Molecules 2016, 21, 793
6 of 8
3
.2.4. Preparation of Intermediates 5a–d
Cesium carbonate (1.5 equiv.), potassium iodide (0.6 equiv.), and 4-, 5-, 6-, or 7-hydroxyindole
1.1 equiv.) were added to a solution of 3b (1.0 equiv.) in dimethylformamide (DMF, 40 mL).
(
˝
The mixture was stirred and heated to 40 C for 12 h. The solution was filtered and the solvent
was evaporated. Following the addition of ethyl acetate to the residue, the organic phase was washed
with 0.5 N NaOH and a saturated NaCl solution. The products were purified with silica gel column
chromatography using petroleum ether-ethyl acetate = 5:1 as the eluent to give the compounds 5a–d.
3
.2.5. Preparation of Target Compounds 6a–d
A solution of L-alaninamide hydrochloride (1.1 equiv.), sodium cyanoborohydride (0.8 equiv.),
Å molecular sieve (1 g), and triethylamine (1 mL) in methanol (80 mL) was stirred at room
3
temperature for 15 min. Then, 4a–d (1.0 equiv.) were added rapidly to the reaction mixture.
˝
The mixture was stirred at 40 C for 8 h. After reaction completion, the solution was filtered and the
solvent was evaporated. Water (300 mL) and ethyl acetate (500 mL) were added to the residue, the
organic phase was washed with a saturated NaCl solution and dried over Na SO for 8 h. The products
2
4
were purified by silica gel column chromatography using methanol–dichloromethane = 5:1 as the
eluent to give the compounds 6a–d as grey solids in 33.3%–41.0% yield.
1
(
S)-2-((4-(((1H-Indol-4-yl)oxy)methyl)benzyl)amino)propanamide (6a): H-NMR
δ
H
(DMSO-d , ppm): 10.92
6
(
s, 1H, NH indole), 6.98–7.43 (m, 11H, HAr and NH ), 5.06 (s, 2H, O-CH ), 3.54–3.71 (m, 2H, CH2-NH),
2 2
2
.99–3.02 (m, 1H, CH-CH ), 1.13 (d, 3H, J = 6.7 Hz, CH ). MS (ESI) m/z: 323.2 (M + H).
3 3
(
1
S)-2-((4-(((1H-Indol-5-yl)oxy)methyl)benzyl)amino)propanamide (6b): 1H-NMR
0.85 (s, 1H, NH indole), 6.98–7.43 (m, 11H, HAr and NH ), 5.06 (s, 2H, O-CH ), 3.53–3.70 (m, 2H,
δ
(DMSO-d , ppm):
H 6
2
2
CH -NH), 2.99–3.02 (m, 1H, CH-CH ), 1.13 (d, 3H, J = 6.7 Hz, CH ). MS (ESI) m/z: 323.2 (M + H).
2
3
3
1
(
S)-2-((4-(((1H-Indol-6-yl)oxy)methyl)benzyl)amino)propanamide (6c): H-NMR δ (DMSO-d , ppm): 10.68
H 6
(
s, 1H, NH indole), 6.98–7.40 (m, 11H, HAr and NH ), 5.04 (s, 2H, O-CH ), 3.53–3.70 (m, 2H, CH2-NH),
2 2
2
.99–3.02 (m, 1H, CH-CH ), 1.12 (d, 3H, J = 6.7 Hz, CH ). MS (ESI) m/z: 323.2 (M + H).
3 3
(
1
S)-2-((4-(((1H-Indol-7-yl)oxy)methyl)benzyl)amino)propanamide (6d): 1H-NMR
0.74 (s, 1H, NH indole), 6.98–7.40 (m, 11H, HAr and NH ), 5.04 (s, 2H, O-CH ), 3.53–3.70 (m, 2H,
δ
(DMSO-d , ppm):
H 6
2
2
CH -NH), 3.09–3.13 (m, 1H, CH-CH ), 1.14 (d, 3H, J = 6.7 Hz, CH ). MS (ESI) m/z: 323.2 (M + H).
2
3
3
The hydrogen atoms of the aliphatic NH groups, which are highly split due to the surrounding
groups, are not visible in the NMR of these compounds.
3
.2.6. Preparation of Target Compounds 7a–d
Compounds 7a were synthesized by a similar procedure as 6a
replaced by 5a at this reaction procedure. The resulting compounds 7a
solids in yields of 31.0%–43.5%.
–d
–d, except compounds 4a–d were
–
d
–d
were obtained as grey
1
(
S)-2-((3-(((1H-Indol-4-yl)oxy)methyl)benzyl)amino)propanamide (7a): H-NMR
δ
H
(DMSO-d , ppm): 10.75
6
(
s, 1H, NH indole), 6.99–7.40 (m, 11H, HAr and NH ), 5.05 (s, 2H, O-CH ), 3.55–3.71 (m, 2H, CH2-NH),
2 2
2
.99–3.02 (m, 1H, CH-CH ), 1.14 (d, 3H, J = 6.7 Hz, CH ). MS (ESI) m/z: 323.2 (M + H).
3 3
(
1
S)-2-((3-(((1H-Indol-5-yl)oxy)methyl)benzyl)amino)propanamide (7b): 1H-NMR
0.77 (s, 1H, NH indole), 6.99–7.40 (m, 11H, HAr and NH ), 5.05 (s, 2H, O-CH ), 3.55–3.73 (m, 2H,
δ
(DMSO-d , ppm):
H 6
2
2
CH -NH), 3.01–3.05 (m, 1H, CH-CH ), 1.12 (d, 3H, J = 6.7 Hz, CH ). MS (ESI) m/z: 323.2 (M + H).
2
3
3
1
(
S)-2-((3-(((1H-Indol-6-yl)oxy)methyl)benzyl)amino)propanamide (7c): H-NMR δ (DMSO-d , ppm): 10.82
H 6
(
s, 1H, NH indole), 6.99–7.45 (m, 11H, HAr and NH ), 5.08 (s, 2H, O-CH ), 3.55–3.73 (m, 2H, CH2-NH),
2 2
3
.02–3.05 (m, 1H, CH-CH ), 1.14 (d, 3H, J = 6.7 Hz, CH ). MS (ESI) m/z: 323.2 (M + H).
3 3