3796 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19
Owa et al.
) 5.6 Hz), 7.24 (1H, dd, J ) 5.6, 3.2 Hz), 7.29 (1H, dd, J )
2.8, 2.4 Hz), 7.34-7.41 (2H, m), 9.48 (1H, s), 10.66 (1H, s);
MS (FAB+) m/e 287 (M+). Anal. (C14H13N3O2S) C, H, N.
Compounds 1-4 were synthesized as described for 5 by
using the appropriate sulfonyl chlorides.
N-(7-In d olyl)-4-m eth oxyben zen esu lfon a m id e (1). Ob-
tained as a colorless solid in 95% yield: mp 161-162 °C (after
recrystallization from EtOAc-hexane); 1H NMR (DMSO-d6)
δ 3.766 and 3.772 (total 3H, s × 2), 6.36-6.44 (1H, m), 6.76
(1H, d, J ) 7.7 Hz), 6.82 (1H, td, J ) 7.7, 2.2 Hz), 6.97-7.08
(2H, m), 7.26-7.36 (1H, m), 7.28 (1H, d, J ) 7.7 Hz), 7.64-
7.74 (2H, m), 9.80 (1H, s), 10.72 (1H, br s); MS (FAB+) m/e
302 (M+). Anal. (C15H14N2O3S) C, H, N.
7.49 (1H, d, J ) 8.0 Hz), 7.74 (1H, dd, J ) 8.0, 7.6 Hz), 7.94
(1H, d, J ) 8.0 Hz), 8.11-8.14 (2H, m), 8.23 (1H, d, J ) 2.8
Hz), 10.30 (1H, br s), 12.05 (1H, br s); MS (FAB+) m/e 322 (M+).
Anal. (C16H10N4O2S) C, H, N.
2-Cyan o-N-(3-cyan o-7-in dolyl)ben zen esu lfon am ide (10).
Obtained as a colorless solid in 35% yield: mp 116.5-118.5
°C (after recrystallization from EtOAc-hexane); 1H NMR
(DMSO-d6) δ 6.65 (1H, d, J ) 7.7 Hz), 7.05 (1H, dd, J ) 7.9,
7.7 Hz), 7.44 (1H, d, J ) 7.9 Hz), 7.81 (1H, ddd, J ) 7.5, 7,3,
1.1 Hz), 7.87 (1H, ddd, J ) 7.9, 7.5, 1.1 Hz), 7.96 (1H, dd, J )
7.9, 1.1 Hz), 8.03 (1H, dd, J ) 7.3, 1.1 Hz), 8.18-8.25 (1H, m),
10.56 (1H, br s), 12.01 (1H, br s); MS (FAB+) m/e 322 (M+).
Anal. (C16H10N4O2S) C, H, N.
N-(7-In d olyl)-4-m et h ylb en zen esu lfon a m id e (2). Ob-
tained as a colorless solid in 96% yield: mp 157-159 °C (after
recrystallization from EtOAc-hexane); 1H NMR (DMSO-d6)
δ 2.31 (3H, s), 6.39 (1H, dd, J ) 3.1, 1.8 Hz), 6.75 (1H, dd, J
) 7.7, 0.92 Hz), 6.81 (1H, t, J ) 7.7 Hz), 7.26-7.32 (4H, m),
7.60-7.66 (2H, m), 9.84 (1H, s), 10.68-10.75 (1H, m); MS
(FAB+) m/e 286 (M+). Anal. (C15H14N2O2S) C, H, N.
4-[N-(3-Cya n o-7-in d olyl)su lfa m oyl]ben zoic Acid (11).
Obtained as a colorless solid in 82% yield: mp 275-276 °C
dec (after recrystallization from EtOAc-hexane); 1H NMR
(DMSO-d6) δ 6.71 (1H, d, J ) 7.6 Hz), 7.06 (1H, dd, J ) 8.0,
7.6 Hz), 7.44 (1H, d, J ) 8.0 Hz), 7.78-7.84 (2H, m), 8.02-
8.04 (2H, m), 8.21 (1H, d, J ) 2.7 Hz), 11.96-12.06 (1H, m);
MS (FAB+) m/e 341 (M+). Anal. (C16H11N3O4S) C, H, N.
4-Ch lor o-N-(7-in d olyl)b en zen esu lfon a m id e (3). Ob-
tained as a colorless solid in 93% yield: mp 163-164.5 °C
(after recrystallization from EtOAc-hexane); 1H NMR (DMSO-
d6) δ 6.41 (1H, d, J ) 2.1 Hz), 6.70 (1H, d, J ) 7.8 Hz), 6.83
(1H, t, J ) 7.8 Hz), 7.31 (1H, d, J ) 2.1 Hz), 7.33 (1H, d, J )
7.8 Hz), 7.55-7.65 (2H, m), 7.68-7.78 (2H, m), 10.01 (1H, s),
N-(3-Cyan o-7-in dolyl)-4-n itr oben zen esu lfon am ide (13).
Obtained as a pale-yellow solid in 90% yield: mp 229-232 °C
dec (after recrystallization from EtOAc-hexane); 1H NMR
(DMSO-d6) δ 6.70 (1H, d, J ) 7.7 Hz), 7.07 (1H, dd, J ) 7.9,
7.7 Hz), 7.47 (1H, d, J ) 7.9 Hz), 7.91-7.98 (2H, m), 8.22 (1H,
d, J ) 2.9 Hz), 8.32-8.39 (2H, m), 10.44 (1H, s), 12.05 (1H, s);
MS (FAB+) m/e 342 (M+). Anal. (C15H10N4O4S) C, H, N.
10.75 (1H, s); MS (FAB+) m/e 307 (MH+). Anal. (C14H11
-
ClN2O2S) C, H, N.
4-Ca r ba m oyl-N-(3-cya n o-7-in d olyl)ben zen esu lfon a m -
id e (12). To a mixture of 11 (450 mg, 1.32 mmol), NH4HCO3
(209 mg, 2.63 mmol), and Et3N (370 µL, 2.65 mmol) in DMSO
(4.5 mL) was added DPPA (diphenyl phosphorazidate; 340 µL,
1.58 mmol). After stirring at room temperature overnight, the
reaction mixture was diluted with EtOAc and washed succes-
sively with 0.2 N aqueous HCl, saturated aqueous NaHCO3,
and brine. The organic layer was dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. Purification by flash
chromatography (eluted with EtOAc-hexane) afforded 12 (354
mg, 79%) as a colorless solid: mp 291.5-293.5 °C dec (after
recrystallization from EtOH-hexane); 1H NMR (DMSO-d6) δ
6.71 (1H, d, J ) 7.9 Hz), 7.04 (1H, t, J ) 7.9 Hz), 7.42 (1H, d,
J ) 7.9 Hz), 7.59 (1H, s), 7.75 (2H, d, J ) 8.2 Hz), 7.94 (2H, d,
J ) 8.2 Hz), 8.12 (1H, s), 8.19 (1H, s), 10.20 (1H, s), 11.96 (1H,
s); MS (FAB+) m/e 340 (M+). Anal. (C16H12N4O3S) C, H, N.
4-Am in o-N-(3-cyan o-7-in dolyl)ben zen esu lfon am ide (14).
To a solution of 13 (3.77 g, 11.0 mmol) in MeOH (100 mL) and
concentrated aqueous HCl (5 mL) was added portionwise Zn
powder (2.20 g, 33.6 mmol). The mixture was heated under
reflux for 30 min and then cooled, neutralized with a large
excess of NaHCO3, and filtered to remove insolubles. After the
filtrate was concentrated in vacuo, the resulting residue was
suspended in EtOAc and washed with saturated aqueous
NaHCO3 and brine. The organic layer was dried over anhy-
drous MgSO4, filtered, and concentrated under reduced pres-
sure. Purification by flash chromatography (eluted with EtOAc-
hexane) afforded 14 (3.02 g, 88%) as a colorless solid: mp 252-
255 °C dec (after recrystallization from EtOH-hexane); 1H
NMR (DMSO-d6) δ 6.05 (2H, s), 6.51-6.58 (2H, m), 6.93 (1H,
d, J ) 8.0 Hz), 7.13 (1H, dd, J ) 8.0, 7.6 Hz), 7.36-7.43 (2H,
m), 7.41 (1H, d, J ) 7.6 Hz), 8.23 (1H, d, J ) 3.2 Hz), 9.73
(1H, s), 11.79-11.91 (1H, m); MS (FAB+) m/e 312 (M+). Anal.
(C15H12N4O2S) C, H, N.
4-Cyan o-N-(7-in dolyl)ben zen esu lfon am ide (4). Obtained
as a colorless solid in 93% yield: mp 170-170.5 °C (after
recrystallization from EtOAc-hexane); 1H NMR (DMSO-d6)
δ 6.41 (1H, dd, J ) 2.8, 2.0 Hz), 6.65 (1H, dd, J ) 7.5, 0.55
Hz), 6.83 (1H, dd, J ) 8.0, 7.5 Hz), 7.31 (1H, t, J ) 2.8 Hz),
7.35 (1H, d, J ) 8.0 Hz), 7.84-7.91 (2H, m), 7.98-8.04 (2H,
m), 10.16 (1H, s), 10.72-10.84 (1H, m); MS (FAB+) m/e 297
(M+). Anal. (C15H11N3O2S) C, H, N.
3-Cya n o-7-n itr oin d ole. 7-Nitroindole-3-carboxaldehyde22
(10.2 g, 53.6 mmol) was dissolved in DMF (150 mL), and then
hydroxylamine hydrochloride (3.93 g, 56.6 mmol) and pyridine
(4.5 mL, 55.6 mmol) were added to the solution. The obtained
mixture was stirred at 80 °C for 2 h, followed by the addition
of SeO2 (6.30 g, 56.8 mmol) and anhydrous MgSO4 (ca. 5 g).
After stirring at 80 °C for 2.5 h, the reaction mixture was
filtered to remove insolubles and concentrated in vacuo. H2O
was added to the residue to precipitate solid materials. The
crude product was collected by filtration, washed with H2O,
and purified by flash chromatography (eluted with EtOAc-
hexane) to give the title compound (8.61 g, 86%) as a yellow
solid: 1H NMR (DMSO-d6) δ 7.48 (1H, t, J ) 8.1 Hz), 8.17
(1H, d, J ) 8.1 Hz), 8.27 (1H, d, J ) 8.1 Hz), 8.47 (1H, s),
12.70-13.00 (1H, br); MS (FAB+) m/e 188 (MH+).
Compounds 7-11 and 13 were prepared by the procedure
described for 5, proceeding from 3-cyano-7-nitroindole instead
of 7-nitroindole.
N -(3-Cya n o-7-in d olyl)-4-m et h oxyb en zen esu lfon a m -
id e (7). Obtained as a colorless solid in 90% yield: mp 259-
261 °C dec (after recrystallization from EtOAc-hexane); 1H
NMR (DMSO-d6) δ 3.79 (3H, s), 6.80 (1H, dd, J ) 7.6, 2.4 Hz),
7.03 (2H, d, J ) 8.8 Hz), 7.07 (1H, dd, J ) 8.0, 7.6 Hz), 7.40
(1H, d, J ) 8.0 Hz), 7.64 (2H, d, J ) 8.8 Hz), 8.20 (1H, dd, J
) 2.4, 1.2 Hz), 9.96 (1H, s), 11.82-11.94 (1H, m); MS (FAB+)
m/e 327 (M+). Anal. (C16H13N3O3S) C, H, N.
4-Cya n o-N-(3-cya n o-7-in d olyl)ben zen esu lfon a m id e (8).
Obtained as a colorless solid in 91% yield: mp 250.5-252 °C
(after recrystallization from EtOAc-hexane); 1H NMR (DMSO-
d6) δ 6.67 (1H, d, J ) 7.7 Hz), 7.05 (1H, t, J ) 7.9 Hz), 7.44
(1H, d, J ) 7.7 Hz), 7.78-7.87 (2H, m), 7.97-8.05 (2H, m),
8.16-8.23 (1H, m), 10.28-10.43 (1H, br), 11.92-12.09
(1H, m); MS (FAB+) m/e 322 (M+). Anal. (C16H10N4O2S) C, H,
N.
N -(3-Cya n o -7-in d olyl)-4-(m et h a n esu lfon a m id o)b en -
zen esu lfon a m id e (15). To a solution of 14 (625 mg, 2.00
mmol) in pyridine (10 mL) was added dropwise methanesulfo-
nyl chloride (155 µL, 2.00 mmol). After stirring at room
temperature overnight, the reaction mixture was concentrated
in vacuo. The obtained residue was diluted with EtOAc and
washed successively with 0.2 N aqueous HCl, saturated
aqueous NaHCO3, and brine. The organic layer was dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. Purification by flash chromatography (eluted with
EtOH-hexane) afforded 15 (718 mg, 92%) as a colorless
solid: mp 258.5-259.5 °C (after recrystallization from EtOH-
3-Cya n o-N-(3-cya n o-7-in d olyl)ben zen esu lfon a m id e (9).
Obtained as a colorless solid in 88% yield: mp 214-215 °C
(after recrystallization from EtOAc-hexane); 1H NMR (DMSO-
d6) δ 6.71 (1H, d, J ) 7.6 Hz), 7.09 (1H, dd, J ) 8.0, 7.6 Hz),
1
hexane); H NMR (DMSO-d6) δ 3.09 (3H, s), 6.81 (1H, d, J )