December 2003
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(35 ml) under nitrogen at 0 °C was added n-butyllithium (6.4 ml, 1.6 M;
10.2 mmol). After 30 min, black selenium powder (0.4 g, 5.1 mmol) was
added to the reaction mixture and the reaction was continued for another
30 min. Upon cooling to Ϫ78 °C, CuBr2 (2.3 g, 10.2 mmol) was added and
the mixture was stirred for 30 min. The cooling bath was removed after
30 min, and the temperature was allowed to reach ambient temperature.
taining the allylseleno moiety, displayed the highest activity
and could serve as a lead compound to be further developed
as antiinflammation agent.
Experimental
General Melting points (mp) were taken on a BUCHI 530 apparatus After 2 h, the reaction mixture was poured into water (100 ml) containing
and are uncorrected. Merck Art No 105554 plates precoated with Silica gel acetic acid (1 ml) and, after filtration, extracted with dichloromethane. The
60 containing a fluorescent indicator were used for thin-layer chromatogra- organic layer was concentrated under reduced pressure. Column chromatog-
phy, and Silica gel 60 (Merck Art No 109385, 230—400 mesh) was em-
raphy on silica gel with 3 : 1 n-hexane/ethyl acetate as eluent gave 3a (0.2 g,
ployed for column chromatography. Evaporations were carried out at 14%) as a solid white product.
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Ͻ50 °C using a rotary evaporator at reduced pressure (water aspirator). H-
3b—f were obtained under the same conditions.
2-Phenyl-1,2-benzisoselenazol-3(2H)-one (3a): Rf: 0.33 (n-hexane/ethyl
and 13C-NMR spectra were obtained on a Varian 300 NMR spectrometer at
300 and 75 MHz, respectively. Where necessary, deuterium exchange experi- acetateϭ3/1). mp 180—181 °C (lit.13) mp 182—183 °C). H-NMR (DMSO-
ments were used to obtained proton shift assignments. Mass spectra were d6) d: 8.08 (d, 1H, Jϭ7.9 Hz, H-4), 7.90 (d, 1H, Jϭ7.7 Hz, H-7), 7.71—7.43
recorded on a JEOL J.M.S-300 spectrophotometer. Analytical samples were (m, 3H, H-6, H-2Ј, H-6Ј), 7.47 (dd, Jϭ7.7, 7.9 Hz, 3H, H-5, H-3Ј, H-5Ј),
dried under reduced pressure at 78 °C in the presence of P2O5 for at least 7.27 (t, Jϭ6.9 Hz, 1H, H-4Ј). 13C-NMR (DMSO-d6) d: 132.6, 129.6, 128.3,
12 h unless otherwise specified. Elemental analyses were obtained using a 126.6, 126.2, 125.0. IR (KBr) cmϪ1: 3071, 1654. UV lmax (MeOH) nm
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Perkin-Elmer 2400 Elemental Analyzer.
N-Substituted-benzoylamide (2a—f), General Procedure Freshly dis- C13H9NOSe: C, 56.95; H, 3.31; N, 5.11. Found: C, 56.78; H, 3.22; N, 5.22.
tilled thionyl chloride (20 ml) was added to a solution of benzoic acid (5.0 g,
2-(4-Methylphenyl)-1,2-benzisoselenazol-3(2H)-one (3b): Rf: 0.36 (n-
(log e): 327 (3.98). FAB-MS m/z: 276 (MϩHϩ). Anal. Cacld for
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41.0 mmol), pyridine (2.0 ml), and dichloromethane (20 ml) and the reaction hexane/ethyl acetateϭ3/1). mp 163—164 °C. H-NMR (DMSO-d6) d: 8.07
mixture was heated under reflux for 2 h. The mixture was concentrated (d, 1H, Jϭ8.4 Hz, H-4), 7.89 (d, 1H, Jϭ7.6 Hz, H-7), 7.67 (t, 1H, Jϭ7.7 Hz,
under reduced pressure and the residue was coevaporated with toluene (5 ml) H-6), 7.51—7.44 (m, 3H, H-5, H-2Ј, H-6Ј), 7.25 (d, 2H, Jϭ8.6 Hz, H-3Ј, H-
three times. Toluene (50 ml) and aniline (3.8 ml, 50 mmol) were added to the 5Ј), 2.32 (s, 3H, CH3). 13C-NMR (DMSO-d6) d: 132.5, 130.0, 128.3, 126.6,
residue and the mixture was heated under reflux for 3 h. The solvent was re- 126.1, 125.0, 20.9. IR (KBr) cmϪ1: 3014, 1652. UV lmax (MeOH) nm
moved under reduced pressure, 10% sodium bicarbonate (20 ml) was added, (log e): 327 (3.98). FAB-MS m/z: 289 (Mϩ). Anal. Cacld for C14H11NOSe:
and the mixture was extracted with dichloromethane (30 mlϫ3). The organic C, 58.34; H, 3.85; N, 4.86. Found: C, 58.68; H, 3.72; N, 5.02.
layer was concentrated and the residue was crystallized with enthanol to give
pure 2a (6.4 g, 80%).
2b—f were obtained under the same conditions.
2-(3-Methylphenyl)-1,2-benzisoselenazol-3(2H)-one (3c): Rf: 0.35 (n-
hexane/ethyl acetateϭ3/1). mp 154—155 °C. H-NMR (DMSO-d6) d: 8.13
(d, 1H, Jϭ8.1 Hz, H-4), 7.66 (d, 2H, Jϭ5.7 Hz, H-2Ј, H-6Ј), 7.50—7.27 (m,
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N-Phenyl-benzoylamide (2a): Rf: 0.40 (n-hexane/ethyl acetateϭ3/1). mp 4H, H-5, H-6, H-7, H-5Ј), 7.11 (d, 1H, Jϭ7.1 Hz, H-4Ј), 2.41 (s, 3H, CH3).
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161—162 °C (EtOH). H-NMR (DMSO-d6) d: 7.84 (d, 2H, Jϭ5.2 Hz, H-2, 13C-NMR (DMSO-d6) d: 140.0, 133.5, 130.4, 129.3, 128.0, 127.6, 127.2,
H-6), 7.62 (d, 2H, Jϭ7.7 Hz, H-2Ј, H-6Ј), 7.52 (t, 1H, Jϭ6.8 Hz, H-4), 7.46 126.6, 123.2, 22.4. IR (KBr) cmϪ1: 3004, 1654. UV lmax (MeOH) nm
(t, 2H, Jϭ6.9 Hz, H-3, H-5), 7.35 (t, 2H, Jϭ7.0 Hz, H-3Ј, H-5Ј), 7.14 (t, 1H,
(log e): 327 (3.81). FAB-MS m/z: 289 (Mϩ). Anal. Cacld for C14H11NOSe:
Jϭ7.4 Hz, H-4Ј). 13C-NMR (DMSO-d6) d: 132.9, 130.0, 129.7, 129.0, C, 58.34; H, 3.85; N, 4.86. Found: C, 58.01; H, 3.70; N, 4.66.
125.0, 121.8, 107.4. Anal. Cacld for C13H11NO: C, 79.16; H, 5.62; N, 7.10.
Found: C, 79.06; H, 5.32; N, 7.06.
2-(2-Methylphenyl)-1,2-benzisoselenazol-3(2H)-one (3d): Rf: 0.29 (n-
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hexane/ethyl acetateϭ3/1). mp 173—174 °C. H-NMR (CDCl3) d: 7.89 (d,
N-p-Toluidyl-benzoylamide (2b): Rf: 0.36 (n-hexane/ethyl acetateϭ3/1). 2H, Jϭ6.5 Hz, H-4, H-7), 7.61—7.50 (m, 4H, H-5, H-6, H-5Ј, H-6Ј), 7.33
mp 158—159 °C (EtOH). 1H-NMR (CDCl3) d: 7.88 (d, 2H, Jϭ6.7 Hz, H-2,
H-6), 7.75 (s, 1H, H-4), 7.56—7.50 (m, 4H, H-3, H-5, H-2Ј, H-6Ј), 7.19 (d,
(d, 2H, H-3Ј, H-4Ј), 2.33 (s, 1H, CH3). 13C-NMR (CDCl3) d: 139.0, 135.6,
131.1, 129.3, 128.4, 127.7, 127.2, 125.6, 123.2, 23.4. IR (KBr) cmϪ1: 3065,
2H, Jϭ8.3 Hz, H-3Ј, H-5Ј), 2.35 (s, 3H, CH3). 13C-NMR (CDCl3) d: 137.0, 1647. UV lmax (MeOH) nm (log e): 327 (3.82). FAB-MS m/z: 289 (Mϩ).
136.7, 135.8, 133.2, 131.1, 130.3, 128.5, 121.9, 22.4. Anal. Cacld for Anal. Cacld for C14H11NOSe: C, 58.34; H, 3.85; N, 4.86. Found: C, 58.21;
C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.26; H, 6.32; N, 6.96.
H, 3.67; N, 4.51.
N-m-Toluidyl-benzoylamide (2c): Rf: 0.34 (n-hexane/ethyl acetateϭ3/1).
2-(4-Methoxybenzyl)-1,2-benzisoselenazol-3(2H)-one (3e): Rf: 0.30 (n-
mp 119—120 °C (EtOH). 1H-NMR (DMSO-d6) d: 7.95 (d, 2H, Jϭ6.7 Hz, hexane/ethyl acetateϭ4/1). mp 150—151 °C. H-NMR (CDCl3) d: 8.07 (d,
H-2, H-6), 7.63—7.51 (m, 5H, H-3, H-4, H-5, H-2Ј, H-6Ј), 7.24 (t, 1H, 1H, Jϭ8.2 Hz, H-4), 7.56 (d, 2H, Jϭ5.7 Hz, H-5, H-7), 7.41—7.27 (m, 3H,
Jϭ8.3 Hz, H-5), 6.93 (d, 1H, Jϭ7.7 Hz, H-4Ј), 2.32 (s, 3H, CH3). 13C-NMR H-6, H-3Ј, H-5Ј), 6.94 (dd, 2H, Jϭ8.19, 8.13 Hz, H-2Ј, H-6Ј), 5.05 (s, 2H,
(DMSO-d6) d: 137.0, 136.7, 135.8, 133.2, 132.1, 130.3, 129.5, 128.6, 121.7, CH2), 3.91 (s, 3H, CH3). 13C-NMR (CDCl3) d: 131.7, 130.8, 129.7, 128.7,
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22.5. Anal. Cacld for C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C,
79.33; H, 6.04; N, 6.86.
125.9, 123.7, 120.8, 110.5, 55.3, 43.4. IR (KBr) cmϪ1: 3065, 1647. UV lmax
(MeOH) nm (log e): 319 (3.80). FAB-MS m/z: 318 (Mϩ). Anal. Cacld for
N-o-Toluidyl-benzoylamide (2d): Rf: 0.36 (n-hexane/ethyl acetateϭ3/1). C15H13NO2Se: C, 56.61; H, 4.12; N, 4.40. Found: C, 56.23; H, 3.97; N, 4.51.
mp 144—145 °C (EtOH). 1H-NMR (CDCl3) d: 7.98—7.89 (m, 3H, H-2, H-
2-(2-Methoxybenzyl)-1,2-benzisoselenazol-3(2H)-one (3f): Rf: 0.35 (n-
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6, H-6Ј), 7.69 (s, 1H, H-4), 7.58—7.49 (m, 3H, H-3, H-5, H-5Ј), 7.30—7.24 hexane/ethyl acetateϭ4/1). mp 144—145 °C. H-NMR (CDCl3) d: 8.08 (d,
(m, 1H, H-4Ј), 7.15 (d, 1H, Jϭ7.7 Hz, H-3Ј), 2.35 (s, 3H, CH3). 13C-NMR d 1H, Jϭ7.7 Hz, H-4), 7.57 (d, 2H, Jϭ5.7 Hz, H-5, H-7), 7.45—7.41 (m, 2H,
(75 MHz, CDCl3): 137.0, 136.7, 135.8, 133.2, 132.1, 130.3, 129.5, 121.7, H-6, H-5Ј), 7.31 (d, 1H, Jϭ8.6 Hz, H-3Ј), 6.90 (t, 2H, H-4Ј, H-6Ј), 4.95 (s,
23.4. Anal. Cacld for C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C,
2H, CH2), 3.82 (s, 3H, CH3). 13C-NMR (CDCl3) d: 161.4, 133.4, 131.6,
130.4, 127.7, 125.5, 115.8, 56.8, 49.8. IR (KBr) cmϪ1: 3045, 1642. UV lmax
79.41; H, 6.45; N, 6.47.
N-(4-Methoxybenzyl)-benzoylamide (2e): Rf: 0.32 (n-hexane/ethyl ac- (MeOH) nm (log e): 319 (3.79). FAB-MS m/z: 318 (Mϩ). Anal. Cacld for
etateϭ4/1). mp 91—92 °C (EtOH). 1H-NMR (DMSO-d6) d: 8.99 (s, 1H, C15H13NO2Se: C, 56.61; H, 4.12; N, 4.40. Found: C, 56.33; H, 4.07; N, 4.21.
NH), 7.89 (d, 2H, Jϭ7.7 Hz, H-2, H-6), 7.53—7.44 (m, 3H, H-3, H-4, H-5),
7.25 (d, 2H, Jϭ8.2 Hz, H-2Ј, H-6Ј), 6.90 (d, 2H, Jϭ8.6 Hz, H-3Ј, H-5Ј), 4.41 To a stirred solution of 2a (1.5 g, 7.6 mmol) in dry tetrahydrofuran (50 ml)
(s, 2H, CH2), 3.35 (s, 3H, CH3). 13C-NMR (DMSO-d6) d: 169.0, 137.0,
under nitrogen at 0 °C was added n-butyllithium (11 ml, 1.6 M; 17.4 mmol).
136.5, 133.7,132.8, 131.9, 120.0, 128.5, 121.7, 57.6, 39.7. Anal. Cacld for After 30 min, black selenium powder (0.6 g, 7.6 mmol) was added to the re-
C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found: C, 74.41; H, 6.42; N, 6.02.
action mixture and the reaction was continued for another 4 h. To the reac-
N-Phenyl-(2-alkylseleno)benzoylamide (4a—c), General Procedure
N-(2-Methoxybenzyl)-benzoylamide (2f): Rf: 0.36 (n-hexane/ethyl ac- tion mixture methyl iodide (4.6 ml, 7.6 mmol) was added and the mixturre
etateϭ4/1). mp 79—80 °C (EtOH). 1H-NMR (DMSO-d6) d: 8.87 (s, 1H, was poured into water. Precipitated solid was recrystallized from methanol
NH), 7.92 (d, 2H, Jϭ7.3 Hz, H-2, H-6), 7.55—7.46 (m, 3H, H-3, H-4, H-5), to give pure 4a (0.9 g, 42%) as a white solid.
7.24—7.16 (m, 2H, H-3Ј, H-5Ј), 7.01—6.90 (m, 2H, H-4Ј, H-6Ј), 4.45 (s,
4a—c were obtained under the same conditions.
N-Phenyl-N-methyl-(2-methylseleno)benzoylamide (4a): Rf: 0.3 (n-
2H, CH2), 3.83 (s, 3H, CH3). 13C-NMR (DMSO-d6) d: 169.0, 136.7, 133.5,
133.2, 132.1, 131.9, 129.5, 128.6, 121.7, 58.4, 40.1. Anal. Cacld for hexane/ethyl acetateϭ3/1). mp 113—114 °C. 1H-NMR (CDCl3) d: 7.34—
C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found: C, 74.98; H, 6.22; N, 5.92.
7.13 (m, 8H, H-3, H-4, H-5, H-6, H-2Ј, H-3Ј, H-5Ј, H-6Ј), 7.0 (t, 1H,
N-Substituted-1,2-benzisoselenazol-3(2H)-one (3a—f), General Proce- Jϭ7.2 Hz, H-4Ј), 3.49 (s, 3H, N-CH3), 2.31 (s, 3H, SeCH3). 13C-NMR
dure To a stirred solution of 2a (1.0 g, 5.1 mmol) in dry tetrahydrofuran (CDCl3) d: 132.4, 130.8, 130.4, 129.5, 128.3, 128.2, 127.1, 39.3, 9.3. IR