496
N. Takahashi et al. / Bioorg. Med. Chem. 22 (2014) 488–498
136–138 °C; 1H NMR (CDCl3) d 1.07 (18H, d, J = 7.3 Hz), 1.15 (6H, d,
J = 7.0 Hz), 1.25 (3H, m), 1.46 (3H, t, J = 7.1 Hz), 2.55 (3H, s), 3.32
(1H, m), 4.45 (2H, q, J = 7.1 Hz), 5.23 (2H, s), 6.33 (1H, s), 6.44
(1H, dd, J = 2.2, 8.4 Hz), 6.61 (1H, d, J = 8.1 Hz), 6.96 (1H, d,
J = 2.2 Hz), 7.12–7.15 (2H, m), 7.91 (1H, d, J = 2.2 Hz), 9.14 (1H,
s); MS (ESI) m/z 551 (M+H)+; HRMS (ESI) m/z calcd for C32H47N2O4-
Si (M+H)+ 551.3300, found 551.3301.
381(M+H)+, 379 (MꢀH)ꢀ; HRMS (ESI) m/z calcd for C22H25N2O4
(M+H)+ 381.1809, found 381.1809.
3.1.35. Ethyl N-[1-(4-hydroxy-3-isopropylbenzyl)-2-methyl-1H-
indol-4-yl]oxamate (10b)
The title compound was prepared according to the procedure
described for 10a, using 9b as a yellow solid (23%): mp 143–
145 °C; 1H NMR (CDCl3) d 1.19 (6H, d, J = 6.9 Hz), 1.46 (3H, t,
J = 6.9 Hz), 2.40 (3H, s), 3.15 (1H, m), 4.45 (2H, q, J = 6.9 Hz), 4.66
(1H, s), 5.24 (2H, s), 6.34 (1H, s), 6.50 (1H, dd, J = 2.2, 8.1 Hz),
6.59 (1H, d, J = 8.1 Hz), 6.95 (1H, d, J = 2.2 Hz), 7.09–7.15 (2H, m),
7.87 (1H, dd, J = 1.8, 6.6 Hz), 9.12 (1H, br s); IR (ATR) 3339, 2959,
1687, 1538 cmꢀ1; MS (ESI) m/z 395 (M+H)+, 393 (MꢀH)ꢀ; HRMS
(ESI) m/z calcd for C23H27N2O4 (M+H)+ 395.1965, found 395.1954.
3.1.31. Ethyl N-[1-(3-isopropyl-4-triisopropylsilanyloxybenzyl)-
2-methyl-1H-indol-5-yl]oxamate (9d)
The title compound was prepared according to the procedure
described for 9a, using 8d as a white solid (75%): mp 150–
151 °C; 1H NMR (CDCl3) d 1.07 (18H, d, J = 7.4 Hz), 1.15 (6H, d,
J = 7.0 Hz), 1.26 (3H, m), 1.42 (3H, t, J = 7.1 Hz), 2.52 (3H, s), 3.31
(1H, m), 4.42 (2H, q, J = 7.1 Hz), 5.20 (2H, s), 6.31 (1H, s), 6.43
(1H, dd, J = 2.2, 8.4 Hz), 6.60 (1H, d, J = 8.4 Hz), 6.95 (1H, d,
J = 2.2 Hz), 7.20 (1H, d, J = 8.8 Hz), 7.26 (1H, dd, J = 2.2, 8.8 Hz),
7.91 (1H, d, J = 2.2 Hz), 8.89 (1H, br s); MS (ESI) m/z 551 (M+H)+;
HRMS (ESI) m/z calcd for C32H47N2O4Si (M+H)+ 551.3300, found
551.3303.
3.1.36. Ethyl N-[1-(4-hydroxy-3-isopropylbenzyl)-7-methyl-1H-
indol-4-yl]oxamate (10c)
The title compound was prepared according to the procedure
described for 10a, using 9c as a yellow solid (12%): mp 138–
139 °C; 1H NMR (CDCl3) d 1.19 (6H, d, J = 7.0 Hz), 1.46 (3H, t,
J = 7.1 Hz), 2.55 (3H, s), 3.16 (1H, m), 4.45 (2H, q, J = 7.1 Hz), 4.69
(1H, s), 5.51 (2H, s), 6.48 (1H, dd, J = 2.2, 8.1 Hz), 6.54 (1H, d,
J = 3.3 Hz), 6.62 (1H, d, J = 8.1 Hz), 6.88 (1H, d, J = 2.6 Hz), 6.90
(1H, d, J = 8.4 Hz), 7.08 (1H, d, J = 3.3 Hz), 7.80 (1H, d, J = 7.7 Hz),
9.14 (1H, br s); IR (ATR) 3316, 2958, 1764, 1682, 1541 cmꢀ1; MS
(ESI) m/z 395 (M+H)+, 393 (MꢀH)ꢀ; HRMS (ESI) m/z calcd for
3.1.32. Ethyl N-[1-(3-isopropyl-4-triisopropylsilanyloxybenzyl)-
2-methyl-1H-indol-4-yl]malonamate (9b’)
Ethyl malonyl chloride (248
ture of 8b (829.8 mg, 1.8 mmol) and Et3N (284
l
L, 1.9 mmol) was added to a mix-
L, 2.0 mmol) in
l
CH2Cl2 (40 mL) at 0 °C. The mixture was stirred at room tempera-
ture for 30 min and diluted with EtOAc. The resulting mixture was
washed with water and brine, and dried over Na2SO4. After evapo-
ration of the solvent, the residue was purified by flash chromatog-
raphy on silica gel (hexane/EtOAc = 4/1) to give the title compound
(737.6 mg, 71%) as a foam: 1H NMR (CDCl3) d 1.07 (18H, d,
J = 7.0 Hz), 1.15 (6H, d, J = 6.8 Hz), 1.25 (3H, m), 1.35 (3H, t,
J = 7.1 Hz), 2.39 (3H, s), 3.31 (1H, m), 3.55 (2H, s), 4.31 (2H, q,
J = 7.1 Hz), 5.21 (2H, s), 6.37 (1H, s), 6.45 (1H, d, J = 8.4 Hz), 6.59
(1H, d, J = 8.4 Hz), 6.97 (1H, s), 7.05–7.11 (2H, m), 7.82 (1H, d,
J = 7.3 Hz), 9.66 (1H, s); MS (ESI) m/z 565 (M+H)+; HRMS (ESI) m/
z calcd for C33H49N2O4Si (M+H)+ 565.3456, found 565.3455.
C
23H27N2O4 (M+H)+ 395.1965, found 395.1956.
3.1.37. Ethyl N-[1-(4-hydroxy-3-isopropylbenzyl)-2-methyl-1H-
indol-4-yl]malonamate (10b0)
The title compound was prepared according to the procedure
described for 10a, using 9b as a foam (88%): 1H NMR (CDCl3) d
1.20 (6H, d, J = 7.0 Hz), 1.35 (3H, t, J = 7.4 Hz), 2.39 (3H, s), 3.16
(1H, m), 3.55 (2H, s), 4.30 (2H, q, J = 7.4 Hz), 4.83 (1H, s), 5.22
(2H, s), 6.37 (1H, s), 6.49 (1H, dd, J = 2.2, 8.0 Hz), 6.58 (1H, d,
J = 8.4 Hz), 6.96 (1H, d, J = 2.2 Hz), 7.02–7.11 (2H, m), 7.81 (1H, d,
J = 6.6 Hz), 9.68 (1H, s); IR (ATR) 3312, 2960, 1717, 1659,
1551 cmꢀ1; MS (ESI) m/z 409 (M+H)+, 407 (MꢀH)ꢀ; HRMS (ESI)
m/z calcd for C24H29N2O4 (M+H)+ 409.2122, found 409.2113.
3.1.33. Ethyl N-[1-(3-isopropyl-4-triisopropylsilanyloxybenzyl)-
7-methyl-1H-indol-4-yl]malonamate (9c’)
The title compound was prepared according to the procedure
described for 9b’, using 8c as a white solid (62%): mp 118–
120 °C; 1H NMR (CDCl3) d 1.08 (18H, d, J = 4.9 Hz), 1.14 (6H, d,
J = 7.0 Hz), 1.26 (3H, m), 1.35 (3H, m), 2.53 (3H, s), 3.33 (1H, m),
3.55 (2H, s), 4.30 (2H, q, J = 7.3 Hz), 5.50 (2H, s), 6.42 (1H, dd,
J = 2.2, 8.4 Hz), 6.59–6.62 (2H, m), 6.86 (1H, d, J = 7.6 Hz), 6.91
(1H, d, J = 2.2 Hz), 7.05 (1H, d, J = 3.3 Hz), 7.73 (1H, d, J = 7.7 Hz),
9.69 (1H, s)); MS (ESI) m/z 565 (M+H)+, 563 (MꢀH)ꢀ; HRMS (ESI)
m/z calcd for C33H49N2O4Si (M+H)+ 565.3456, found 565.3455.
3.1.38. Ethyl N-[1-(4-hydroxy-3-isopropylbenzyl)-7-methyl-1H-
indol-4-yl]malonamate (10c0)
The title compound was prepared according to the procedure
described for 10a, using 9c as a white solid (87%): mp 141–
142 °C; 1H NMR (CDCl3) d 1.19 (6H, d, J = 7.0 Hz), 1.34 (3H, t,
J = 7.1 Hz), 2.52 (3H, s), 3.16 (1H, m), 3.55 (2H, s), 4.30 (2H, q,
J = 7.1 Hz), 4.93 (1H, s), 5.49 (2H, s), 6.46 (1H, dd, J = 2.0, 8.2 Hz),
6.59 (1H, d, J = 3.3 Hz), 6.60 (1H, d, J = 8.1 Hz), 6.85 (1H, d,
J = 7.7 Hz), 6.90 (1H, d, J = 1.2 Hz), 7.04 (1H, d, J = 3.3 Hz), 7.72
(1H, d, J = 8.1 Hz), 9.70 (1H, s); IR (ATR) 3262, 2957, 1719, 1652,
1621, 1556 cmꢀ1; MS (ESI) m/z 409 (M+H)+, 407 (MꢀH)ꢀ; HRMS
(ESI) m/z calcd for C24H29N2O4 (M+H)+ 409.2122, found 409.2120.
3.1.34. Ethyl N-[1-(4-hydroxy-3-isopropylbenzyl)-1H-indol-4-
yl]oxamate (10a)
A mixture of 9a (112.0 mg, 0.2 mmol) and tetrabutylammonium
fluoride (1 M in THF, 230
l
L, 0.2 mmol) in THF (1.0 mL) was stirred
3.1.39. Ethyl N-[1-(4-hydroxy-3-isopropylbenzyl)-2-methyl-1H-
indol-5-yl]oxamate (10d)
at room temperature for 30 min. The reaction mixture was then di-
luted with EtOAc, successively washed with water and brine, and
dried over Na2SO4. After evaporation of the solvent, the residue
was purified by flash chromatography on silica gel hexane/
EtOAc = 1/0–4/1) to give the title compound (33.1 mg, 42%) as a
white solid: mp 145–146 °C; 1H NMR (CDCl3) d 1.20 (6H, d,
J = 6.9 Hz), 1.45 (3H, t, J = 7.3 Hz), 3.17 (1H, m), 4.45 (2H, q,
J = 7.3 Hz), 5.24 (2H, s), 6.54 (1H, d, J = 3.3 Hz), 6.65 (1H, d,
J = 4.5 Hz), 6.74 (1H, dd, J = 2.2, 10.2 Hz), 7.04 (1H, d, J = 2.2 Hz),
7.13 (1H, d, J = 3.3 Hz), 7.19–7.20 (2H, m), 7.92 (1H, m), 9.18 (1H,
br s); IR (ATR) 3359, 2960, 1761, 1692, 1536 cmꢀ1; MS (ESI) m/z
The title compound was prepared according to the procedure
described for 10a, using 9c as a pale yellow solid (30%): mp 126–
129 °C; 1H NMR (CDCl3) d 1.18 (6H, d, J = 7.0 Hz), 1.41 (3H, t,
J = 7.0 Hz), 2.35 (3H, s), 3.18 (1H, m), 4.40 (2H, q, J = 7.0 Hz), 5.45
(2H, s), 5.57 (1H, s), 6.28 (1H, s), 6.45 (1H, dd, J = 1.9, 8.1 Hz),
6.61 (1H, d, J = 8.5 Hz), 6.93 (1H, d, J = 1.9 Hz), 7.15 (1H, d,
J = 8.8 Hz), 7.24 (1H, dd, J = 2.2, 9.1 Hz), 7.89 (1H, s), 8.92 (1H, br
s); IR (ATR) 1736, 1683 cmꢀ1; MS (ESI) m/z 395 (M+H)+, 393
(MꢀH)ꢀ; HRMS (ESI) m/z calcd for C23H27N2O4 (M+H)+ 395.1965,
found 395.1959.