194
Vol. 53, No. 2
1-(3-Chlorophenyl)-2-[2-(1H-indol-3-yl)butyl]aminoethanol (40) 1H-
NMR d: 1.00 (dt, 3H, Jꢀ1, 6), 1.42—1.62 (m, 2H), 2.59 (ddd, 1H, Jꢀ9, 7,
12.5), 2.65—3.05 (m, 6H), 4.48 (dd, 0.5H, Jꢀ4, 7), 4.61 (dd, 0.5H, Jꢀ4, 7),
7.00 (dd, 1H, Jꢀ2, 8), 7.02—7.4 (m, 7H), 7.58 (m, 1H), 8.01 (br s, 1H). MS
m/z: 343 (MHꢅ), 212, 172, 130.
1-(3-Chlorophenyl)-2-[2-(6-methoxy-1H-indol-3-yl)propyl]amino-
ethanol (66) 1H-NMR d: 1.15 (dd, 3H, Jꢀ3, 6), 2.4—3.15 (m, 7H), 3.81
(s, 3H), 4.52 (dd, 0.5H, Jꢀ4, 6), 4.64 (dd, 0.5H, Jꢀ4, 6), 6.7—6.94 (m, 3H),
7.05—7.47 (m, 4H), 7.42 (dd, 1H, Jꢀ6, 10), 7.96 (br s, 1H). MS m/z: 359
(MHꢅ).
yloxy]acetate as an oil. 1H-NMR d: 1.56 (d, 3H, Jꢀ7), 3.10—3.48 (m, 2H),
3.77 (s, 3H), 4.64 (s, 2H), 4.92 (m, 1H), 6.76—7.05 (m, 3H), 7.48 (m, 1H),
8.08 (s, 1H). MS m/z: 293 (MHꢅ).
(2) A solution of methyl [3-(2-nitropropyl)-1H-indol-6-yloxy]acetate
(2.1 g, 7.2 mmol) in EtOH (50 ml) was hydrogenated over Raney-nickel (ca.
100 mg) at 50 °C under atmospheric pressure. After the theoretical amount
of hydrogen was consumed, the catalyst was filtered off. The filtrate was
concentrated to dryness to give ca. 1.9 g (quantitative yield) of the title com-
pound as an oil, which was used in the next step without further purification.
MS m/z: 263 (MHꢅ).
1-(3-Chlorophenyl)-2-[2-(6-trifluoromethyl-1H-indol-3-yl)propyl]-
aminoethanol (80) 1H-NMR d: 1.13 (d, 3H, Jꢀ6), 2.5—3.12 (m, 6H),
4.52 (dd, 0.5H, Jꢀ2, 6), 4.64 (dd, 0.5H, Jꢀ2, 6), 6.93 (m, 1H), 7.05—7.43
(m, 5H), 7.58—7.65 (m, 2H), 8.35 (br s, 1H). MS m/z: 397 (MHꢅ).
(1R)-(3-Chlorophenyl)-2-[2-(7-methoxy-1H-indol-3-yl)propyl]amino-
ethanol (82) 1H-NMR d: 1.13 (d, 3H, Jꢀ6), 1.8 (br, 2H), 2.61 (dt, 1H,
Jꢀ12, 8), 2.77—3.12 (m, 4H), 3.96 (s, 3H), 4.50 (dd, 0.5H, Jꢀ4, 7), 4.61
(dd, 0.5H, Jꢀ4, 7), 6.65 (d like, 1H, Jꢀ8), 6.98 (dd, 1H, Jꢀ2, 6), 7.04 (dt,
1H, Jꢀ2, 8), 7.12—7.25 (m, 4H), 7.32 (m, 1H), 8.20 (br s, 1H). MS m/z:
359 (MHꢅ).
(1R)-(3-Chlorophenyl)-2-[2-(7-ethoxy-1H-indol-3-yl)propyl]amino-
ethanol (85) 1H-NMR d: 1.12 (d, 3H, Jꢀ6), 1.48 (t, 3H, Jꢀ7), 2.4 (br,
2H), 2.60 (dt, 1H, Jꢀ12, 8), 2.77—2.96 (m, 3H), 3.04 (m, 1H), 4.20 (q, 2H,
Jꢀ7), 4.49 (dd, 0.5H, Jꢀ4, 9), 4.60 (dd, 0.5H, Jꢀ4, 9), 6.63 (d, 1H, Jꢀ7),
6.91—7.06 (m, 2H), 7.10—7.25 (m, 4H), 7.32 (m, 1H), 8.27 (br s, 1H). MS
m/z: 373 (MHꢅ).
(1R)-(3-Chlorophenyl)-2-[2-(7-propoxy-1H-indol-3-yl)propyl]amino-
ethanol (86) 1H-NMR d: 1.05 (d, 3H, Jꢀ6), 1.11 (t, 3H, Jꢀ7), 1.90 (sex,
2H, Jꢀ7), 2.1 (br, 2H), 2.61 (dt, 1H, Jꢀ12, 12), 2.81 (d, 2H, Jꢀ6), 2.87—
3.12 (m, 2H), 4.10 (t, 2H, Jꢀ7), 4.49 (dd, 0.5H, Jꢀ3, 8), 4.60 (dd, 0.5H,
Jꢀ3, 8), 6.62 (d, 1H, Jꢀ7), 6.95 (m, 1H), 7.03 (dd, 1H, Jꢀ2, 7), 7.1—7.25
(m, 4H), 7.31 (d, 1H, Jꢀ2), 8.25 (br s, 1H). MS m/z: 387 (MHꢅ), 188.
(1R)-(3-Chlorophenyl)-2-[2-(7-isopropoxy-1H-indol-3-yl)propyl]-
aminoethanol (87) 1H-NMR d: 1.12 (d, 3H, Jꢀ6), 1.40 (d, 6H, Jꢀ7), 2.0
(br, 2H), 2.61 (m, 1H), 2.81 (d, 2H, Jꢀ7), 2.88—3.15 (m, 2H), 4.50 (dd,
0.5H, Jꢀ4, 9), 4.60 (dd, 0.5H, Jꢀ4, 9), 4.72 (quint, 1H, Jꢀ7), 6.64 (d, 1H,
Jꢀ7), 6.9—7.1 (m, 2H), 7.1—7.3 (m, 4H), 7.32 (d, 1H, Jꢀ3), 8.22 (br s,
1H). MS m/z: 387 (MHꢅ), 188.
Methyl [3-[2-[[(2R)-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-
1H-indol-7-yloxy]acetate (88) 1H-NMR d: 1.13 (d, 3H, Jꢀ6), 2.38 (br,
2H), 2.62 (dt, 1H, Jꢀ12, 8), 2.77—3.13 (m, 4H), 2.81 (s, 3H), 4.52 (dd,
0.5H, Jꢀ4, 7), 4.62 (dd, 0.5H, Jꢀ4, 7), 4.75 (s, 2H), 6.57 (d, 1H, Jꢀ8),
6.92—7.06 (m, 2H), 7.11—7.36 (m, 5H), 8.77 (br s, 1H). MS m/z: 417
(MHꢅ), 385.
(1R)-(3-Chlorophenyl)-2-[2-[7-(2-cyanoethoxy)-1H-indol-3-yl]propyl]-
aminoethanol (89) 1H-NMR d: 1.14 (d, 3H, Jꢀ6), 2.22 (br, 2H), 2.63 (dt,
2H, Jꢀ10, 14), 2.90 (t, 2H, Jꢀ6), 3.05 (m, 1H), 2.7—3.0 (m, 2H), 4.36 (t,
2H, Jꢀ6), 4.54 (dd, 0.5H, Jꢀ4, 9), 4.63 (dd, 0.5H, Jꢀ4, 9), 6.62 (d, 1H,
Jꢀ8), 6.95—7.10 (m, 2H), 7.10—7.40 (m, 5H), 8.35 (br s, 1H). MS m/z:
398 (MHꢅ), 345.
Method Y. Typical Procedure; (2R)-[2-(3-Chlorophenyl)-2-hydroxy-
ethyl]amino-3-(1H-indol-3-yl)propionamide Oxalate (45) A mixture of
the free base of 43 (1.0 g, 2.7 mmol), 28% aqueous NH3 (10 ml), and satu-
rated NH3 in EtOH (10 ml) was stirred at room temperature for 20 h and
concentrated. The residue was dissolved in CHCl3 and the solution was
washed successively with water and brine and dried over anhydrous MgSO4.
The solvent was evaporated to give ca. 1 g (quantitative yield) of the free
base of 45 as an oil. The oil was converted to the oxalate in usual manner.
1H-NMR [dimethylsulfoxide (DMSO)-d6] d: 2.73—3.0 (br, 2H), 3.1—3.35
(br, 2H), 3.89 (br, 1H), 4.86 (br, 1H), 6.85—7.6 (m, 10H), 7.64 (d, 1H,
Jꢀ7), 7.75 (s, 2H), 10.99 (s, 1H). MS m/z: 358 (MHꢅ).
Method B-2. Typical Procedure; 3-(Aminopropyl)-7-(2-cyanoethoxy)-
1H-indole (1)
A
mixture of 7-(2-cyanoethoxy)-1H-indole (6.1 g,
33 mmol), a solution of 2-nitro-1-propene (8.6 g, 99 mmol) in toluene
(62 ml), molecular sieves 13X (1.2 g), and toluene (60 ml) was heated at
100 °C for 16 h and cooled to room temperature. After evaporation of the
solvent, the residue was chromatographed on silica gel with AcOEt/
hexaneꢀ1/2 to give 6.3 g of crude 7-(2-cyanoethoxy)-3-(2-nitropropyl)-1H-
indole. MS m/z: 274 (MHꢅ).
(2) A solution of crude 7-(2-cyanoethoxy)-3-(2-nitropropyl)-1H-indole
(6.0 g) in EtOH (50 ml) was added to a mixture of Fe (12 g, 0.21 mol),
NH4Cl (3.0 g, 56 mmol), EtOH (100 ml), and water (100 ml) at room temper-
ature. The mixture was heated to reflux for 2.5 h and cooled to room temper-
ature. The insoluble materials were filtered off, and the volatiles were evapo-
rated. After addition of aqueous K2CO3 to the resulting aqueous solution, the
mixture was extracted with CHCl3. The extract was washed with brine and
concentrated to dryness to give 2.3 g (30% yield for 2 steps) of the title com-
pound as a brown oil, which was used in the next step without further purifi-
cation. MS m/z: 244 (MHꢅ).
Methyl [3-(2-Aminopropyl)-1H-indol-7-yloxy]acetate (8) (1) A so-
lution of 3-(2-aminopropyl)-7-benzyloxy-1H-indole (4, 3.7 g, 13 mmol), di-
tert-butyl dicarbonate (2.9 g, 13 mmol), and Et3N (1.8 ml, 13 mmol) in
CHCl3 (50 ml) was stirred at room temperature for 16 h. The reaction mix-
ture was washed successively with water, 10% aqueous citric acid, water,
and brine and dried over anhydrous MgSO4. The solvent was evaporated and
the residue was chromatographed on silica gel with CHCl3 to 4.0 g (80%) of
7-benzyloxy-3-[2-(tert-butoxycarbonyl)aminopropyl]-1H-indole (5) as
a
white solid, which was used in the next step without further purification.
(2) A solution of 5 (8.0 g, 21 mmol) in EtOH (80 ml) was hydrogenated
at atmospheric pressure over 10% Pd on carbon (0.8 g) at ca. 50 °C. After
the theoretical amount of hydrogen was absorbed, the catalyst was filtered
off. The filtrate was concentrated to dryness to give ca. 6 g of 3-[2-(tert-bu-
toxycarbonyl)aminopropyl]-7-hydroxy-1H-indole (6) as an oil.
(3) A mixture of crude 6 (ca. 6 g, ca. 21 mmol), methyl chloroacetate
(2.3 g, 21 mmol), K2CO3 (2.9 g, 21 mmol), KI (0.2 g), MeOH (40 ml), and
acetone (80 ml) was heated to reflux for 4 h and cooled to room temperature.
After the insoluble materials were filtered off, the filtrate was concentrated to
dryness. The residue was chromatographed on silica gel with AcOEt/
hexaneꢀ2/3 to give 4.5 g (59% yield from 5) of methyl [3-[2-(tert-butoxy-
carbonyl)aminopropyl]-1H-indol-7-yloxy]acetate (7) as a brown oil. 1H-
NMR d: 1.10 (d, 3H, Jꢀ6), 1.44 (s, 9H), 2.82—3.02 (m, 2H), 3.81 (s, 3H),
4.00 (m, 1H), 4.42 (br s, 1H), 4.86 (s, 2H), 6.57 (d, 1H, Jꢀ8), 7.00 (t, 1H,
Jꢀ8), 7.02 (d, 1H, Jꢀ2), 7.31 (d, 1H, Jꢀ8), 8.65 (br s, 1H). MS m/z: 363
(MHꢅ), 307, 263, 231.
(4) A solution of 7 (4.2 g, 12 mmol) in 10% HCl in MeOH (21 ml) was
stirred at room temperature for 1 h. After addition of aqueous K2CO3, the
mixture was extracted with CHCl3. The extract was washed with brine and
concentrated to dryness to give 3.0 g (quantitative yield) of 8 as a gray solid,
which was used in the next step without further purification. 1H-NMR d:
1.16 (d, 3H, Jꢀ6), 1.45 (br s, 2H), 2.63 (dd, 1H, Jꢀ8, 15), 2.86 (ddd, 1H,
Jꢀ1, 6, 15), 3.28 (m, 1H), 3.81 (s, 3H), 4.76 (s, 2H), 6.58 (d, 1H, Jꢀ8), 6.99
(t, 1H, Jꢀ8), 7.04 (s, 1H), 7.28 (d, 1H, Jꢀ8), 8.74 (br s, 1H). MS m/z: 263
(MHꢅ).
1-(3-Chlorophenyl)-2-[3-hydroxy-(2R)-(1H-indol-3-yl)propyl]amino-
ethanol Oxalate (47) To a mixture of the free base of 43 (1.12 g,
3.0 mmol), anhydrous LiCl (0.25 g, 5.9 mmol), NaBH4 (0.22 g, 5.8 mmol),
and anhydrous THF (10 ml) was added dropwise anhydrous EtOH (20 ml)
under ice-cooling. The mixture was stirred at ca. 20 °C for 16 h and concen-
trated to dryness. The resultant residue was diluted with water and extracted
with CHCl3. The extract was washed with brine, and the solvent was evapo-
rated. The residue was chromatographed on silica gel with
CHCl3/MeOHꢀ10/1 to give 0.42 g (41%) of the free base of 47 as an oil.
Method X. Typical Procedure; 1-(3-Chlorophenyl)-2-[2-(7-methoxy-
1H-indol-3-yl)propyl]aminoethanol Fumarate (68)
A
solution of
3-chlorostyrene oxide (9, 0.77 g, 5.0 mmol) and 3-(2-aminopropyl)-7-
methoxy-1H-indole (2.16 g, 10.6 mmol) in MeOH (20 ml) was stirred at
room temperature for 64 h. After evaporation of the solvent, the residue was
chromatographed on silica gel with CHCl3/MeOHꢀ12/1 to give 1.1 g (62%
from 9) of the free base of 68 as an oil. 1H-NMR d: 1.12 (d, 3H, Jꢀ7), 2.61
(m, 1H), 2.78—2.86 (m, 2H), 2.88—3.12 (m, 2H), 3.95 (s, 3H), 4.56 (m,
1H), 6.65 (m, 1H), 6.93—7.09 (m, 2H), 7.11—7.29 (m, 4H), 7.33 (m, 1H),
8.25 (br s, 1H). MS m/z: 359 (MHꢅ). The oil was converted to the fumarate
in the usual manner.
1
The oil was converted to the oxalate in usual manner. H-NMR (DMSO-d6)
d: 2.88—3.73 (m, 7H), 4.98 (m, 1H), 6.94—7.16 (m, 3H), 7.24 (s, 1H),
7.26—7.55 (m, 4H), 7.64 (d, 1H, Jꢀ7), 11.00 (s, 1H). MS m/z: 345 (MHꢅ).