6390 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 20
Deng et al.
first column was eluted with petroleum ether/ethyl acetate (5:
1∼2:1 v/v) and the second column was eluted with petroleum
ether/acetone (3:1 v/v) to provide 9 as a yellow solid (871 mg,
28%). Recrystallization from ethyl acetate afforded 9 as yellow
naphthalic acid (12) (0.52 g, 2.4 mmol) prepared from 4-nitro-
1,8-naphthalic anhydride13 was treated with thionyl chloride
(5 mL) and heated at reflux for 3 h. After removal of the excess
amount of SOCl2, the residue was transferred to a suspension
of aluminum chloride in dichloromethane, which had been
stirred at room temperature for 15 min. The suspension was
stirred for another 30 min and then was added to a solution
of racemic 1-(1-methylpiperidin-2-ylmethyl)-1H-indole (18)
(0.54 g, 2.4 mmol; see Supporting Information) in dichlo-
romethane. The reaction mixture was stirred at 55 °C for 6 h
followed by the addition of 2 N NaOH until no further
precipitate formed. The mixture was extracted with dichlo-
romethane and the organic layer was washed with brine, dried
over Na2SO4, and concentrated under vacuum. The residue
was purified by flash column chromatography (silica gel,
toluene/diisopropylamine (10:1 v/v) and recrystallization from
ethanol to afford 13 (360 mg, 35%), mp 174-175 °C. 1H NMR
(500 MHz, CDCl3) δ 1.04-1.26 (m, 3H), 1.49-1.60 (m, 3H),
2.11 (m, 1H), 2.37 (br s, 4H), 2.84 (m, 1H), 3.85 (dd, J ) 9.0
and 14.1 Hz, 1H), 4.50 (dd, J ) 4.1 and 14.1 Hz, 1H), 7.32 (s,
1H), 7.40 (m, 3H), 7.59 (t, J ) 7.4 Hz, 1H), 7.67 (d, J ) 7.8
Hz, 1H), 7.74 (t, J ) 7.8 Hz, 1H), 8.18 (d, J ) 8.5 Hz, 1H),
8.21 (d, J ) 7.5 Hz, 1H), 8.46 (br s, 1H), 8.55 (d, J ) 8.7 Hz,
1H). Anal. (C26H25N3O3) C, H, N.
4-Aminonaphthalen-1-yl-[1-(1-methylpiperidin-2-yl-
methyl)-1H-indol-3-yl]methanone (14). A mixture of 13
(320 mg, 0.468 mmol), hydrazine (63.3 µM, 2.02 mmol), Raney
nickel (wet, 12 mg), and ethanol (10 mL) was stirred at room
temperature for 3 h. The insoluble material was removed by
filtration and the filtrate was concentrated by rotary evapora-
tion under vacuum to afford the crude product (170 mg, 91%),
which was used for the next reaction without further purifica-
tion. The analytical sample was obtained by flash column
chromatography (silica gel; CH2Cl2/MeOH, 10:1 v/v) followed
by recrystallization from ethyl acetate/hexane, mp 75-76 °C.
1H NMR (500 MHz, CDCl3) δ 1.04-1.35 (m, 3H), 1.39-1.62
(m, 3H), 2.04-2.40 (m, 1H), 2.43 (br s, 4H), 2.83 (m, 1H), 3.85
(dd, J ) 9.0 and 14.1 Hz, 1H), 4.57 (dd, J ) 4.1 and 14.1 Hz,
1H), 5.45 (br s, 2H), 6.77 (d, J ) 7.8 Hz, 1H), 7.31-7.41 (m,
3H), 7.45 (s, 1H), 7.49 (d, J ) 3.1 Hz, 1H), 7.52 (d, J ) 3.2 Hz,
1H), 7.62 (d, J ) 7.8 Hz, 1H), 7.87 (dd, J ) 3.0 and 6.5 Hz,
1H), 8.43 (m, 2H). Anal. (C26H27N3O‚0.56C4H8O2) C, H, N:
calcd, C 75.91, H 7.10, N 9.40; found, C 75.94, H 7.57, N 9.23.
1
crystals, mp 2-3 °C. H NMR (500 MHz, DMSO-d6) δ 7.51-
7.60 (m, 2H), 7.66 (d, J ) 7.5 Hz, 1H), 7.76 (d, J ) 6.8 Hz,
1H), 8.04 (t, J ) 6.1 Hz, 2H), 8.10 (s, 1H), 8.14 (d, J ) 8.7 Hz,
1H), 8.18 (d, J ) 8.7 Hz, 1H), 8.44 (s, 1H), 8.46 (d, J ) 8.8 Hz,
1H), 12.68 (br s, 1H). Anal. (C19H12N2O3) C, H, N.
[1-(1-Methylpiperidin-2-ylmethyl)-6-nitro-1H-indol-3-
yl]naphthalen-1-ylmethanone (10). To a suspension of 9
(1.48 g, 4.68 mmol) and NaH (281 mg, 60% in mineral oil, 7.02
mmol) in N,N-dimethylformamide (DMF; 5 mL) was added
dropwise a solution of 2-chloromethyl-1-methylpiperidine (691
mg, 4.68 mmol; see Supporting Information) in DMF (5 mL).
The reaction was heated at 60∼70 °C overnight and then
diluted with ethyl acetate, washed with brine, dried over
anhydrous Na2SO4, and the ethyl acetate was removed by
rotary evaporation under vacuum. The residue was chromato-
graphed twice on silica gel flash columns; the first column was
eluted with toluene/triethylamine (90:10 v/v) and the second
column was eluted with petroleum ether/ethyl acetate/triethyl-
amine (3.5:1:0.3 v/v/v) to afford 10 as a yellow solid (863 mg,
44%), mp 194-195 °C (recrystallization from ethanol/hexane).
1H NMR (500 MHz, CDCl3) δ 1.12 (m, 2H), 1.25 (m, 1H), 1.46
(m, 1H), 1.61 (m, 2H), 2.14 (t, J ) 10.5 Hz, 1H), 2.40 (s, 4H),
2.86 (m,1H), 4.02 (dd, J ) 8.2 and 14.3 Hz, 1H), 4.53 (dd, J )
4.0 and 14.2 Hz, 1H), 7.52 (m, 3H), 7.67 (d, J ) 6.0 Hz, 1H),
7.69 (s, 1H), 7.93 (d, J ) 8.0 Hz, 1H), 8.01 (d, J ) 8.0 Hz, 1H),
8.20 (d, J ) 8.5 Hz, 1H), 8.22 (d, J ) 8.5 Hz, 1H), 8.36 (s, 1H),
8.54 (d, J ) 8.7 Hz, 1H). Anal. (C26H25N3O3) C, H, N.
[6-Amino-1-(1-methylpiperidin-2-ylmethyl)-1H-indol-
3-yl]naphthalen-1-ylmethanone (11). To a solution of 10
(863 mg, 2.02 mmol) and hydrazine (0.41 mL) in ethanol (80
mL) was added a suspension of Raney Ni (wet, ∼90 mg). The
resulting suspension was stirred vigorously at room temper-
ature for 1 h and was then carefully filtered. The solvent was
removed by rotary evaporation under vacuum and the residue
was recrystallized from ethyl acetate/hexane to afford 11 as a
pale solid (665 mg, 83%), mp 198-199 °C. 1H NMR (200 MHz,
CDCl3) δ 1.06 (m, 3H), 1.26 (br s, 1H), 1.58 (m, 2H), 2.11 (m,
1H), 2.33 (br s, 1H), 2.38 (s, 3H), 2.83 (m, 1H), 3.70 (dd, J )
9.3 and 14.0 Hz, 1H), 4.43 (dd, J ) 4.1 and 14.0 Hz, 1H), 6.40
(d, J ) 1.7 Hz, 1H), 6.78 (dd, J ) 1.7 and 8.4 Hz, 1H), 7.17 (s,
1H), 7.45-7.55 (m, 3H), 7.66 (d, J ) 7.8 Hz, 1H), 7.90 (d, J )
7.3 Hz, 1H), 7.96 (dd, J ) 8.0 Hz, 1H), 8.19 (br s, 1H), 8.25 (d,
J ) 8.2 Hz, 1H). Anal. (C26H27N3O‚1.25H2O) C, H, N.
[6-Iodo-1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-
yl]naphthalen-1-ylmethanone (3). A solution of 11 (449 mg,
1.13 mmol) in 3 N HCl (2.4 mL) was stirred at room temper-
ature for 1 h and then cooled to 0 °C, and 1 M NaNO2 (1.4
mL) was added slowly. The reaction mixture was continuously
stirred for another 1 h followed by the addition of sulfamic
acid until starch-KI test paper did not change to blue. KI (750
mg, 4.52 mmol) was added with stirring at 0 °C for 30 min
and then at room temperature for 1 h. The reaction was
quenched by the addition of saturated aqueous Na2CO3. After
extraction with dichloromethane, the organic layer was dried
over Na2SO4 and the solvent was removed by rotary evapora-
tion under vacuum. The residue was purified by chromato-
graphy on a silica gel column eluting with toluene/diisopro-
pylamine (10:1 v/v) and afforded 3 as a pale solid (350 mg,
61%), mp 204-205 °C (recrystallization from ethyl acetate/
hexane). 1H NMR (500 MHz, CDCl3) δ 1.09 (br s, 2H), 1.23 (br
s, 1H), 1.47 (m, 1H), 1.60 (m, 2H), 2.13 (m, 1H), 2.33 (br s,
1H), 2.38 (s, 3H), 2.83 (m, 1H), 3.82 (dd, J ) 8.9 and 13.9 Hz,
1H), 4.43 (dd, J ) 3.6 and 13.9 Hz, 1H), 7.32 (s, 1H), 7.52 (m,
3H), 7.63 (d, J ) 8.0 Hz, 1H), 7.66 (d, J ) 6.9 Hz, 1H), 7.75 (s,
1H), 7.92 (d, J ) 8.0 Hz, 1H), 7.99 (d, J ) 8.3 Hz, 1H), 8.18 (d,
J ) 8.5 Hz, 1H), 8.20 (d, J ) 8.7 Hz, 1H). Anal. (C26H25IN2O)
C, H, N: calcd, C 61.43, H 4.96, N 5.51; found, C 61.90, H
5.44, N 5.54.
4-Iodonaphthalen-1-yl-[1-(1-methylpiperidin-2-yl-
methyl)-1H-indol-3-yl]methanone (4). With 14 (170 mg,
0.43 mmol) as starting material, 4 was prepared analogously
to the synthesis of 3. The crude sample was purified by flash
chromatography (silica gel; toluene/triethylamine, 100:4 v/v)
to afford 4 as a white solid (121 mg, 56%), mp 161.5-162.0 °C
(recrystallization from ethanol). 1H NMR (200 MHz, CDCl3) δ
1.04-1.35 (m, 3H), 1.39-1.62 (m, 3H), 2.04-2.40 (m, 1H),
2.40-2.42 (s, 4H), 2.84 (m, 1H), 3.78-3.89 (m, 1H), 4.47-4.56
(m, 1H), 7.31-7.64 (m, 8H), 8.17-8.21 (m, 2H), 8.45-8.48 (m,
1H). Anal. (C26H25IN2O) C, H, N.
2-Iodophenyl-[2-methyl-1-(1-methylpiperidin-2-yl-
methyl)-1H-indol-3-yl]methanone (5). To anhydrous dichlo-
romethane (10 mL) was added aluminum chloride (2.0 g, 15
mmol), and the mixture was stirred for 15 min. To this sus-
pension was slowly added a solution of 2-iodobenzoyl chloride
(1.8 g, 6.75 mmol) in dichloromethane (5 mL), and stirring was
continued for another 30 min. Compound 17 (1.48 g, 6.0 mmol;
see Supporting Information) in dichloromethane (10 mL) was
then added to the above mixture carefully in order to maintain
the reaction temperature below 40 °C. The reaction was stirred
overnight before being quenched with 2 N sodium hydroxide.
The organic layer was separated, washed with brine, dried over
sodium sulfate, and the solvent was removed by rotary
evaporation under vacuum to give the crude product, which
was further purified by silica gel chromatography (toluene/
triethylamine, 10:1 v/v) to afford 5 as a white solid (2.0 g, 83%),
1
mp 153-154 °C. H NMR (500 MHz, CDCl3) δ 1.12-1.29 (m,
3H), 1.59-1.72 (m, 3H), 2.19 (m, 1H), 2.47 (m, 1H), 2.55 (s,
3H), 2.60 (s, 3H), 2.95 (m, 1H), 4.07 (dd, J ) 14.2 and 10.5
Hz, 1H), 4.59 (dd, J ) 13.7 and 4.3 Hz, 1H), 7.10 (t,
[1-(1-Methylpiperidin-2-ylmethyl)-1H-indol-3-yl]-4-ni-
tronaphthalen-1-ylmethanone (13). The crude 4-nitro-1-