Indole Cyclopropylmethylamines as SSRIs
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 6029
vigorous bubbling had ceased, the organic layer (containing
diazomethane) was decanted into a chilled (0 °C) Erlenmeyer
flask containing KOH chips (20 g). The mixture was swirled
for 10 min, and the yellow solution was decanted into a
dropping funnel. The solution of diazomethane was added over
30 min to an open flask containing a stirred mixture of 9a
(8.0 g, 19.6 mmol) and palladium acetate (132 mg, 0.58 mmol)
in CH2Cl2 (200 mL) maintained at 0 °C. After the mixture was
stirred for 1 h, a second batch of freshly prepared diaz-
omethane (98 mmol) in ∼250 mL of diethyl ether was added
over 30 min. After the mixture was stirred for 1 h, the reaction
was quenched with AcOH (4 mL) and the mixture was poured
into an aqueous saturated solution of NaHCO3 (250 mL). The
aqueous layer was extracted with EtOAc (3 × 100 mL). The
organic layers were washed with brine, dried over anhydrous
magnesium sulfate, and concentrated in vacuo. The crude
product was triturated with EtOAc (150 mL) and cooled with
vigorous stirring to 0 °C for 1 h. The product was collected by
vacuum filtration and rinsed with cold EtOAc (25 mL). The
white solid was dried under vacuum to afford 4.46 g (54%) of
10a. An analytical sample was obtained by recrystallization
from EtOAc/hexane: mp 174-175 °C; 1H NMR (400 MHz,
DMSO-d6) δ 8.23 (1H, d, J ) 1.1 Hz), 8.07 (1H, d, J ) 8.6 Hz),
7.91 (2H, d, J ) 8.4 Hz), 7.86 (1H, s), 7.75 (1H, dd, J ) 8.6,
1.5 Hz), 7.40 (2H, d, J ) 8.2 Hz), 3.64 (3H, s), 3.16 (3H, s),
2.43 (2H, m), 2.33 (3H, s), 1.43 (2H, m); MS m/e 424 (M + H)+.
Anal. (C22H21N3O4S) C, H, N.
trans-2-[7-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl)-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10b.
10b was prepared from 9b in a manner similar to 10a (71%).
1H NMR (400 MHz, CDCl3) δ 7.88-7.92 (m, 3H), 7.65 (dd, J
) 1.08, 7.56 Hz, 1H), 7.55 (d, J ) 0.96 Hz, 1H), 7.26-7.34 (m,
3H), 3.73 (s, 3H), 3.27 (s, 3H), 2.52 (m, 1H), 2.39 (s, 3H), 1.63-
1.66 (m, 2H), 1.2-1.33 (m, 1H); MS (ESI) m/e 424.15 (M +
H)+.
trans-2-[6-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10c.
10c was prepared from 9c in a manner similar to 10a (64%).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (1H, d, J ) 1.0 Hz), 7.98
(3H, m), 7.83 (1H, m), 7.67 (1H, dd, J ) 8.2, 1.3 Hz), 7.41 (2H,
d, J ) 8.1 Hz), 3.63 (3H, s), 3.15 (3H, s), 2.40 (2H, m), 2.33
(3H, s), 1.45 (2H, m); MS m/e 422 (M - H)-. Anal. (C22H21N3O4S)
C, H, N.
trans-2-[4-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10h.
10h was prepared from 9h in a manner similar to 10a (98%).
1H NMR (300 MHz, CDCl3) δ 7.74 (3H, m), 7.23 (4H, m), 6.89
(1H, dd, J ) 8.0, 10.0 Hz), 3.70 (3H, s), 3.26 (3H, s), 2.47 (2H,
m), 2.36 (3H, s), 1.60 (1H, m), 1.29 (1H, m); MS m/e 417.11 (M
+ H)+.
trans-2-[5-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11a. Powdered LAH (1.79
g, 47.3 mmol) was carefully added portionwise to a stirred
solution of 10a (4.0 g, 9.45 mmol) in anhydrous THF (250 mL)
at -40 °C. The resulting mixture was stirred at -40 °C for 2
h. The reaction was quenched with EtOAc (25 mL), and the
mixture was warmed to room temperature. After 30 min, H2O
(1.79 mL) was added followed by a solution of aqueous NaOH
(15% w/v, 3.58 mL). After the mixture was stirred for 30 min
at room temperature, the aluminum salts were removed by
vacuum filtration. The salts were rinsed with EtOAc (100 mL),
and the combined filtrates were concentrated in vacuo. The
crude material was purified by silica gel chromatography using
hexane/EtOAc (4:1 to 3:1) as the eluent to give 11a (2.86 g,
74%) as a white solid. An analytical sample was obtained by
recrystallization from EtOAc/hexane: mp 165-167 °C; 1H
NMR (400 MHz, DMSO-d6) δ 9.08 (1H, d, J ) 5.5 Hz), 8.32
(1H, d, J ) 1.1 Hz), 8.06 (1H, d, J ) 8.6 Hz), 7.90 (2H, d, J )
8.6 Hz), 7.89 (1H, s), 7.75 (1H, dd, J ) 8.6, 1.5 Hz), 7.40 (2H,
d, J ) 8.2 Hz), 2.77 (1H, m), 2.33 (3H, s), 2.13 (1H, m), 1.74
(2H, m); MS m/e 363 (M - H)-. Anal. (C20H16N2O3S) C, H, N.
trans-2-[7-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11b. 11b was prepared from
10b in a manner similar to 11a (80%). 1H NMR (400 MHz,
CDCl3) δ 9.51 (d, J ) 4.12 Hz, 1H), 7.91 (d, J ) 8.44 Hz, 2H),
7.82 (dd, J ) 1.20, 7.92 Hz, 1H), 7.68 (dd, J ) 1.04, 7.60 Hz,
1H), 7.60 (d, J ) 1.04 Hz, 1H), 7.30-7.35 (m, 3H), 2.62 (m,
1H), 2.40 (s, 3H), 2.17-2.20 (m, 1H), 1.75-1.80 (m, 1H), 1.51-
1.55 (m, 1H).
trans-2-[6-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11c. 11c was prepared from
10c in a manner similar to 11a (37%). 1H NMR (400 MHz,
DMSO-d6) δ 9.11 (1H, d, J ) 5.5 Hz), 8.33 (1H, d, J ) 1.0 Hz),
7.99 (3H, m), 7.88 (1H, d, J ) 8.1 Hz), 7.69 (1H, dd, J ) 8.2,
1.4 Hz), 7.41 (2H, d, J ) 8.0 Hz), 2.76 (1H, m), 2.33 (3H, s),
2.14 (1H, m), 1.70 (2H, m); MS m/e 363 (M - H)-. Anal.
(C20H16N2O3S) C, H, N.
trans-2-[4-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11d. 11d was prepared from
10d in a manner similar to 11a (74%). 1H NMR (400 MHz,
CDCl3) δ 9.33 (d, J ) 4.92 Hz, 1H), 8.21 (dd, J ) 0.88, 8.48
Hz, 1H), 7.74 (dd, J ) 1.76, 6.68 Hz, 2H), 7.59 (dd, J ) 0.88,
7.56 Hz, 1H), 7.45 (d, J ) 1.20 Hz, 1H), 7.39 (dd, J ) 7.80,
8.32 Hz, 1H), 7.26-7.28 (m, 2H), 2.90-2.91 (m, 1H), 2.38 (s,
3H), 2.09-2.12 (m, 1H), 1.78-1.80 (m, 1H), 1.47-1.52 (m, 1H).
trans-2-[5-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11e. 11e was prepared from
10e in a manner similar to 11a (76%). 1H NMR (400 MHz,
DMSO-d6) δ 9.08 (1H, d, J ) 5.6 Hz), 7.90 (1H, m), 7.84 (2H,
d, J ) 8.4 Hz), 7.75 (1H, s), 7.51 (1H, dd, J ) 9.1, 2.6 Hz),
7.38 (2H, d, J ) 8.1 Hz), 7.20 (1H, t, J ) 9.2 Hz), 2.69 (1H,
m), 2.32 (3H, s), 2.09 (1H, m), 1.68 (2H, m); MS m/e 358 (M +
H)+. Anal. (C19H16FNO3S) C, H, N.
trans-2-[4-Cyano-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10d.
10d was prepared from 9d in a manner similar to 10a (78%).
1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J ) 0.40, 7.96 Hz, 1H),
7.76 (d, J ) 8.40 Hz, 2H), 7.57 (dd, J ) 0.44, 7.56 Hz, 1H),
7.44 (d, J ) 1.24 Hz, 1H), 7.37 (t, J ) 8.08 Hz, 1H), 3.73 (s,
3H), 3.27 (s, 3H), 2.72-2.74 (m, 1H), 2.36-2.38 (m, 4H), 1.68-
1.72 (m, 1H), 1.30-1.35 (m, 1H); MS (ESI) m/e 424.16 (M +
H)+.
trans-2-[5-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10e.
10e was prepared from 9d in a manner similar to 10a (99%).
1H NMR (400 MHz, CDCl3) δ 7.89 (1H, m), 7.72 (2H, d, J )
8.4 Hz), 7.30 (1H, s), 7.23 (3H, m), 7.04 (1H, t, J ) 9.0 Hz),
3.71 (3H, s), 3.26 (3H, s), 2.40 (2H, m), 2.34 (3H, s), 1.59 (1H,
m), 1.25 (1H, m); MS m/e 417 (M + H)+.
trans-2-[7-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10f. 10f
trans-2-[7-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11f. 11f was prepared from
10f in a manner similar to 11a (52%). 1H NMR (300 MHz,
CDCl3) δ 9.48 (1H, d, J ) 4.3 Hz), 7.81 (2H, d, J ) 7.6 Hz),
7.51 (1H, d, J ) 0.9 Hz), 7.29 (4H, m), 7.16 (1H, m), 6.98 (1H,
dd, J ) 7.8, 12 Hz), 2.61 (1H, m), 2.37 (3H, s), 2.16 (1H, m),
1.76 (1H, m), 1.53 (1H, m); MS m/e 358.07 (M + H)+.
1
was prepared from 9d in a manner similar to 10a (87%). H
NMR (300 MHz, CDCl3) δ 7.81 (2H, d, J ) 7.7 Hz), 7.47 (1H,
d, J ) 0.9 Hz), 7.38 (1H, dd, J ) 7.9, 0.8 Hz), 7.27 (2H, m),
7.09 (1H, m), 6.89 (1H, m), 3.73 (3H, s), 3.27 (3H, s), 2.41 (2H,
m), 2.39 (3H, s), 1.60 (1H, m), 1.31 (1H, m); MS m/e 417.09 (M
+ H)+.
trans-2-[6-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cycloprop-1-yl-N-methoxy-N-methylcarboxamide, 10g.
10g was prepared from 9g in a manner similar to 10a (95%).
1H NMR (300 MHz, CDCl3) δ 7.83-7.66 (4H, m), 7.50 (1H,
dd, J ) 5.2, 8.6 Hz), 7.23 (2H, m), 6.99 (1H, m), 3.70 (3H, s),
3.25 (3H, s), 2.44 (2H, m), 2.35 (3H, s), 1.58 (m, 1H), 1.25 (1H,
m); MS m/e 417.09 (M + H)+.
trans-2-[6-Fluoro-1-(4-toluenesulfonyl)-1H-indol-3-yl]-
cyclopropanecarboxaldehyde, 11g. 11g was prepared from
10g in a manner similar to 11a (59%). 1H NMR (300 MHz,
CDCl3) δ 9.43 (1H, d, J ) 4.4 Hz), 7.75 (2H, d, J ) 8.4 Hz),
7.69 (1H, dd, J ) 2.3, 9.7 Hz), 7.44 (1H, dd, J ) 8.7, 5.2 Hz),
7.27 (3H, m), 6.99 (1H, m), 2.56 (1H, m), 2.37 (3H, s), 2.13
(1H, m), 1.72 (1H, m), 1.48 (1H, m); MS m/e 358.08 (M + H)+.