36
C.-H. Yao et al. / European Journal of Medicinal Chemistry 55 (2012) 32e38
60 ꢀC and further stirred for 20 h. The reaction was cooled to 0 ꢀC
and neutralized by the addition of 1 N HCl(aq). The mixture was
extracted with EtOAc and the organic layer was dried over MgSO4,
filtered and concentrated under reduced pressure. The residue was
purified by column chromatography to afford the desired product 8.
4.43 (d, J ¼ 9.3 Hz, 1H), 3.98 (dd, J ¼ 11.1, 5.4 Hz, 1H), 3.76 (t,
J ¼ 9.3 Hz, 1H), 3.68 (ddd, J ¼ 10.5, 9.3, 5.4 Hz, 1H), 3.48e3.35 (m,
2H); 13C NMR (100 MHz, CD3OD):
d 138.5, 137.0, 135.0, 134.4, 129.6,
129.2, 129.0, 128.81, 128.80, 127.4, 127.1, 126.8, 126.3, 123.0, 121.2,
120.5, 114.3, 111.3, 80.2, 79.0, 75.1, 71.8, 71.4, 51.1; ESMS m/z: 390
(MHþ), 412 (MNaþ); HPLC purity 100%.
4.1.6. General procedure for the synthesis of compounds 9ae9g
NaH (1.2 equiv) and aryl bromides or aryl chlorides (1.2 equiv) were
sequentially added to a stirred solution of 8 (1.0 equiv) in DMF at 0 ꢀC.
The reaction was slowly warmed to room temperature and stirred for
16 h. The reaction was quenched by the addition of H2O at 0 ꢀC and
extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered
and concentrated under reduced pressure. The residue was purified by
column chromatography to afford the desired products 9ae9g.
4.1.7.6. 4-Fluoro-1-(4-methoxybenzyl)-3-(
b
-
D
-xylopyranosyl)-1H-
indole (1f). 1H NMR (300 MHz, CD3OD):
d
7.34 (s, 1H), 7.16e7.01 (m,
4H), 6.85e6.80 (m, 2H), 6.75e6.69 (m, 1H), 5.27 (s, 2H), 4.51 (dd,
J ¼ 9.6, 1.2 Hz, 1H), 3.93 (dd, J ¼ 10.8, 5.1 Hz, 1H), 3.79e3.73 (m, 1H),
3.73 (s, 3H), 3.64 (ddd, J ¼ 10.8, 9.0, 5.1 Hz, 1H), 3.43 (t, J ¼ 9.0 Hz,
1H), 3.36 (t, J ¼ 10.8 Hz, 1H); 13C NMR (75 MHz, CD3OD):
d 160.8,
159.7, 156.5, 141.1, 140.9, 130.8, 129.7, 123.4, 123.3, 117.6, 117.3, 115.2,
112.61, 112.57, 107.72, 107.67, 106.0, 105.7, 80.3, 78.5, 75.2, 75.1, 71.7,
71.2, 55.8, 50.8; ESMS m/z: 388 (MHþ), 410 (MNaþ); HPLC purity
98.7%.
4.1.7. General procedure for the synthesis of compounds 1ae1g
A mixture of 9ae9gand 10%Pd/C inMeOH/THF(1/1)wasstirred at
room temperature under 1 atm H2(g) for 1w3 h. The reaction was
filtered through a pad of Celite and the filtrate was concentrated
under reduced pressure. The residue was then purified by column
chromatography (MeOH/CH2Cl2) to providethe final products 1ae1g.
4.1.7.7. 7-Fluoro-1-(4-methoxybenzyl)-3-(
b
-
d
D-xylopyranosyl)-1H-
indole (1g). 1H NMR (300 MHz, CD3OD):
7.46 (d, J ¼ 7.8 Hz, 1H),
7.30 (s, 1H), 7.11 (d, J ¼ 8.7 Hz, 2H), 6.95 (td, J ¼ 7.8, 4.5 Hz, 1H),
6.85e6.78 (m, 3H), 5.39 (s, 2H), 4.37 (d, J ¼ 9.9 Hz, 1H), 3.96 (dd,
J ¼ 11.1, 5.1 Hz, 1H), 3.73 (s, 3H), 3.73e3.61 (m, 2H), 3.45e3.32 (m,
4.1.7.1. 1-Benzyl-3-(
(400 MHz, CD3OD):
b
-
D
-xylopyranosyl)-1H-indole (1a). 1H NMR
7.71e7.69 (m, 1H), 7.34 (s, 1H), 7.30e7.17 (m,
d
2H); 13C NMR (75 MHz, CD3OD):
d 160.7, 153.2, 150.0, 133.0, 132.9,
6H), 7.11 (ddd, J ¼ 8.0, 7.2, 1.2 Hz, 1H), 7.04 (ddd, J ¼ 8.0, 7.2, 1.2 Hz,
1H), 5.36 (s, 2H), 4.42 (d, J ¼ 9.2 Hz, 1H), 3.98 (dd, J ¼ 11.2, 5.2 Hz,
1H), 3.75 (t, J ¼ 9.2 Hz, 1H), 3.68 (ddd, J ¼ 10.4, 9.2, 5.2 Hz, 1H), 3.45
(t, J ¼ 9.2 Hz,1H), 3.38 (dd, J ¼ 11.2,10.4 Hz,1H); 13C NMR (100 MHz,
132.0, 130.5, 129.5, 125.9, 125.7, 120.8, 120.7, 117.3, 117.2, 115.4, 115.3,
115.1, 108.5, 108.2, 80.1, 78.6, 75.1, 71.7, 71.4, 55.8, 52.7, 52.6; ESMS
m/z: 388 (MHþ), 410 (MNaþ); HPLC purity 99.0%.
CD3OD):
d
139.5, 138.4, 129.8, 129.1, 128.8, 128.6, 128.2, 123.0, 121.1,
4.1.8. General procedure for the synthesis of compounds 10he10j
A mixture of 8 and 10% Pd/C in MeOH/THF (1/1) was stirred at
room temperature under 1 atm H2(g) for 3 h. The reactionwas filtered
through a pad of Celite and the filtrate was concentrated under
reduced pressure. The residue was then purified by column chro-
matography (MeOH/CH2Cl2) to provide the final products 10he10j.
120.5, 114.2, 111.2, 80.2, 79.0, 75.1, 71.8, 71.4, 51.0; ESMS m/z: 340
(MHþ), 362 (MNaþ); HPLC purity 89.5%.
4.1.7.2. 1-(4-Fluorobenzyl)-3-(
b
-
D
-xylopyranosyl)-1H-indole (1b).
1H NMR (400 MHz, CD3OD):
d
7.69 (d, J ¼ 8.0 Hz,1H), 7.33 (s,1H), 7.28
(d, J ¼ 8.0 Hz,1H), 7.21e7.17 (m, 2H), 7.12e7.08 (m,1H), 7.05e6.97 (m,
3H), 5.34 (s, 2H), 4.41 (d, J ¼ 9.2 Hz,1H), 3.97 (dd, J ¼ 10.8, 5.2 Hz, 1H),
3.74 (t, J ¼ 9.2 Hz, 1H), 3.67 (ddd, J ¼ 10.8, 9.2, 5.2 Hz, 1H), 3.44 (t,
J ¼ 9.2 Hz, 1H), 3.37 (t, J ¼ 10.8 Hz, 1H); 13C NMR (75 MHz, CD3OD):
4.1.9. General procedure for the synthesis of compounds 1he1j
Cs2CO3 (5 equiv) was added to a stirred solution of 10he10j (1.0
equiv) and 4-cyclopropylbenzyl bromide (1.2 equiv) in DMF at room
temperature. After 24 h, the reaction was quenched by the addition
of H2O, and the resulting mixture was extracted with EtOAc. The
organic layer was dried over MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by column
chromatography to afford the desired products 1he1j.
d
165.3,162.1,138.3,135.6,135.5,130.2,130.1,129.0,128.8,123.0,121.2,
120.5,116.6,116.3,114.4,111.2, 80.2, 79.0, 75.1, 71.8, 71.4, 50.2;ESMSm/
z: 358 (MHþ), 380 (MNaþ); HPLC purity 91.5%.
4.1.7.3. 1-(4-Methoxybenzyl)-3-(
b
-
D
-xylopyranosyl)-1H-indole (1c).
1H NMR (400 MHz, CD3OD):
d
7.67 (d, J ¼ 8.0 Hz, 1H), 7.32e7.30 (m,
2H), 7.14e7.08 (m, 3H), 7.04e7.00 (m, 1H), 6.84e6.81 (m, 2H), 5.27
(s, 2H), 4.40 (d, J ¼ 9.2 Hz, 1H), 3.96 (dd, J ¼ 10.8, 5.2 Hz, 1H),
3.75e3.71 (m, 1H), 3.73 (s, 3H), 3.67 (ddd, J ¼ 10.8, 9.2, 5.2 Hz, 1H),
3.44 (t, J ¼ 9.2 Hz, 1H), 3.37 (t, J ¼ 10.8 Hz, 1H); 13C NMR (75 MHz,
4.1.9.1. 1-(4-Cyclopropylbenzyl)-3-(
b
-
D
-xylopyranosyl)-1H-indole
(1h). 1H NMR (400 MHz, CD3OD):
d
7.67 (d, J ¼ 8.0 Hz, 1H),
7.30e7.28 (m, 2H), 7.11e6.96 (m, 6H), 5.28 (s, 2H), 4.40 (d,
J ¼ 9.6 Hz,1H), 3.96 (dd, J ¼ 10.8, 5.2 Hz,1H), 3.73 (dd, J ¼ 9.6, 8.8 Hz,
1H), 3.67 (ddd, J ¼ 10.8, 8.8, 5.2 Hz, 1H), 3.43 (t, J ¼ 8.8 Hz, 1H), 3.37
(t, J ¼ 10.8 Hz, 1H), 1.86e1.82 (m, 1H), 0.93e0.88 (m, 2H), 0.62e0.58
CD3OD):
d 160.8, 138.4, 131.4, 129.7, 128.9, 128.8, 122.9, 121.1, 120.4,
115.1, 114.0, 111.3, 80.2, 79.0, 75.1, 71.8, 71.4, 55.8, 50.5; ESMS m/z:
370 (MHþ), 392 (MNaþ); HPLC purity 99.0%.
(m, 2H); 13C NMR (75 MHz, CD3OD):
d 144.9, 138.4, 136.4, 129.0,
128.8, 128.3, 126.9, 122.9, 121.1, 120.4, 114.1, 111.3, 80.2, 79.0, 75.1,
71.8, 71.4, 50.7, 16.0, 9.7; ESMS m/z: 380 (MHþ), 402 (MNaþ); HPLC
purity 96.6%.
4.1.7.4. 1-(4-tert-Butylbenzyl)-3-(
b-D-xylopyranosyl)-1H-indole (1d).
1H NMR (400 MHz, CD3OD):
d
7.68 (d, J ¼ 8.0 Hz, 1H), 7.32e7.30 (m,
4H), 7.12e7.08 (m, 3H), 7.04e7.01 (m, 1H), 5.31 (s, 2H), 4.41 (d,
J ¼ 9.6 Hz, 1H), 3.96 (dd, J ¼ 10.8, 5.2 Hz, 1H), 3.74 (dd, J ¼ 9.6, 8.8 Hz,
1H), 3.67 (ddd, J ¼ 10.8, 8.8, 5.2 Hz, 1H), 3.44 (t, J ¼ 8.8 Hz,1H), 3.37 (t,
4.1.9.2. 1-(4-Cyclopropylbenzyl)-7-fluoro-3-(
b
-
D
-xylopyranosyl)-1H-
indole (1i). 1H NMR (400 MHz, CD3OD):
d
7.46 (d, J ¼ 8.0 Hz, 1H),
J ¼ 10.8 Hz, 1H), 1.26 (s, 9H); 13C NMR (75 MHz, CD3OD):
d
151.7,
7.30 (s, 1H), 7.05e6.92 (m, 5H), 6.83e6.78 (m, 1H), 5.41 (s, 2H), 4.37
(d, J ¼ 9.6 Hz, 1H), 3.96 (dd, J ¼ 10.8, 5.2 Hz, 1H), 3.69e3.62 (m, 2H),
3.42 (t, J ¼ 8.8 Hz, 1H), 3.36 (t, J ¼ 10.8 Hz, 1H), 1.90e1.80 (m, 1H),
0.94e0.88 (m, 2H), 0.62e0.58 (m, 2H); 13C NMR (100 MHz, CD3OD):
138.4, 136.5, 129.0, 128.7, 128.1, 126.7, 122.9, 121.1, 120.4, 114.1, 111.3,
80.2, 79.0, 75.1, 71.8, 71.4, 50.6, 35.5, 31.9; ESMS m/z: 396 (MHþ), 418
(MNaþ); HPLC purity 95.4%.
d
152.9, 150.5, 144.9, 137.0, 133.0, 132.9, 130.6, 128.1, 126.9, 120.82,
4.1.7.5. 1-(2-Naphthylmethyl)-3-(
1H NMR (300 MHz, CD3OD):
7.45e7.39 (m, 3H), 7.35e7.30 (m, 2H), 7.12e7.01 (m, 2H), 5.51 (s, 2H),
b
-
D
-xylopyranosyl)-1H-indole (1e).
120.75, 117.3, 117.2, 115.4, 108.5, 108.3, 80.2, 78.7, 75.1, 71.8, 71.4,
53.0, 52.9, 16.0, 9.8; ESMS m/z: 398 (MHþ), 420 (MNaþ); HPLC
purity 100%.
d
7.80e7.70 (m, 4H), 7.61 (s, 1H),