6812
Y. Yamamoto et al. / Bioorg. Med. Chem. 23 (2015) 6807–6814
ppm: 8.18 (dd, J = 2.4, 8.6 Hz, 1H), 7.99 (dd, J = 3.1, 5.3 Hz, 2H), 7.93
(dd, J = 2.9, 5.5 Hz, 2H), 7.88 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 2.6 Hz,
1H), 7.28 (t, J = 7.7 Hz, 1H), 6.76 (m, 1H), 6.62 (m, 2H), 3.69 (s,
3H); FTIR(KBr) cmꢀ1: 1736, 1716, 1605; EI-MS m/z: 390 [M]+;
HR-MS: Calcd for C21H14N2O6 [M]+: 390.0852. Found 390.0853.
3467, 3365, 1627; EI-MS m/z: 260 [M]+; HR-MS: Calcd for
13H12N2O4 [M]+: 260.0797. Found 260.0802.
C
4.1.10. Synthesis of N-(4-nitro-2-phenoxyphenyl)
methanesulfonamide (1a)
A solution of 4a (500 mg, 2.2 mmol) in anhydrous CH2Cl2
4.1.5. Synthesis of 2-(2-(4-methoxyphenoxy)-4-nitrophenyl)
isoindoline-1,3-dione (3d)
(2.2 mL) was treated with dry Et3N (484
mixture was allowed to stir for 1 min at room temperature. To
the reaction mixture, CH3SO2Cl (840 L, 10.9 mmol) was added
lL, 3.5 mmol) and the
Compound 3d was obtained in a similar manner to the synthe-
sis of 3a from 2 using 4-methoxy phenyl boronic acid. The crude
product was purified by chromatography on silica gel with CHCl3/
hexane/acetone = 1:8:1 to provide 3d (87.5 mg, 63.7%) as a pale
yellow solid: mp: 62–64 °C; 1H NMR (600 MHz, DMSO-d6) d
ppm: 8.12 (dd, J = 2.4, 8.6 Hz, 1H), 8.02 (dd, J = 3.1, 5.7 Hz, 2H),
7.95 (dd, J = 2.9, 5.5 Hz, 2H), 7.86 (d, J = 8.8 Hz, 1H), 7.57 (d,
J = 2.6 Hz, 1H), 7.08 (d, J = 6.8 Hz, 2H), 6.99 (d, J = 6.8 Hz, 2H),
3.75 (s, 3H); FTIR(KBr) cmꢀ1: 1738, 1534, 1505; EI-MS m/z: 390
[M]+; HR-MS: Calcd for C21H14N2O6 [M]+: 390.0852. Found
390.0853.
l
drop-wise at ice-cold temperature. The resulting mixture was stir-
red for 23 h and the reaction was quenched with distilled water.
After extraction with CHCl3, the combined organic phases were
dried and filtered, and the solvent was removed in vacuo. To the
residue 3 M NaOHaq (10 mL) was added and the mixture stirred
at 80–90 °C for 16 h. Afterwards, 5 M HCl was added and it was
extracted with CHCl3. The combined organic phases were dried
and filtered, and the solvent was removed in vacuo. The residue
was purified by chromatography on silica gel with CHCl3/hexane/
acetone = 1:8:1 to provide 1a (497.4 mg, 74.3%) as a pale yellow
solid: mp: 142–144 °C (lit16 mp: 143–144.5 °C); 1H NMR
(600 MHz, DMSO-d6) d ppm: 10.16 (s, 1H), 8.03 (dd, J = 2.7,
9.0 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.6 Hz, 2H), 7.49
(t, J = 8.1 Hz, 2H), 7.28 (t, J = 7.0 Hz, 1H), 7.17 (d, J = 8.2 Hz, 2H),
3.20 (s, 3H); FTIR(KBr) cmꢀ1: 3285, 1589, 1521; EI-MS m/z: 308
[M]+; HR-MS: Calcd for C13H12N2O5S [M]+: 308.0467. Found
308.0468.
4.1.6. Synthesis of 4-nitro-2-phenoxyaniline (4a)
A solution of 3a (500 mg, 1.4 mmol) in MeOH (13.9 mL) was
treated with hydrazine monohydride (344 lL, 7.1 mmol). After-
wards, the mixture was heated under reflux for 6 h. The resulting
mixture was concentrated in vacuo. The residue was diluted with
10% NaOHaq and extracted with CHCl3. The combined organic
phases were dried and filtered, and the solvent was removed in
vacuo. The residue was purified by chromatography on silica gel
with CHCl3/hexane/acetone = 1:8:1 to provide 4a (310.2 mg,
97.0%) as a yellow solid: mp: 111–112 °C; 1H NMR (600 MHz,
DMSO-d6) d ppm: 7.85 (dd, J = 2.2, 9.8 Hz, 1H), 7.45 (d, J = 2.4 Hz,
1H), 7.41 (t, J = 7.8 Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H), 7.06 (d,
J = 8.0 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 6.64 (s, 2H); FTIR(KBr)
cmꢀ1: 3476, 3352, 1624; EI-MS m/z: 230 [M]+; HR-MS: Calcd for
4.1.11. Synthesis of N-(2-(2-methoxyphenoxy)-4-nitrophenyl)
methanesulfonamide (1b)
Compound 1b was obtained in
a similar manner to the
synthesis of 1a from 4b. The crude product was purified by chro-
matography on silica gel with CHCl3/hexane/acetone = 1:8:1 to
provide 1b (91.9 mg, 70.7%) as a yellow solid: mp: 133–134 °C;
1H NMR (600 MHz, DMSO-d6) d ppm: 10.07 (s, 1H), 7.95 (dd,
J = 2.6, 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.34 (dt, J = 1.7, 7.9 Hz,
1H), 7.27 (dd, J = 1.5, 8.1 Hz, 1H), 7.24 (dd, J = 1.6, 7.9 Hz, 1H),
7.21 (d, J = 2.6 Hz, 1H), 7.08 (dt, J = 1.5, 7.7 Hz, 1H), 3.75 (s, 3H),
3.23 (s, 3H); FTIR(KBr) cmꢀ1: 3342, 3269, 1602; EI-MS m/z: 338
[M]+; HR-MS: Calcd for C14H14N2O6S [M]+: 338.0573. Found
338.0578.
C
12H10N2O3 [M]+: 230.0691. Found 230.0687.
4.1.7. Synthesis of 2-(2-methoxyphenoxy)-4-nitroaniline (4b)
Compound 4b was obtained in a similar manner to the synthe-
sis of 4a from 3b. The product was obtained without purification
(26.5 mg, 99.4%) as a yellow solid: mp: 133–134 °C; 1H NMR
(600 MHz, DMSO-d6) d ppm: 7.78 (dd, J = 2.6, 9.2 Hz, 1H), 7.28
(dt, J = 1.5, 7.7 Hz, 1H), 7.23 (dd, J = 1.6, 8.2 Hz, 1H), 7.13 (dd,
J = 1.6, 7.9 Hz, 1H), 7.09 (d, J = 2.6 Hz, 1H), 7.03 (dt, J = 1.6, 7.6 Hz,
1H), 6.78 (d, J = 8.8 Hz, 1H), 6.70 (s, 2H), 3.77 (s, 3H); FTIR(KBr)
cmꢀ1: 3473, 3352, 1624; EI-MS m/z: 260 [M]+; HR-MS: Calcd for
4.1.12. Synthesis of N-(2-(3-methoxyphenoxy)-4-nitrophenyl)
methanesulfonamide (1c)
Compound 1c was obtained in a similar manner to the synthesis
of 1a from 4c. The crude product was purified by chromatography
on silica gel with CHCl3/hexane/acetone = 1:8:1 to provide 1c
(88.2 mg, 67.8%) as a pale yellow solid: mp: 121–123 °C; 1H NMR
(600 MHz, DMSO-d6) d ppm: 10.14 (s, 1H), 8.03 (dd, J = 2.6,
8.8 Hz, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.57 (d, J = 2.6 Hz, 1H), 7.38
(t, J = 7.6 Hz, 1H), 6.86 (dd, J = 2.2, 8.2 Hz, 1H), 6.76 (t, J = 2.2 Hz,
1H), 6.71 (dd, J = 2.0, 7.9 Hz, 1H), 3.78 (s, 3H), 3.20 (s, 3H); FTIR
(KBr) cmꢀ1: 3244, 1600, 1526; EI-MS m/z: 338 [M]+; HR-MS: Calcd
for C14H14N2O6S [M]+: 338.0573. Found 338.0575.
C
13H12N2O4 [M]+: 260.0797. Found 260.0791.
4.1.8. Synthesis of 2-(3-methoxyphenoxy)-4-nitroaniline (4c)
Compound 4c was obtained in a similar manner to the synthesis
of 4a from 3c. The product was obtained without purification
(33.3 mg, 99.9%) as a yellow solid: mp: 122–123 °C; 1H NMR
(600 MHz, DMSO-d6) d ppm: 7.87 (dd, J = 2.6, 9.2 Hz, 1H), 7.49 (d,
J = 2.6 Hz, 1H), 7.31 (t, J = 8.2 Hz, 1), 6.83 (d, J = 9.2 Hz, 1H), 6.77
(dd, J = 2.4, 8.2 Hz, 1H), 6.67 (s, 2H), 6.66 (t, J = 2.4 Hz, 1H), 6.59
(dd, J = 2.4, 8.2 Hz, 1H), 3.76 (s, 3H); FTIR(KBr) cmꢀ1: 3455, 3351,
1630; EI-MS m/z: 260 [M]+; HR-MS: Calcd for C13H12N2O4 [M]+:
260.0797. Found 260.0793.
4.1.13. Synthesis of N-(2-(4-methoxyphenoxy)-4-nitrophenyl)
methanesulfonamide (1d)
Compound 1d was obtained in a similar manner to the synthe-
sis of 1a from 4d. The crude product was purified by chromatogra-
phy on silica gel with CHCl3/hexane/acetone = 1:8:1 to provide 1d
(216.6 mg, 66.6%) as a pale yellow solid: mp: 128–129 °C; 1H NMR
(600 MHz, DMSO-d6) d ppm: 10.11 (s, 1H), 7.98 (dd, J = 2.6, 8.8 Hz,
1H), 7.70 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.16 (d,
J = 9.2 Hz, 2H), 7.05 (d, J = 9.2 Hz, 2H), 3.79 (s, 3H), 3.22 (s, 3H);
FTIR(KBr) cmꢀ1: 3290, 1596, 1522; EI-MS m/z: 338 [M]+; HR-MS:
Calcd for C14H14N2O6S [M]+: 338.0573. Found 338.0575.
4.1.9. Synthesis of 2-(4-methoxyphenoxy)-4-nitro aniline (4d)
Compound 4d was obtained in a similar manner to the synthe-
sis of 4a from 3d. The product was obtained without purification
(279.0 mg, quant.) as a yellow solid: mp: 89–91 °C; 1H NMR
(600 MHz, DMSO-d6) d ppm: 7.81 (dd, J = 2.6, 9.2 Hz, 1H), 7.30
(d, J = 2.6 Hz, 1H), 7.07 (d, J = 9.2 Hz, 2H), 7.00 (d, J = 9.2 Hz, 2H),
6.80 (d, J = 8.8 Hz, 1H), 6.70 (s, 2H), 3.77 (s, 3H); FTIR(KBr) cmꢀ1
: