Journal of Medicinal Chemistry
Article
NMR (500 MHz, CDCl3): δ 7.97 (s, 1H), 7.24 (s, 1H), 7.22 (s, 1H),
7.14 (t, J = 8.0 Hz, 3H), 7.08 (t, J = 2.8 Hz, 1H), 6.76 (d, J = 2.2 Hz,
1H), 6.54 (dd, J = 8.6, 2.2 Hz, 1H), 6.38−6.37 (m, 1H), 3.85 (d, J =
14.2 Hz, 1H), 3.55 (d, J = 14.3 Hz, 2H), 3.42 (tt, J = 7.8, 3.1 Hz, 1H),
3.13 (dd, J = 11.9, 3.8 Hz, 1H), 2.92−2.82 (m, 2H), 2.61 (dd, J =
13.6, 4.1 Hz, 1H), 2.34 (s, 3H), 1.20 (s, 9H). 13C NMR (126 MHz,
CDCl3): δ 142.77, 138.75, 136.60, 130.20, 129.33, 128.83, 128.35,
124.38, 112.66, 111.59, 102.45, 101.82, 67.15, 55.83, 55.51, 54.54,
49.01, 27.59, 21.22. HRMS (ESI+) m/z: [M + H]+, calcd for
C23H32N3O+, 366.2540; found, 366.2555.
The solvent was evaporated under reduced pressure, and the residue
was purified by flash column chromatography (hexane/EA = 90:10)
to obtain tert-butyl 4-hydroxy-1H-indole-1-carboxylate 9 as a colorless
solid. 1H NMR (600 MHz, CDCl3): δ 7.74 (d, J = 7.3 Hz, 1H), 7.53
(d, J = 3.3 Hz, 1H), 7.16 (t, J = 8.1 Hz, 1H), 6.70−6.65 (m, 2H), 1.68
(s, 9H). 13C NMR (151 MHz, CDCl3): δ 150.10, 148.89, 137.01,
125.30, 124.82, 119.82, 108.38, 107.93, 103.74, 84.04, 28.31. EI (M +
H)+ = 234.
tert-Butyl 4-(Oxiran-2-ylmethoxy)-1H-indole-1-carboxylate (10).
To a solution of 9 (1 equiv) in acetonitrile were added 2-
(chloromethyl)oxirane 4 (3 equiv), K2CO3 (3 equiv), and KI (3
equiv). The mixture was heated to 70 °C for 16 h, cooled, and filtered,
washing with EA. The filtrate was concentrated in vacuo and purified
by flash chromatography on silica gel (EtOAc/hexanes) to afford tert-
butyl 4-(oxiran-2-ylmethoxy)-1H-indole-1-carboxylate 10 as a color-
1-((1H-Indol-7-yl)amino)-3-(tert-butyl(4-methylbenzyl)amino)-
1
propan-2-ol (34). Off-white solid, Rf = 0.2 (DCM/EA = 3:1). H
NMR (500 MHz, CDCl3): δ 8.58 (s, 1H), 7.23 (d, J = 8.0 Hz, 2H),
7.13 (dd, J = 14.9, 7.8 Hz, 3H), 7.01 (d, J = 2.7 Hz, 1H), 6.95 (t, J =
7.7 Hz, 1H), 6.47−6.45 (m, 1H), 6.36 (d, J = 7.6 Hz, 1H), 3.81 (d, J
= 14.2 Hz, 2H), 3.58 (d, J = 14.1 Hz, 1H), 3.47 (d, J = 3.4 Hz, 1H),
3.23 (dd, J = 12.6, 3.1 Hz, 1H), 2.95−2.84 (m, 2H), 2.61 (dd, J =
13.6, 4.3 Hz, 1H), 2.36 (s, 3H), 1.22 (d, J = 1.4 Hz, 9H). 13C NMR
(126 MHz, CDCl3): δ 138.59, 136.77, 134.47, 129.38, 128.57, 128.53,
126.95, 123.51, 120.47, 111.77, 104.56, 103.00, 67.48, 55.97, 55.59,
53.77, 48.13, 27.58, 21.27. HRMS (ESI+) m/z: [M + H]+, calcd for
C23H32N3O+, 366.2540; found, 366.2555.
1
less solid. H NMR (600 MHz, CDCl3): δ 7.78 (d, J = 7.5 Hz, 1H),
7.51 (d, J = 3.5 Hz, 1H), 7.21 (t, J = 8.1 Hz, 1H), 6.73 (d, J = 3.7 Hz,
1H), 6.66 (d, J = 7.9 Hz, 1H), 4.35 (dd, J = 11.1, 3.1 Hz, 1H), 4.09
(dd, J = 11.1, 5.6 Hz, 1H), 3.43 (ddt, J = 5.7, 4.0, 3.0 Hz, 1H), 2.94−
2.92 (m, 1H), 2.80 (dd, J = 4.9, 2.7 Hz, 1H), 1.67 (s, 9H). 13C NMR
(151 MHz, CDCl3): δ 151.86, 149.93, 136.71, 125.09, 124.63, 121.15,
108.99, 104.42, 104.29, 83.82, 69.09, 50.35, 44.88, 28.29. EI (M +
H)+ = 290.
1-(tert-Butyl(4-methylbenzyl)amino)-3-((1-methyl-1H-indol-4-
yl)oxy)propan-2-ol (32). To a solution of 16 (1 equiv) in THF
cooled to 0 °C was added NaH (1.5 equiv) in one portion. After
stirring at 0 °C for 1 h, MeI (1 equiv) was added. The mixture was
allowed to warm to room temperature overnight with stirring. The
reaction mixture was quenched with saturated aqueous NH4Cl
solution and extracted with EA. The organic layer was washed with
saturated sodium bicarbonate solution, brine, dried (Na2SO4), and
concentrated in vacuo. The crude residue was purified on silica gel
General Procedure for the Synthesis of 11 or 25. A solution
of 10 (1 equiv) and amine 3 (1 equiv) in toluene was heated to 130
°C overnight. The solution was cooled and concentrated in vacuo to
purify on silica gel (DCM/EA) to afford the title compound.
tert-Butyl 4-(3-(tert-Butyl(4-methylbenzyl)amino)-2-hydroxypro-
poxy)-1H-indole-1-carboxylate (11a). Off-white solid, Rf = 0.3
1
(DCM/EA = 3:1). H NMR (600 MHz, CDCl3): δ 7.72 (d, J = 8.4
Hz, 1H), 7.47 (d, J = 3.8 Hz, 1H), 7.21 (d, J = 7.7 Hz, 2H), 7.16 (t, J
= 8.1 Hz, 1H), 7.11 (d, J = 7.7 Hz, 2H), 6.64 (d, J = 3.8 Hz, 1H), 6.51
(d, J = 8.0 Hz, 1H), 3.84 (m, 3H), 3.57 (d, J = 14.4 Hz, 2H), 2.85 (m,
1H), 2.77 (dd, J = 13.7, 4.9 Hz, 1H), 2.32 (s, 3H), 1.65 (s, 9H), 1.19
(s, 11H). 13C NMR (126 MHz, CDCl3): δ 152.22, 149.96, 138.74,
136.59, 129.31, 128.37, 125.09, 124.32, 121.05, 108.50, 104.49,
104.22, 83.69, 70.56, 67.42, 55.84, 55.56, 53.86, 28.29, 27.55, 21.20.
ESI (M + H)+ = 467.
1
(DCM/EA) to give the desired product 32 as an off-white solid. H
NMR (500 MHz, CDCl3): δ 7.25−7.23 (m, 1H), 7.15−7.08 (m, 3H),
6.97−6.92 (m, 2H), 6.56 (d, J = 3.1 Hz, 1H), 6.41 (d, J = 7.7 Hz,
1H), 3.97−3.88 (m, 2H), 3.85 (d, J = 14.4 Hz, 1H), 3.77 (s, 3H),
3.62 (td, J = 9.7, 5.0 Hz, 2H), 2.86 (qd, J = 14.0, 7.0 Hz, 2H), 2.35 (s,
3H), 1.22 (s, 10H). 13C NMR (126 MHz, CDCl3): δ 152.70, 138.95,
138.35, 136.55, 129.32, 128.37, 127.26, 122.39, 119.27, 102.85,
100.50, 98.47, 70.46, 67.55, 55.85, 55.57, 54.19, 33.14, 27.59, 21.23.
tert-Butyl 4-(3-(tert-Butyl(2-methylbenzyl)amino)-2-hydroxypro-
+
HRMS (ESI+) m/z: [M + H]+, calcd for C24H33N2O2 , 381.2537;
poxy)-1H-indole-1-carboxylate (11b). Off-white solid, Rf = 0.3
1
found, 381.2551.
(DCM/EA = 3:1). H NMR (600 MHz, CDCl3): δ 7.72 (d, J = 7.0
N-(tert-Butyl)-2-methoxy-3-((1-methyl-1H-indol-4-yl)oxy)-N-(4-
methylbenzyl)propan-1-amine (38). To a solution of 16 (1 equiv) in
THF cooled to 0 °C was added NaH (3 equiv) in one portion. After
stirring at 0 °C for 1 h, MeI (3 equiv) was added. The mixture was
allowed to warm to room temperature overnight with stirring. The
reaction mixture was quenched with saturated aqueous NH4Cl
solution and extracted with EA. The organic layer was washed with
saturated sodium bicarbonate solution, brine, dried (Na2SO4), and
concentrated in vacuo. The crude residue was purified on silica gel
Hz, 1H), 7.47 (d, J = 3.1 Hz, 1H), 7.40−7.38 (m, 1H), 7.17−7.13 (m,
4H), 6.63 (d, J = 3.7 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 3.91 (d, J =
14.1 Hz, 1H), 3.81 (dd, J = 4.8, 3.0 Hz, 2H), 3.62 (d, J = 14.1 Hz,
1H), 3.32 (dt, J = 10.0, 5.0 Hz, 1H), 2.86 (dd, J = 13.8, 8.6 Hz, 1H),
2.78 (dd, J = 13.9, 5.1 Hz, 1H), 2.38 (s, 3H), 1.66 (s, 9H), 1.22 (s,
9H). 13C NMR (126 MHz, CDCl3): δ 152.21, 150.02, 138.98, 136.45,
130.62, 129.60, 127.19, 126.10, 125.13, 124.39, 121.06, 108.54,
104.48, 104.25, 70.54, 67.94, 56.15, 53.40, 53.20, 28.34, 27.25, 19.54.
ESI (M + H)+ = 467.
1
(DCM/EA) to give the desired product 38 as an off-white solid. H
tert-Butyl 4-(3-(tert-Butyl(4-methylbenzyl)amino)-2-hydroxypro-
NMR (500 MHz, CDCl3): δ 7.42−7.37 (m, 2H), 7.27−7.21 (m, 3H),
7.09−7.05 (m, 2H), 6.69 (dd, J = 3.1, 0.8 Hz, 1H), 6.49 (d, J = 7.7
Hz, 1H), 4.26 (dd, J = 10.0, 3.3 Hz, 1H), 3.97 (dd, J = 10.1, 6.0 Hz,
1H), 3.89 (s, 3H), 3.88−3.85 (m, 2H), 3.53 (s, 3H), 3.50 (ddt, J =
8.5, 5.6, 2.7 Hz, 1H), 3.02 (dd, J = 13.9, 8.2 Hz, 1H), 2.90 (dd, J =
14.0, 5.2 Hz, 1H), 2.47 (s, 3H), 1.28 (s, 9H). 13C NMR (126 MHz,
CDCl3): δ 152.93, 140.07, 138.33, 135.98, 128.96, 128.29, 127.10,
122.35, 119.41, 102.58, 100.39, 98.72, 80.07, 69.16, 58.37, 55.72,
55.65, 52.62, 33.13, 27.41, 21.20. HRMS (ESI+) m/z: [M + H]+, calcd
poxy)-1H-indole-1-carboxylate (25). Off-white solid, Rf = 0.3
1
(DCM/MeOH = 10:1). H NMR (600 MHz, DMSO-d6): δ 11.07
(s, 1H), 7.20 (s, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.97 (t, J = 7.4 Hz,
1H), 7.21 (t, J = 7.2 Hz, 2H), 6.44 (s, 1H), 4.00−4.06 (m, 2H),
3.87−3.93 (m, 1H), 2.74 (dd, J = 11.2, 6.5 Hz, 1H), 2.64 (dd, J =
11.2, 6.5 Hz, 1H), 1.19 (s, 11H). 13C NMR (126 MHz, DMSO-d6): δ
152.09, 137.33, 123.43, 121.74, 118.42, 104.80, 99.93, 98.38, 70.57,
68.87, 50.01, 45.38, 28.62. HRMS (ESI+) m/z: [M + H]+, calcd for
+
C15H22N2O2 , 263.1754; found, 263.1763.
+
for C25H35N2O2 , 395.2693; found, 395.2708.
General Procedure for the Synthesis of 12. To a solution of
11 (1 equiv) in THF cooled to 0 °C was added NaH (1.5 equiv) in
one portion. The reaction mixture was stirred at 0 °C for 1 h, and
then, MeI (1.5 equiv) was added dropwise. The mixture was allowed
to warm to room temperature overnight with stirring. The reaction
mixture was quenched with saturated aqueous NH4Cl solution and
extracted with EA. The organic layer was washed with saturated
sodium bicarbonate solution, brine, dried (Na2SO4), and concen-
trated in vacuo. The crude residue was purified on silica (DCM/EA)
gel to give the desired product 12.
tert-Butyl 4-Hydroxy-1H-indole-1-carboxylate (9). To a solution
of 4-hydroxyindole (8, 1 equiv) in acetonitrile were added di-tert-
butyl dicarbonate (3 equiv) and dimethylaminopyridine (DMAP)
(0.1 equiv). The solution was aged at room temperature for 1 h and
then concentrated in vacuo. Solid potassium carbonate (5 equiv) was
added to a solution of the crude residue in methanol, and the mixture
was stirred at room temperature for 3 h. The reaction mixture was
acidified with acetic acid and extracted with EA. The organic layer was
washed with saturated brine and dried over anhydrous sodium sulfate.
987
J. Med. Chem. 2021, 64, 980−990