90 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 1
Ward et al.
1-({2-Fluoro-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-
indazol-1-yl]phenyl}methyl)-2-pyrrolidinone (7l). Yield 15%. LCMS
(ESþ) m/z found 382, retention time 3.28 min. C19H19F4N3O
J = 8 Hz), 3.25 (2H, t, J = 7 Hz), 4.39 (2H, s), 7.00 (2H, d, J = 8
Hz), 7.66 (2H, m).
1-[(4-Bromo-2-fluorophenyl)methyl]-2-pyrrolidinone (6l). To a
solution of 2-pyrrolidinone (0.62 g, 7.35 mmol) in DMF (20 mL)
was added sodium hydride (60% suspension in mineral oil, 0.33
g, 8.2 mmol) portionwise under argon at room temperature, and
the mixture was stirred for 15 min. Then 2-fluoro-4-bromoben-
zyl bromide (2.0 g, 7.46 mmol) was added. The resulting mixture
was allowed to stir at room temperature for 5 h and allowed to
stand at room temperature overnight. The reaction was
quenched by the addition of water (2 mL). Then the mixture
was evaporated under reduced pressure, partitioned between
ethyl acetate and water, and dried with sodium sulfate. The
solvent was removed by rotary evaporation to give an oil which
was purified by column chromatography on silica using
10-100% ethyl acetate in n-pentane to give the title compound
as colorless oil (1.70 g, 85%). LCMS (ESþ) m/z found 272 and
274, retention time 2.52 min. C11H11BrFNO requires 271 and
1
requires 381. H NMR (400 MHz, CDCl3): 1.82 (4H, m), 2.20
(2H,m),2.43(2H,m),2.66(2H,m),2.72(2H, m), 3.32(2H, m), 4.54
(2H, s), 7.22-7.30 (2H, m), 7.50 (1H, t, J = 8 Hz).
1-{4-[(1,1-Dioxido-2-isothiazolidinyl)methyl]phenyl}-3-(trifluo-
romethyl)-4,5,6,7-tetrahydro-1H-indazole (7n). Yield 26%. LCMS
(ESþ) m/z found 400, retention time 3.31 min. C18H20F3N3O2S
1
requires 399. H NMR (400 MHz, CDCl3): 1.83 (4H, m), 2.34
(2H, m), 2.69 (4H, m), 3.12 (2H, t, J = 6 Hz), 3.23 (2H, t, J = 8
Hz), 4.23 (2H, s), 7.47 (4H, m).
{4-[3-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-
phenyl}methanol (7q). Yield 86%. LCMS (ESþ) m/z found 297,
retention time 3.06 min. C15H15F3N2O requires 296. 1H NMR
(400 MHz, CDCl3): 1.76 (1H, t, J = 6 Hz), 1.82 (4H, m), 2.69
(4H, m), 4.77 (2H, m), 7.48 (4H, m).
{4-[3-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-
phenyl}acetonitrile (7r). Yield 60%. LCMS (ESþ) m/z found
306, retention time 3.34 min. C16H14F3N3 requires 305. 1H
NMR (400 MHz, CDCl3): 1.83 (4H, m), 2.70 (4H, m), 3.82 (2H,
s), 7.44 (2H, d, J = 8 Hz), 7.53 (2H, m).
Preparation of 6-Substituted Bromo/Iodobenzene Reagents for
Ullmann Couplings. 4-[(4-Iodophenyl)carbonyl]morpholine (6b).
A solution of morpholine (653 mg, 7.5 mmol) in dichloro-
methane (40 mL) was cooled in an ice/methanol bath and then
treated with stirring under argon with triethylamine (7.5 mmol,
1.05 mL) followed by the portionwise addition of 4-iodobenzoyl
chloride (2.0 g, 7.5 mmol). The reaction mixture was allowed to
stir at room temperature for 0.5 h before the solution was
washed with water (2 ꢀ 20 mL). The organic layer was dried
over sodium sulfate and evaporated under reduced pressure to
give the title compound as a yellow solid (2.4 g, 100%). LCMS
(ESþ) m/z found 318, retention time 2.36 min. C11H12INO2
requires 317. 1H NMR (400 MHz, CDCl3): 3.32-3.94 (8H, m),
7.15 (2H, m), 7.77 (2H, m).
1
273. H NMR (400 MHz, CDCl3): 2.0 (2H, m), 2.43 (2H, m),
3.31 (2H, m), 4.46 (2H, s), 7.13-7.28 (3H, m).
2-[(4-Bromophenyl)methyl]isothiazolidine 1,1-Dioxide (6n). A
solution of 4-bromobenzylamine (1.85 g, 10 mmol) and triethy-
lamine (2 g, 20 mmol) in dimethylformamide (30 mL) was
treated with 3-chloropropanesulfonyl chloride (1.78 g, 10 mmol)
by dropwise addition over 10 min with stirring under argon.
This mix was stirred for 30 min before being treated with a 60%
suspension of sodium hydride in mineral oil (1.2 g, 30 mmol of
NaH) portionwise and the whole mixture stirred at room
temperature for 3 days. The reaction mixture was partitioned
between water (50 mL) and dichloromethane (30 mL). The
organic layer was dried over sodium sulfate and reduced to
minimum volume by rotary evaporation. The residue was added
to a 20 g prepacked silica column and eluted from 0% to 50%
ethyl acetate in petroleum ether to give the title compound as a
yellow oil (2.72 g, 94%). LCMS (ESþ) m/z found 290, retention
time 2.68 min. C10H1279BrNO2S requires 289. H NMR (400
1
1-[(4-Bromo-2-fluorophenyl)acetyl]pyrrolidine (6i). A mixture
of (4-bromo-2-fluorophenyl)acetic acid (1.0 g, 4.29 mmol),
pyrrolidine (305 mg, 4.30 mmol), and diisopropylethylamine
(1.49 mL, 8.58 mmol) in dimethylformamide (15 mL) was stirred
at room temperature under argon. Then HATU (1.79 g, 4.72
mmol) was added. The reaction mixture was allowed to stir at
room temperature for 16 h. Dimethylformamide was removed
by rotary evaporation, and the residual material was partitioned
between ethyl acetate and water. The organic layer was sepa-
rated and dried with sodium sulfate, and solvent was removed
by rotary evaporation. The desired product was isolated by
column chromatography on silica using 5-100% ethyl acetate
in n-pentane to afford a white solid (0.97 g, 80%). LCMS (ESþ)
m/z found 286 and 288, retention time 2.61 min. C12H13BrFNO
MHz, CDCl3): 2.32 (2H, m), 3.11 (2H, m), 3.21 (2H, m), 3.13
(2H, s), 7.24 (2H, m), 7.49 (2H, m).
1-[4-(1-Pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,
7-tetrahydro-1H-indazole (9a).
A solution of 4-[3-(trifluo-
romethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid (87 mg,
0.28 mmol) in dichloromethane (3 mL) was treated in one portion
with solid 1,10-carbonyldiimidazole (46 mg, 0.28 mmol). This
mixture was allowed to stir at room temperature for 15 min.
Pyrrolidine (23 mg, 0.32 mmol) was then added, and the stirring
continued for 1 h at room temperature. The reaction mixture was
then added to a 5 g prepacked silica column and eluted from 0% to
50% ethyl acetate in petroleum ether to give the title compound as a
yellow oil (51 mg, 50%). LCMS (ESþ) m/z found 364, retention
1
time 3.22 min. C19H20F3N3O requires 363. H NMR (400 MHz,
1
CDCl3): 1.83 (4H, m), 1.91 (2H, m), 1.98 (2H, m), 2.70 (4H, m), 3.43
(2H, t, J= 6 Hz), 3.67 (2H, t, J=6Hz), 7.53(2H, m), 7.64(2H, m).
1-{4-[2-Oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-
4,5,6,7-tetrahydro-1H-indazole (10a). A solution of {4-[3-(trifluo-
romethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid
(113 mg, 0.35 mmol) in dichloromethane (4 mL) in a Sarstedt
tube was treated in one portion with solid 1,10-carbonyldiimida-
zole (60 mg, 0.37 mmol). This mixture was shaken at room
temperature for 30 min. Pyrrolidine (34 mg, 0.48 mmol) in
dichloromethane (2 mL) was then added, and the shaking con-
tinued for 16 h at room temperature. The reaction mixture was
washed with a mix of saturated sodium bicarbonate solution
(4 mL) and brine (2 mL). The organic layer was then added to a
2 g SCX column and eluted with ethyl acetate (25 mL). The solvent
was removed under reduced pressure and the residue purified by
mass directed autoprep to give the title compound as a yellow oil
(30 mg, 23%). LCMS (ESþ) m/z found 378, retention time 3.28
requires 285 and 287. H NMR (400 MHz, CDCl3): 1.85 (2H,
m), 1.96 (2H, m), 3.46 (4H, m), 3.60 (2H, s), 7.20-7.28 (3H, m).
1-[(4-Iodophenyl)methyl]-2-pyrrolidinone (6j). A solution of
2-pyrrolidinone (850 mg, 10 mmol) in dimethylformamide
(40 mL) was cooled in an ice/methanol bath with stirring under
an atmosphere of argon. Then a solid suspension of sodium
hydride (60% in mineral oil, 440 mg, 11 mmol) was added
portionwise over 10 min. The reaction mixture was allowed to
stir with cooling for 30 min. Then 4-iodobenzyl bromide (2.97 g,
10 mmol) was added portionwise over 10 min. The whole
mixture was allowed to warm slowly to room temperature and
then stirred for a further 2 h. The reaction mixture was parti-
tioned between ethyl acetate (100 mL) and water (200 mL). The
organic layer was removed and reduced to minimum volume
under reduced pressure. The residue was purified by column
chromatography on a 20 g prepacked silica column, eluting
from 0% to 100% ethyl acetate in petroleum ether to give the
title compound as a yellow solid (2.97 g, 99%). LCMS (ESþ)
m/z found 302, retention time 2.59 min. C11H12INO requires
1
min. C20H22F3N3O requires 377. H NMR (400 MHz, CDCl3):
1.81 (4H, m), 1.88 (2H, m), 1.96 (2H, m), 2.69 (4H, m), 3.44 (2H, t,
J = 7 Hz), 3.50 (2H, t, J = 7 Hz), 3.71 (2H, s), 7.38 (2H, d, J = 8
1
301. H NMR (400 MHz, CDCl3): 2.01 (2H, m), 2.44 (2H, t,