424 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2
Gill et al.
brine solution. The organic layer was separated, dried (Mg-
SO4), filtered, and evaporated and the residue purified by
column chromatography on silica. Elution with mixtures of
petroleum ether and ethyl acetate afforded 0.021 g of 8 as an
residue subjected to column chromatography on silica. Elution
with diethyl ether afforded 0.064 g of 19 as a pale yellow solid
(82%). 1H NMR (400 MHz, DMSO-d6): δ 10.77 (br s, 1H), 9.10
(d, J ) 1 Hz, 1H), 8.63 (d, J ) 5 Hz, 1H), 7.52 (d, J ) 8 Hz,
1H), 7.42 (dd, J ) 5, 1 Hz, 1H), 7.32 (d, J ) 8 Hz, 1H), 7.09 (s,
1H), 7.06 (t, J ) 8 Hz, 1H), 6.97 (t, J ) 8 Hz, 1H), 3.11 (s, 4H);
MS (+ES): m/e 224 (MH+).
1-(2-(4-Pyridyl)ethyl)indole (18). A mixture of 4-vinylpy-
ridine (1.05 g, 10.0 mmol), indole (0.585 g, 5.0 mmol), sodium
(0.03 g) and anhydrous copper sulfate (0.03 g) in absolute
ethanol (3 mL) was stirred at 130 °C in a sealed tube for 16 h.
Upon cooling to room temperature, the solvent was removed
under reduced pressure and the residue subjected to purifica-
tion by flash chromatography on silica. Elution with 5%
methanol in ethyl acetate afforded 0.6 g of 18 as a pale yellow
oil (54%). 1H NMR (400 MHz, DMSO-d6): δ 8.41 (d, J ) 6 Hz,
2H), 7.51 (t, J ) 7.5 Hz, 2H), 7.27 (d, J ) 3 Hz, 1H), 7.20 (d,
J ) 6 Hz, 2H), 7.11 (tm, J ) 7.5 Hz, 1H), 6.99 (tm, J ) 7.5 Hz,
1H), 6.37 (d, J ) 3 Hz, 1H), 4.46 (t, J ) 7.5 Hz, 2H), 3.09 (t,
J ) 7.5 Hz, 2H); MS (+ES): m/e 223 (MH+).
1
off-white solid (34%). Η ΝΜR (400 MHz, CDCl3): δ 8.47 (br
s 1H), 8.29 (br s, 1H), 8.2 (br s, 1H), 7.9 (br m, 3H), (7.74 (br
m, 2H), 7.63 (br m, 1H), 7.52 (br m, 3H), 7.43 (d, J ) 8.8 Hz,
1H), 5.31 (s, 2H). MS (+ES): m/e 340 (MH+).
N-[4-Chloro-3-(3-pyridinyloxymethyl)phenyl]-3-fluoro-
5-(4-morpholino)-benzamide (9). A stirred solution of 15
(0.047 g, 0.2 mmol) in dry DCM (5 mL) was treated with 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.383
g, 2 mmol) and 1-hydroxy-7-azabenzotriazole (0.272 g, 2 mmol).
3-Fluoro-5-(4-morpholino)benzoic acid (0.045 g, 0.2 mmol) was
added and the reaction mixture stirred at room-temperature
overnight. The reaction mixture was diluted with DCM and
washed with 5% aqueous citric acid, saturated sodium bicar-
bonate solution and then brine solution. The organic layer was
separated, dried (MgSO4), filtered, and evaporated and the
residue purified by column chromatography on silica. Elution
with mixtures of petroleum ether and ethyl acetate afforded
2-[4-(2-(3-Indolyl)ethyl]-2-pyrimidinylamino]-2-meth-
yl-1-propanol (21). A mixture of 20 (0.055 g, 0.2 mmol) and
2-amino-2-methyl-1-propanol (0.5 mL) was stirred and irradi-
ated with microwaves at 200 °C for 5 min. Upon cooling to
room-temperature, water was added, the organics were ex-
tracted into ethyl acetate, dried (Na2SO4), filtered and evapo-
rated and the resulting residue was subjected to column
chromatography on silica. Elution with ethyl acetate afforded
1
0.035 g of 9 as a pale yellow solid (39%). Η ΝΜR (400 MHz,
CDCl3): δ 8.42 (br s, 1H), 8.23 (d, J ) 4.8 Hz, 1H), 8.12 (s,
1H), 7.76 (m, 2H), 7.35 (m, 3H), 7.20 (s, 1H), 6.95 (d, J ) 8.3
Hz, 1H), 6.71 (m, 1H), 5.22 (s, 2H), 3.84 (t, J ) 9.9, 4.8 Hz,
4H), 3.21 (t, J ) 9.9, 4.8 Hz, 4H). MS (+ES): m/e 443 (MH+).
1-(5-tert-Butyl-2H-pyrazol-3-yl)-3-[4-chloro-3-(pyridin-
3-yloxymethyl)-phenyl]urea (10). A stirred solution of 15
(0.049 g, 0.21 mmol) in dry DCM (5 mL) at 0 °C was treated
with N,N-diisopropylethylamine (0.37 mL, 2.13 mmol), fol-
lowed by triphosgene (0.077 g, 0.25 mmol). The mixture was
stirred at 0 °C for 3 h and then treated with 3-amino-5-tert-
butyl pyrazole (0.058 g, 0.42 mmol). The reaction mixture was
allowed to warm to room-temperature overnight, the solvent
was removed under reduced pressure and the residue parti-
tioned between ethyl acetate and saturated sodium bicarbon-
ate solution. The organic layer was separated, dried (MgSO4),
filtered, and evaporated and the residue purified by column
chromatography on silica. Elution with mixtures of petroleum
ether and ethyl acetate afforded 0.02 g of 10 as a pale yellow
solid (24%). 1Η ΝΜR (400 MHz, MeOD): δ 8.38 (br s, 1H),
8.21 (d, J ) 4.9 Hz, 1H), 7.93 (br s, 1H), 7.76 (m, 2H), 7.68
(dd, J ) 9.1, 2 Hz, 1H), 7.57 (dd, J ) 9.2, 2.2 Hz, 1H), 7.42 (m,
2H), 5.39 (s, 1H), 5.28 (s, 2H), 1.31 (s, 9H). MS (+ES): m/e
401 (MH+).
1
0.03 g of 21 as a pale yellow solid (50%). H NMR (400 MHz,
DMSO-d6): δ 10.76 (br s, 1H), 8.11 (d, J ) 5 Hz, 1H), 7.51 (d,
J ) 8 Hz, 1H), 7.32 (d, J ) 8 Hz, 1H), 7.10 (s, 1H), 7.06 (t, J
) 8 Hz, 1H), 6.96 (t, J ) 8 Hz, 1H), 6.50 (d, J ) 5 Hz, 1H),
6.31 (br s, 1H), 5.11 (t, J ) 5.5 Hz, 1H), 3.49 (d, J ) 5.5 Hz,
2H), 3.05 (t, J ) 7.5 Hz, 2H), 2.86 (t, J ) 7.5 Hz, 2H), 1.32 (s,
6H); MS (+ES): m/e 311 (MH+).
N-(5-Indolyl)-3-fluoro-5-(4-morpholino)benzamide (22).
A mixture of 5-aminoindole (0.132 g, 1.0 mmol), 3-fluoro-5-(4-
morpholino)benzoic acid (0.225 g, 1.0 mmol), 1-hydroxyben-
zotriazole (0.15 g, 1.1 mmol) and 1-(3-dimethylaminopropyl)-
3-ethylcarbodiimide hydrochloride (0.21 g, 1.1 mmol) in DMF
(5 mL) was stirred at room temperature for 16 h. The solvent
was removed under reduced pressure and the residue parti-
tioned between water and ethyl acetate. The organic layer was
separated, dried (Na2SO4), filtered, and evaporated and the
residue purified by column chromatography on silica. Elution
with 50% diethyl ether in petroleum ether afforded 0.25 g of
3-(2-(4-Pyridyl)ethyl)indole (2). A mixture of 4-vinylpy-
ridine (0.105 g, 1.0 mmol) and indole (0.117 g, 1.0 mmol) in
acetic acid (1 mL) was stirred and refluxed for 16 h. The
reaction mixture was cooled to room temperature and the
solvent removed under reduced pressure. The residue was
subjected to purification by flash chromatography on silica,
eluting with ethyl acetate and afforded 0.145 g of 2 as a pale
1
22 as a colorless foam (74%). H NMR (400 MHz, CDCl3): δ
8.25 (br s, 1H), 7.94 (s, 1H), 7.81 (br s, 1H), 7.38 (d, J ) 8.5,
1H), 7.34 (d, J ) 8.5, 1H), 7.24 (m, 2H), 6.98 (d, J ) 8.5, 1H),
6.72 (dt, J ) 11.5, 2, 1H), 6.56 (t, J ) 2, 1H), 3.86 (m, 4H, m),
3.23 (m, 4H). MS (+ES): m/e 340 (MH+).
N-[1-(2-(4-Pyridyl)ethyl)-5-indolyl]-3-fluoro-5-(4-mor-
pholino)benzamide (23). A mixture of 4-vinylpyridine (0.078
g, 0.74 mmol) and 22 (0.25 g, 0.74 mmol) in acetic acid (1 mL)
was stirred and held at reflux for 16 h. Upon cooling to room
temperature, the solvent was removed under reduced pressure
and the residue subjected to purification by flash chromatog-
raphy on silica gel. Elution with ethyl acetate afforded 0.08 g
1
yellow solid, (65%). H NMR (400 MHz, DMSO-d6): δ 10.80
(br s, 1H), 8.45 (d, J ) 6 Hz, 2H), 7.56 (d, J ) 8 Hz, 1H), 7.32
(d, J ) 8 Hz, 1H), 7.29 (d, J ) 6 Hz, 2H), 7.11 (d, J ) 2 Hz,
1H), 7.08 (t, J ) 8 Hz, 1H), 6.97 (t, J ) 8 Hz, 1H), 3.00 (m,
4H); MS (+ES): m/e 223 (MH+).
3-[2-(2-Chloro-4-pyrimidinyl)ethyl]indole (20). A mix-
ture of 2-chloro-4-vinylpyrimidine (0.14 g, 1.0 mmol) and indole
(0.117 g, 1.0 mmol) in acetic acid (1 mL) was stirred and held
at 60-80 °C for 16 h. The reaction mixture was cooled to room
temperature and the solvent removed under reduced pressure.
The residue was subjected to purification by flash chromatog-
raphy on silica, eluting with ethyl acetate and afforded 0.167
g of 20 as a pale yellow solid (65%). 1H NMR (400 MHz, DMSO-
d6): δ 10.79 (br s, 1H), 8.61 (d, J ) 5 Hz, 1H), 7.53 (d, J ) 8
Hz, 1H), 7.47 (d, J ) 5 Hz, 1H), 7.32 (d, J ) 8 Hz, 1H), 7.11
(d, J ) 2 Hz, 1H), 7.06 (t, J ) 8 Hz, 1H), 6.97 (t, J ) 8 Hz,
1H), 3.12 (m, 4H); MS (+ES): m/e 258 (MH+).
3-(2-(4-Pyrimidinyl)ethyl)indole (19). A mixture of 20
(0.09 g, 0.35 mmol), 10% palladium on carbon (20 mg) and
triethylamine (0.07 g, 0.7 mmol) in ethanol (2 mL) was stirred
at room temperature under an atmosphere of hydrogen for 16
h. The mixture was filtered, evaporated and the resulting
1
of 23 as a colorless solid (24%). H NMR (400 MHz, DMSO-
d6): δ 10.77 (br s, 1H), 10.07 (br s, 1H), 8.44 (d, J ) 6, 2H),
7.96 (d, J ) 2, 1H), 7.39 (dd, J ) 9, 2, 1H), 7.36 (t, J ) 2, 1H),
7.30 (d, J ) 8.5, 1H), 7.27 (d, J ) 6, 2H), 7.17 (dm, J ) 9, 1H),
7.09 (d, J ) 2, 1H), 6.98 (dt, J ) 12, 2, 1H), 3.76 (m, 4H), 3.24
(m, 4H), 2.99 (s, 4H). MS (+ES): m/e 445 (MH+).
6-Amino-1-(2-(4-pyridyl)ethyl)indole (25). A mixture of
4-vinylpyridine (0.525 g, 5.0 mmol), 6-aminoindole (0.33 g, 2.5
mmol), sodium (0.03 g) and anhydrous copper sulfate (0.03 g)
in absolute ethanol (2 mL) was stirred at 130 °C in a sealed
tube for 16 h. Upon cooling to room temperature, the solvent
was removed under reduced pressure and the residue sub-
jected to purification by flash chromatography on silica.
Elution with 5% methanol in ethyl acetate afforded 0.08 g of
25 as a dark brown oil (14%). 1H NMR (400 MHz, DMSO-d6):
δ 8.44 (d, J ) 6, 2H), 7.21 (d, J ) 6, 2H), 7.17 (d, J ) 8, 1H),