2212
A. L. Vaccarino et al. / Bioorg. Med. Chem. 15 (2007) 2206–2215
addition was completed, the mixture was stirred at 0 ꢁC
for 2 h and then filtered to give a white solid. The solid
was recrystallized from water to yield 3 as a colorless
crystalline solid.
of 2-[2,3-dihydro-3-oxo-1,2-benzisothiazol-2-yl-1,1-di-
oxide]), 8.16–7.95 (m, 3H, H-5,6,7 of 2-[2,3-dihydro-3-
oxo-1,2-benzisothiazol-2-yl-1,1-dioxide]), 7.31 (d, 2H,
J = 8.7 Hz, H-2,6 p-aminophenol), 6.68 (d, 2H,
J = 8.7 Hz, H-3,5 p-aminophenol), 4.49 (s, 2H, CH2).
Anal. Calcd for C H N O S: C, 54.21; H, 3.64; N,
5
.2.1.2. N-(4-Hydroxyphenyl)-2-chloroacetamide (3a).
The general method was applied to chloroacetylchloride
1a, 6.7 g, 65 mmol). The product 3a was obtained as a
colorless crystalline solid (7.6 g, 69% yield). Mp 144–
1
5
12
2
5
8.43; S, 9.65. Found, C, 54.16; H, 3.77; N, 8.36; S, 9.48.
(
5.2.1.7. N-(4-Hydroxyphenyl)-3-[2,3-dihydro-3-oxo-
1,2-benzisothiazol-2-yl-1,1-dioxide]-propionamide (5b).
The general method was applied to N-(4-hydroxyphe-
nyl)-3-bromopropionamide (3b) (4.9 g, 20 mmol) to
yield 5b as a colorless crystalline solid (5.9 g, 85%).
1
1
46 ꢁC. H NMR (DMSO-d , 300 MHz) d: 10.04 (s,
6
1H, NH), 9.27 (s, 1H, OH), 7.36 (d, 2H, J = 8.6 Hz,
H-2,6 p-aminophenol), 6.71 (d, 2H, J = 8.6 Hz, H-3,5
p-aminophenol), 4.19 (s, 2H, CH ). Anal. Calcd for
2
À1
1
C H ClNO : C, 51.77; H, 4.34; N, 7.55; Cl, 19,10.
8
Mp 237–239 ꢁC, IR (KBr, cm ); 3382, 1746, 1648,
1551, 1438, 1312, 1174, 1157. H NMR (DMSO-d6,
8
2
Found, C, 51.56; H, 4.57; N, 7.36; Cl, 19.33.
3
00 MHz) d: 9.78 (s, 1H, NH), 9.16 (s, 1H, OH), 8.28
5.2.1.3. N-(4-Hydroxyphenyl)-3-bromopropionamide
3b). The general method was applied to 3-bromopropi-
(d, 1H, J = 6.9 Hz, 4-H of 2-[2,3-dihydro-3-oxo-1,2-
benzisothiazol-2-yl-1,1-dioxide]), 8.11–7.95 (m, 3H,
H-5,6,7 of 2-[2,3-dihydro-3-oxo-1,2-benzisothiazol-2-yl-
1,1-dioxide]), 7.29 (d, 2H, J = 8.7 Hz, H-2,6 p-aminophe-
nol), 6.67 (d, 2H, J = 8.7 Hz, H-3,5 p-aminophenol), 4.03
(
onyl chloride (1b, 11 g, 65 mmol), yielding 3b as a color-
less crystalline solid (8.2 g, 63% yield). Mp 130–132 ꢁC.
1
H NMR (DMSO-d , 300 MHz) d: 9.79 (s, 1H, NH),
6
9
.18 (s, 1H, OH), 7.37 (d, 2H, J = 8.7 Hz, H-2,6 p-ami-
(t, 2H, J = 7.3 Hz, C(a)H ), 2.77 (t, 2H, J = 7.6 Hz,
2
nophenol), 6.79 (d, 2H, J = 8.7 Hz, H-3,5 p-aminophe-
nol), 3.71 (t, 2H, C(a)H ), 2.89 (t, 2H, C(b)H ). Anal.
C(b)H ). Anal. Calcd for C H N O S: C, 55.48; H,
4.07; N, 8.08; S, 9.26. Found: C, 55.22; H, 4.22; N,
8.04; S, 9.19.
2
16 14
2
5
2
2
Calcd for C H BrNO : C, 44.29; H, 4.13; N, 5.74; Br,
3
9
10
2
2,74. Found, C, 44.46; H, 4.17; N, 5.56; Br, 32.53.
5.2.1.8. N-(4-Hydroxyphenyl)-4-[2,3-dihydro-3-oxo-1,2-
5.2.1.4. N-(4-Hydroxyphenyl)-4-chlorobutyrylamide
3c). The general method was applied to 4-chlorobuty-
benzisothiazol-2-yl-1,1-dioxide]-butyrylamide (5c). A solu-
tion of 4-chloro-N-(4-hydroxyphenyl)-butyrylamide (3c,
5.8 g, 27 mmol), anhydrous sodium saccharin (4, 8.4 g,
41 mmol) and NaI (0.85 g, 5.6 mmol) in dry DMF
(20 mL) was heated to 90 ꢁC for 1.5 h. The reaction was al-
lowed to cool to room temperature, the precipitate was fil-
tered, and the filtrate was evaporated under reduced
pressure. The residue was dissolved in EtOAc (280 mL),
washed, respectively, with water (100 mL) and brine solu-
tion (100 mL), and dried (Na SO ). The solvent was re-
(
rylchloride (1c, 9.2 g, 65 mmol), to yield 3c as colorless
1
crystalline solid (6.5 g, 56% yield). Mp 112–114 ꢁC. H
NMR (DMSO-d , 300 MHz) d: 9.69 (s, 1H, NH), 9.17
6
(s, 1H, OH), 7.35(d, 2H, J = 8.8 Hz, H-2,6 p-aminophe-
nol), 6.68 (d, 2H, J = 8.8 Hz, H-3,5 p-aminophenol),
3
2
.68 (t, 2H, C(a)H ), 2.41 (t, 2H, C(v)H ), 2.25 (m,
2 2
H, C(b)H ). Anal. Calcd for C H ClNO : C, 56.21;
2
10 12
2
H, 5.66; N, 6.56; Cl, 16,59. Found, C, 56.40; H, 5.57;
N, 6.66; Cl, 16.53.
2
4
moved under reduced pressure and the white solid
residue was recrystallized in ethanol/H O (10:1) to furnish
2
5
.2.1.5. General procedure for the synthesis of N-(4-
hydroxyphenyl)-2-[2,3-dihydro-3-oxo-1,2-benzisothiazol-
-yl-1,1-dioxide]-alkanecarboxamides (5). A solution
of N-(4-hydroxyphenyl)-x-haloalkanecarboxamide (3,
0 mmol) and sodium saccharin (4, 6.2 g, 30 mmol) in
DMF (16 mL) was heated to reflux with stirring for
h. At the end of this time, the NaCl that precipitated
5c as a white crystalline solid (7.9 g, 82%). Mp 190–192 ꢁC.
1
H NMR (DMSO-d , 400 MHz) d: 9.57 (s, 1H, NH), 9.06
6
2
(s, 1H, OH), 8.25–7.95 (m, 4H, H-4,5,6,7 of 2-[2,3-dihydro-
3-oxo-1,2-benzisothiazol-2-yl-1,1-dioxide]), 7.33 (d, 2H,
8.8. Hz, H-2,6 p-aminophenol), 6.70 (d, 2H, 8.8 Hz, H-
2
3,5 p-aminophenol), 3.78 (t, 2H, 7.4 Hz, C(a)H ), 2.37 (t,
2
2
2H, 7.4 Hz, C(v)H ), 2.02 (m, 2H, C(b)H ). Anal. Calcd
2
2
was removed by filtration and the filtrate was evaporat-
ed under reduced pressure. The residue was partitioned
between EtOAc (180 mL) and water (100 mL). The
organic layer was washed with brine (100 mL) and dried
for C H N O S: C, 56.66; H, 4.44; N, 7.77; S, 8.90.
Found: C, 56.72; H, 4.47; N, 7.75; S, 8.81.
17 16 2 5
5.2.2. Method B
(
pressure to afford a white solid. The crude solid was
recrystallized from ethanol/H O (8:1) to furnish 5 as a
2
Na SO ), and the solvent was removed under reduced
2 4
5.2.2.1. General procedure for the synthesis of 2-(2,3-
dihydro-3-oxo-1,2-benzisothiazol-2-yl-1,1-dioxide)alkane-
carboxylic acids (7). A solution of anhydrous sodium
saccharin (4, 8.6 g, 42 mmol) and the corresponding
x-haloalkanecarboxylic acid (6, 4.5 g, 25 mmol) in
DMF (20 mL) was heated to reflux for 3 h. The reaction
mixture was allowed to cool to room temperature, the
precipitate was filtered, and the filtrate was evaporated
under reduced pressure. The residue was dissolved in
EtOAc (200 mL), washed with brine (2· 130 mL), and
dried (Na SO ). The solvent was removed under
colorless crystalline solid.
5.2.1.6. N-(4-Hydroxyphenyl)-2-[2,3-dihydro-3-oxo-
,2-benzisothiazol-2-yl-1,1-dioxide]-acetamide (5a). The
1
general method was applied to N-(4-hydroxyphenyl)-2-
chloroacetamide (3a, 3.7 g, 20 mmol) to yield 5a as a col-
orless crystalline solid (5.7 g, 86%). Mp 204–206 ꢁC. IR
À1
(
1
KBr, cm ); 3339, 3100, 1742, 1676, 1509, 1449, 1332,
1
185, 1063. H NMR (DMSO-d , 300 MHz) d: 10.06 (s,
6
2
4
1
H, NH), 9.27 (s, 1H, OH), 8.33 (d, 1H, J = 7.4 Hz, H-4
reduced pressureand the white solidresidue was recrystal-