; 1H
NMR (DMSO-d6) δ 10.89 (s, 1H), 7.99 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H), 7.84-7.78 (m, 1H), 7.63 (d, J =
7.6 Hz, 1H), 7.46-7.41 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 7.09-6.96 (m, 2H), 4.11 (t, J = 8.1
Hz, 2H), 2.99 (t, J = 8.1 Hz, 2H); HRMS m/z calcd for C18H14N2O3 306.1004, found 306.1017. Anal.
Calcd for C18H14N2O3⋅0.25H2O: C, 69.56; H, 4.70; N, 9.01. Found: C, 69.51; H, 4.60; N, 9.00.
1
3-(2,6-Dimethoxypyridin-3-yl)benzoxazine-2,4-dione (4e): yield 51%; mp 214°C; H NMR (CDCl3) δ
8.15 (dd, J = 1.6 Hz, J = 7.8 Hz, 1H), 7.80-7.74 (m, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.42-7.35 (m, 2H), 6.46
(d, J = 8.3 Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H); MS (CI/CH4) m/z 300 [M]+; HRMS m/z calcd for
C15H12N2O5 300.0746, found 300.0739. Anal. Calcd for C15H12N2O5: C, 60.00; H, 4.03; N, 9.33. Found:
C, 60.10; H, 3.98; N, 9.34.
3-(4-Imidazolylethyl)benzoxazine-2,4-dione (4f): The precipitate was collected by filtration, washed
with H2O and recrystallized from MeOH/Et2O to give 4f as white crystals in the yield of 56%; mp 237°C;
1H NMR (DMSO-d6) δ 8.06 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H), 7.93-7.86 (m, 1H), 7.59-7.50 (m, 3 H),
6.99-6.96 (m, 1H), 4.18 (t, J = 7.7 Hz, 2H), 2.92 (br, 2H); MS (CI/CH4) m/z 257 [M]+.
Preparation of intermediate (6): To a dry ice/acetone cold solution of 5-nitrosalicylic acid (5) (183 mg,
1 mmol) and triethylamine (0.42 mL, 3 mmol) in CHCl3 (10 mL) was added ethyl chloroformate (0.22
mL, 2.2 mmol) over a period of 30 min. The reaction mixture was stirred for 5 h in the dry ice/acetone
bath, and then allowed to rise to rt and stirring was continued at rt overnight. The solvent was removed
under vacuum and the residue was extracted with ether. The ether solution was concentrated to a small
volume and allowed to stand in a refrigerator overnight to afford intermediate (6) as colorless crystals.
General procedure for the reaction of intermediate (6) with amine: To an ice cold solution of
intermediate (6) (1 mmol) and triethylamine (0.42 mL, 3 mmol) in CHCl3 (5 mL) was added amine (1
mmol). The reaction mixture was stirred at 0°C and allowed to rise to rt. The solvent was evaporated, the
residue was applied to column chromatography (eluent: CH2Cl2) for purification and was recrystallized
from ether to give white crystals.
3-(3,4-Dimethylphenyl)-6-nitrobenzoxazine-2,4-dione (7a): yield 69%; mp 195°C; 1H NMR (CDCl3) δ
8.99 (d, J = 2.7 Hz, 1H), 8.58 (dd, J = 2.7 Hz, J = 9.1, 1H), 7.51 (d, J = 9.1 Hz, 1H), 7.30 (d, J = 8.0 Hz,
1H), 7.05-7.01 (m, 2 H), 2.31 (s, 3H), 2.30 (s, 3H); MS (EI) m/z 312 [M]+.
3-(3,4-Dimethoxylphenethyl)-6-nitrobenzoxazine-2,4-dione (7b): yield 9%; mp 206°C; 1H NMR
(CDCl3) δ 8.95 (d, J = 2.7 Hz, 1H), 8.54 (dd, J = 2.7 Hz, J = 9.1 Hz, 1H), 7.44 (d, J =9.1 Hz, 1H), 6.75-

6.74 (m, 3H), 4.23-4.17 (m, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 2.94-2.89 (m, 2H); HRMS m/z calcd for
C18H16N2O7 372.0958, found 372.0945.
N-(3,4-Dimethoxyphenethyl)-2-hydroxy-5-nitrobenzamide (8b): yield 63%; mp 165-166°C; 1H NMR
(CDCl3) δ 13.31 (s, 1H), 8.28-8.23 (m, 2H), 7.06 (d, J = 8.9 Hz, 1H), 6.90-6.75 (m, 3H), 3.88 (s, 3H),
3.86 (s, 3H), 3.75-3.69 (m, 2H), 2.91 (t, J = 6.9 Hz, 2H); HRMS m/z calcd for C17H18N2O6 346.1165,
found 346.1169.
3-Butyl-6-nitrobenzoxazine-2,4-dione (7c): yield 79%; mp 94-95°C; 1H NMR (CDCl3) δ 8.94 (d, J =
2.7 Hz, 1H), 8.52 (dd, J = 2.7 Hz, J = 9.1 Hz, 1H), 4.04 (t, J = 7.5 Hz, 2H), 1.71-1.66 (m, 2H), 1.43-1.36
(m, 2H), 0.95 (q, J = 7.3 Hz, 3H); MS (EI) m/z 264 [M]+.
General procedure for the preparation of compounds (9) and (10): To an ice/salt cold solution of
thiosalicylic acid (154 mg, 1 mmol) and triethylamine (0.42 mL, 3 mmol) in chloroform (10 mL) was
added ethyl chloroformate (0.22 mL, 2.2 mmol). The reaction mixture was allowed to rise to rt and was
stirred at rt for 3 h. The solvent was removed under vacuum to eliminate any remaining ethyl
chloroformate, and the residue then was dissolved in CHCl3 and cooled with ice. To the ice cold solution
was added triethylamine (0.28 mL, 2 mmol) and amine (1 mmol). The ice bath was removed and the
reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue
was applied to column chromatography (eluent: CH2Cl2) for purification and recrystallized from ether.
1
3-Benzylbenzothiazine-2,4-dione (9): yield 66%; mp 107-108°C; H NMR (acetone-d6) δ 8.36-8.33 (m,
1H), 7.80-7.72 (m, 1H), 7.56-7.51 (m, 2H), 7.42-7.40 (m, 2H), 7.34-7.25 (m, 3H), 5.31 (s, 2H); MS (EI)
m/z 269 [M]+. Anal. Calcd for C15H11NO2S: C, 66.89; H, 4.12; N, 5.20. Found: C, 66.79; H, 4.21; N, 5.07.
N-(3,4-Dimethylphenyl)-2-ethoxycarbonylthiobenzamide (10): yield 62%; mp 94°C; 1H NMR
(CDCl3) δ 7.95 (s, 1H), 7.73- 7.65 (m, 2H), 7.60-7.53 (m, 2H), 7.45-7.44 (m, 1H), 7.32 (dd, J = 2.2 Hz, J
= 8.1 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 1.30 (t, J = 7.1
Hz, 3H); MS (EI) m/z 329 [M]+. Anal. Calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25. Found: C,
65.39; H, 5.83; N, 4.28.
Single crystal X-Ray analysis of (6). Data for compound (6) were collected on a Bruker SMART 6K
CCD system mounted on a 6Kw Cu rotating anode using Gobels mirrors to focus the beam. 6860
reflections were measured of which 2449 were unique (Rint = 0.043). The clear colorless (0.09 x 0.22 x
0.50 mm) crystal was monoclinic in space group P21/c with a = 12.394(5)(1), b = 7.873(3), c = 15.588(5)
Å and β = 106.43(3)°. The structures was solved by direct methods and refined by full-matrix least-
squares on F2 values using programs in the SHELXTL-PLUS package.13 The parameters refined included
the coordinates and anisotropic thermal parameters for all non-hydrogen atoms hydrogen atoms included
using a riding model in which the coordinate shifts of their covalently bonded atoms were applied to the

attached hydrogens with C-H = 0.96 Å. H angles were idealized and Uiso(H) set at fixed ratios of Uiso
values of bonded atoms. Final R-factors were 0.048 for the 1974 observed reflections and 0.056 for all
2449 data. The structure exhibited a full molecule disorder that refined to an occupancy of ~20%. The
two components were constrained to have essentially the same bond lengths and angles. Adding the
disorder to the structure reduced the R-factor from 0.147 to 0.048. A full molecule disorder is highly
unusual and it could well be that the crystal is twinned but no twin law could be found that would fit the
experimental data. Coordinates have been deposited with the Cambridge Crystallographic Database.14
ACKNOWLEDGEMENT
NRL author thanks ONR and NIDA for financial support.
REFERENCES
1. A. H. Kahus and H. Bundgaard, Acta Pharm. Nord., 1991, 3, 45.
2. F. Palagiano, F. P. Bonina, L. Nontenegro, A. Biondi, L. Sorrentino and A. Capasso, Pharmazie, 1997,
52, 272.
3. A. Capasso, A. Biondi, F. Palagiano, F. P. Bonina, L. Nontenegro, P. deCaprariis and E. Pistorio, Eur.
Neuropsychopharm., 1997, 7, 57.
4. A. H. Kahus, J. Moss and H. Bundgaard, Int. J. Pharm., 1992, 78, 199.
5. T. Masuda, H. Sato and H. Ono, Ger. Offen., 1977, 2,721,828 (Chem. Abstr., 1978, 88, 161490).
6. C. Larksarpand H. Alper, J. Org. Chem., 1999, 64, 9194.
7. P. Boontheung and P. Perlmutter, Tetrahedron Lett., 1998, 39, 2629.
8. I. Shibuya, M. Goto, M. Shimizu, M. Yanagisawa and Y. Gama, Heterocycles, 1999, 51, 2667; Y.
Gama, I. Shibuya and M. Shimizu, J. Carbohydr. Chem., 2000, 19, 119.
9. R. P. Srivastava and S. Sharma, Pharmazie, 1990, 45, 34.
10. B. Zaleska and S. Lis, Pharmazie, 1995, 50, 150; G. Kumaran and G. H. Kulkarni, Indian J. Chem.,
Sect. B: Org. Chem. Include. Med. Chem., 1994, 33B, 877.
11. G. Wagner and I. Wunderlich, Pharmazie, 1978, 33, 15.
12. I. Shibuya, M. Goto, M. Shimizu, M. Yanagisawa and Y. Gama, Heterocycles, 1999, 51, 2667.
13. Bruker (1995) SHELXTL-PLUS Version 5.03. Bruker Analytical X-Ray Systems, Madison,
Wisconsin, USA.
14. Cambridge Crystallographic Database, 12 Union Road, Cambridge CB2 1EZ, UK
(deposit@ccdc.cam.ac.uk)