Antimitotic Agents
cooling to room temperature, the reaction mixture was diluted
with EtOAc (20 mL) and washed with 5% HCl, saturated aqueous
NaHCO3, and brine. The organic layer was dried over anhydrous
Na2SO4, filtered, and condensed under reduced pressure. The resi-
due was purified by column chromatography (silica gel, 14%
EtOAc in hexane) to give 1 (63.1 mg, 87% for the two steps) as a
white crystalline solid; mp: 180–1818C (EtOAc/hexane); Rf =0.36
(25% EtOAc/hexane); IR (KBr): n˜ =3382, 3260, 2918, 1338,
56.0 ppm; MS (ꢁESI) m/z 453 ([MꢁH]+, 100); Anal.
(C27H22N2O3S·1= H2O) C, H, N.
2
N-{2-[4’-(4’’-Methoxybenzenesulfonamido)phenyl]indol-7-yl}-4-
methoxybenzenesulfonamide (6): Compound 6 was prepared in
81% yield from 14e as a white crystalline solid; mp: 190–1928C
(acetone/hexane); Rf =0.30 (40% EtOAc/PE); 1H NMR (400 MHz,
CDCl3): d=9.94 (brs, 1H), 8.44 (s, 1H), 7.92 (s, 1H), 7.77–7.68 (m,
4H), 7.51 (d, J=8.8 Hz, 2H), 7.30 (t, J=4.4 Hz, 1H), 7.14 (d, J=
8.4 Hz, 2H), 6.90–6.83 (m, 4H), 6.80–6.74 (m, 2H), 6.63 (d, J=
2.0 Hz, 1H), 3.76 (s, 3H), 3.70 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=163.0, 162.9, 137.4, 136.3, 130.7, 130.4, 130.2, 129.3
(ꢁ4), 128.8, 125.9 (ꢁ2), 121.5 (ꢁ2), 121.0, 120.1, 117.7, 115.2, 114.1
(ꢁ3), 113.9 (ꢁ2), 99.2, 55.5, 55.4 ppm; MS (ꢁESI) m/z 562 ([MꢁH]+,
100); Anal. (C28H25N3O6S2) C, H, N.
1162 cmꢁ1 1H NMR (300 MHz, [D6]acetone): d=10.41 (brs, 1H),
;
8.84 (brs, 1H), 7.98–7.92 (m, 2H), 7.82–7.75 (m, 2H), 7.66–7.57 (m,
2H), 7.55–7.46 (m, 2H), 7.43–7.37 (m, 2H), 7.08 (s, 1H), 7.07 (d, J=
8.8 Hz, 1H), 7.02 (d, J=2.3 Hz, 1H), 2.43 ppm (s, 3H); 13C NMR
(75 MHz, [D6]acetone): d=143.3, 138.0, 136.6, 131.9, 131.3, 130.7,
129.1 (ꢁ2), 128.7 (ꢁ2), 127.4, 127.0 (ꢁ2), 124.8 (ꢁ2), 121.2, 119.7,
117.9, 116.4, 99.4, 20.1 ppm; MS (+ESI) m/z 363 ([M+H]+, 100);
Anal. (C21H18N2O2S) C, H, N.
3-Chloro-7-nitro-2-phenylindole (15): To a solution of the 7-nitro-
2-phenylindole 14a[22] (120.0 mg, 0.50 mmol) in THF (2 mL), was
added a drop of 0.5n aqueous HCl and then N-chlorosuccinimide
(68.1 mg, 0.51 mmol).[25] The resulting mixture was stirred at room
temperature for 5 h, and the reaction was quenched by addition of
H2O. The crystalline precipitates were collected by filtration,
washed with H2O and CH3OH/H2O (1:1), and finally dried in vacuo
to give 15 (109.1 mg, 80%) as a yellow solid; mp: 157–1588C
(CH2Cl2/hexane); Rf =0.33 (5% EtOAc/hexane); IR (film): n˜ =3388,
N-(2-Phenylindol-7-yl)-4-methoxybenzenesulfonamide (2): Com-
pound 2 was prepared in 84% yield from 14a as a white crystalline
solid; mp: 176.5–177.58C (EtOAc/hexane); Rf =0.44 (33% EtOAc/
hexane); IR (KBr): n˜ =3470, 3260, 2923, 1332, 1263, 1156 cmꢁ1
;
1H NMR (300 MHz, [D6]acetone): d=10.45 (brs, 1H), 8.81 (brs, 1H),
8.02–7.94 (m, 2H), 7.88–7.81 (m, 2H), 7.67–7.59 (m, 2H), 7.57–7.46
(m, 2H), 7.15–7.01 (m, 5H), 3.92 ppm (s, 3H); 13C NMR (75 MHz,
[D6]acetone): d=162.5, 137.7, 131.6, 131.0, 130.7, 130.4, 128.7 (ꢁ2),
128.3 (ꢁ2), 127.1, 124.5 (ꢁ2), 121.0, 119.3, 117.5, 116.0, 113.3 (ꢁ2),
99.0, 54.5 ppm; MS (+ESI) m/z 379 ([M+H]+, 100); Anal.
(C21H18N2O3S) C, H, N.
1519, 1484, 1343, 1325 cmꢁ1 1H NMR (400 MHz, CDCl3): d=9.94
;
(brs, 1H), 8.21 (dd, J=8.0, 0.4 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H),
7.94–7.88 (m, 2H), 7.62–7.55 (m, 2H), 7.54–7.47 (m, 1H), 7.31 ppm
(t, J=8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=134.8, 132.8,
130.7, 129.5, 129.3, 129.1 (ꢁ2), 128.0, 127.5 (ꢁ2), 126.4, 120.3,
120.1, 104.7 ppm; HRMS (CI+) calcd for C14H10ClN2O2 [M+H]+:
273.0431; found: 273.0434.
N-[2-(4’-Tolyl)indol-7-yl]-4-methoxybenzenesulfonamide
(3):
Compound 3 was prepared in 76% yield from 14b as a white crys-
talline solid; mp: 210–2128C (acetone/hexane); Rf =0.28 (22%
EtOAc/PE); IR (film): n˜ =3364, 3319, 1496, 1300, 1264, 1143 cmꢁ1
;
N-(3-Chloro-2-phenylindol-7-yl)-4-methoxybenzenesulfonamide
(7): Zinc powder (20 mg, 0.30 mmol) was added to a solution of 15
(27.0 mg, 0.10 mmol) in CH3OH (5 mL) and conc. aqueous HCl
(0.5 mL). The resulting mixture was heated at reflux for 30 min. The
reaction mixture was allowed to cool to room temperature and
was carefully neutralized with excess saturated aqueous Na2CO3.
The mixture was extracted with CH2Cl2 (3ꢁ10 mL). The combined
organic layer was dried over anhydrous Na2SO4, filtered, and con-
densed under reduced pressure to give a crude product. 4-Methoxy-
benzenesulfonyl chloride (1.2 equiv) and pyridine (1.2 equiv) were
added via syringe to a solution of the crude product in anhydrous
THF (5 mL) under a nitrogen atmosphere. The resulting mixture
was heated at reflux for ~24 h under a nitrogen atmosphere. After
cooling to room temperature, the reaction mixture was diluted
with CH2Cl2 (20 mL) and washed with 5% HCl, saturated aqueous
NaHCO3, and brine. The organic layer was dried over anhydrous
Na2SO4, filtered, and condensed under reduced pressure. The resi-
due was purified by column chromatography (silica gel, 25%
EtOAc in hexane) to give 7 (20.0 mg, 50% for the two steps) as a
white crystalline solid; mp: 192–1938C (acetone/hexane); Rf =0.23
(25% EtOAc/hexane); IR (film): n˜ =3359, 3241, 1597, 1334, 1263,
1H NMR (400 MHz, [D6]DMSO): d=10.99 (brs, 1H), 9.80 (s, 1H), 7.77
(d, J=8.4 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H),
7.22 (d, J=7.6 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 6.98 (d, J=8.4 Hz,
2H), 6.89 (t, J=8.0 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 3.69 (s, 3H),
2.34 ppm (s, 3H); 13C NMR (100 MHz, [D6]DMSO): d=163.0, 138.3,
137.7, 131.5, 130.7, 130.1 (ꢁ2), 129.6 (ꢁ2), 129.5, 129.2, 125.3 (ꢁ2),
122.6, 120.4, 116.8, 114.8 (ꢁ2), 112.5, 99.3, 56.0, 21.4 ppm; MS
(ꢁESI) m/z 391 ([MꢁH]+, 100); Anal. (C22H20N2O3S) C, H, N.
N-[2-(4’-Methoxyphenyl)indol-7-yl]-4-methoxybenzenesulfona-
mide (4): Compound 4 was prepared in 80% yield from 14c as a
white crystalline solid; mp: 250–2528C (dec.) (acetone/hexane);
1
Rf =0.25 (25% EtOAc/PE); H NMR (400 MHz, [D6]DMSO): d=10.89
(brs, 1H), 9.73 (s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.70 (d, J=8.4 Hz,
2H), 7.20 (d, J=7.6 Hz, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.99 (dd, J=
8.4 Hz, 3H), 6.86 (t, J=7.6 Hz, 1H), 6.72 (d, J=2.0 Hz, 1H), 3.81 (s,
3H), 3.72 ppm (s, 3H); 13C NMR (100 MHz, [D6]DMSO): d=163.0,
159.5, 138.2, 131.5, 130.8, 129.5 (ꢁ2), 129.1, 126.8 (ꢁ2), 124.9,
122.4, 120.2, 116.6, 115.0 (ꢁ2), 114.8 (ꢁ2), 112.4, 98.5, 56.0,
55.7 ppm; MS (ꢁESI) m/z 407 ([MꢁH]+, 100); Anal. (C22H20N2O4S) C,
H, N.
1
1156 cmꢁ1; H NMR (300 MHz, CDCl3): d=9.38 (br, s), 7.93–7.88 (m,
2H), 7.59–7.48 (m, 5H), 7.45–7.37 (m, 1H), 6.98–6.82 (m, 3H), 6.43–
6.38 (m, 2H), 3.81 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=163.5,
133.4, 130.6, 130.5, 129.7 (ꢁ3), 129.4, 129.2, 129.0 (ꢁ2), 128.5, 127.4
(ꢁ2), 120.8, 120.0, 119.1, 117.5, 114.4 (ꢁ2), 55.7 ppm; HRMS (CI+)
calcd for C21H18ClN2O3S [M+H]+: 413.0727; found: 413.0704.
N-[2-(4’-Biphenyl)indol-7-yl]-4-methoxybenzenesulfonamide (5):
Compound 5 was prepared in 83% yield from 14d as a white crys-
talline solid; mp: 252–2568C (dec.) (acetone/hexane); Rf =0.20
1
(25% EtOAc/PE); H NMR (400 MHz, [D6]DMSO): d=11.06 (brs, 1H),
9.77 (s, 1H), 7.88–7.74 (m, 8H), 7.50 (t, J=7.2 Hz, 2H), 7.39 (t, J=
7.2 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.05–6.87 (m, 5H), 3.72 ppm (s,
3H); 13C NMR (100 MHz, [D6]DMSO): d=163.0, 139.9, 139.7, 137.6,
131.5, 131.2, 130.6, 129.5 (ꢁ2), 129.4 (ꢁ2), 128.1, 127.6 (ꢁ2), 127.0
(ꢁ3), 125.9 (ꢁ2), 122.5, 120.4, 117.0, 114.8 (ꢁ2), 112.9, 100.0,
N-(3-Piperidinomethyl-2-phenylindol-7-yl)-4-methoxybenzene-
sulfonamide (8): A mixture of the indole sulfonamide 2 (37.8 mg,
0.1 mmol), piperidine (0.15 mmol), and formaldehyde (0.15 mmol,
30 wt% aqueous solution) in acetic acid (2.0 mL) was stirred at
ChemMedChem 2010, 5, 1489 – 1497
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1495