4380 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Tatsumi et al.
J ) 2 Hz, 1H), 7.53 (dd, J ) 2 Hz, 9 Hz, 1H), 7.64 (d, J ) 9 Hz,
1H), 7.78 (d, J ) 2 Hz, 1H), 8.02 (d, J ) 2 Hz, 1H), 11.02 (brs,
1H). Anal. (C17H18N2O3‚HCl), C, H, N.
3H), 3.10-3.35 (m, 4H), 3.56-3.62 (m, 2H), 4.14 (d, J ) 9 Hz,
1H), 4.31 (d, J ) 9 Hz, 1H), 7.11 (s, 1H), 7.53 (dd, J ) 2 Hz, 9
Hz, 1H), 7.80 (d, J ) 2 Hz, 1H), 7.86 (d, J ) 9 Hz, 1H), 10.45
(brs, 1H). Anal. (C18H20N2O2S‚HCl), C, H, N.
(R)-3′-(Benzo[b]furan-6-yl)spiro[1-azabicyclo[2.2.2]octane-
3,5′-oxazolidin]-2′-one HCl (15). This compound was prepared
from compound 2 (360 mg, 2.0 mmol) and 6-bromo-benzo[b]furan
(900 mg, 4.6 mmol) using the same procedure described for the
preparation of compound 7 to yield compound 15, which was then
converted to the HCl salt (23 mg, 3%) as colorless crystals; mp
5-Bromo-2-ethylbenzo[b]thiophene (30). Under a N2 atmo-
sphere and at -78 °C, to a stirred solution of 5-bromobenzo[b]-
thiophene 29 (2.1 g, 9.9 mmol) in THF (25 mL) was added dropwise
a solution of LDA (5.5 mL, 11.0 mmol, 2.0 M in heptane/THF/
ethylbenzene). After stirring for 1 h at 0 °C, the reaction mixture
was cooled to -78 °C. Ethyl iodide was added dropwise, and the
reaction mixture was allowed to warm up to room temperature and
stirred for 1 h, and then quenched with water. The mixture was
extracted with CHCl3, and the combined CHCl3 phases were dried
over MgSO4. The organic solution was evaporated in vacuo and
purified by silica gel column chromatography (eluent: hexane) to
give compound 30 (2.2 g, 90%) as colorless crystals; mp 59-60C.
1H NMR (CDCl3) δ 1.37 (t, J ) 8 Hz, 3H), 2.93 (q, J ) 8 Hz,
2H), 6.93 (s, 1H), 7.33 (dd, J ) 2 Hz, 8 Hz, 1H), 7.60 (d, J ) 8
Hz, 1H), 7.79 (d, J ) 1 Hz, 1H). Anal. (C10H9BrS), C, H, N.
1
>270 °C. H NMR (DMSO-d6) δ 1.80-1.95 (m, 3H), 2.05-2.17
(m, 1H), 2.41-2.43 (m, 1H), 3.15-3.40 (m, 4H), 3.60-3.70 (m,
2H), 4.17 (d, J ) 10 Hz, 1H), 4.34 (d, J ) 10 Hz, 1H), 6.94 (t, J
) 1 Hz, 1H), 7.49 (dd, J ) 2 Hz, 8 Hz, 1H), 7.67 (d, J ) 9 Hz,
1H), 7.81 (s, 1H), 7.98 (d, J ) 2 Hz, 1H), 10.97 (s, 1H). Anal.
(C17H18N2O3‚HCl‚0.5H2O), C, H, N.
(R)-3′-(2,3-Dihydrobenzo[b]furan-5-yl)spiro[1-azabicyclo[2.2.2]-
octane-3,5′-oxazolidin]-2′-one HCl (16). This compound was
prepared from compound 2 (547 mg, 3.0 mmol) and 5-bromo-2,3-
dihydrobenzo[b]furan (1.2 g, 6.0 mmol) using the same procedure
described for the preparation of compound 7 to yield compound
16, which was then converted to the HCl salt (489 mg, 48%) as
(R)-3′-(2-Ethylbenzo[b]thiophen-5-yl)spiro[1-azabicyclo[2.2.2]-
octane-3,5′-oxazolidin]-2′-one HCl (21). This compound was
prepared from compound 2 (400 mg, 2.2 mmol) and 5-bromo-2-
ethylbenzo[b]thiophene (30) (620 mg, 2.6 mmol) using the same
procedure described for the preparation of compound 7 to yield
compound 21, which was then converted to the HCl salt (85 mg,
1
brown crystals; mp >270 °C. H NMR (DMSO-d6) δ 1.82-1.88
(m, 4H), 2.06-2.09 (m, 1H), 3.15-3.20 (m, 6H), 3.59-3.62 (m,
2H), 4.02-4.04 (m, 1H), 4.18-4.20 (m, 1H), 4.50-4.54 (m, 2H),
6.78 (d, J ) 8 Hz, 1H), 7.18 (dd, J ) 4 Hz, 8 Hz, 1H), 7.44(s,
1H), 10.19 (brs, 1H). Anal. (C17H20N2O3‚HCl‚0.25H2O), C, H, N.
(R)-3′-(2,3-Dihydrobenzo[b]furan-6-yl)spiro[1-azabicyclo[2.2.2]-
octane-3,5′-oxazolidin]-2′-one HCl (17). A solution of compound
15 (1.4 g, 4.2 mmol) in methanol (100 mL) was hydrogenated in
the presence of 10%-Pd/C (700 mg) at 60 °C under 80 atm. After
the reaction mixture was filtered with Celite, the solvent was
removed under reduced pressure, and the resultant product was
washed with ethanol to give compound 17 (1.0 g, 71%) as pale
1
10%) as colorless crystals; mp >270 °C. H NMR (DMSO-d6) δ
1.30 (t, J ) 8 Hz, 3H), 1.85-1.94 (m, 4H), 2.10 (m, 1H), 2.88-
2.92 (m, 2H), 3.29-3.21 (m, 4H), 3.64-3.66 (m, 2H), 4.15 (d, J
) 12 Hz, 1H), 4.32 (d, J ) 8 Hz, 1H), 7.15 (s, 1H), 7.55 (d, J )
8 Hz, 1H), 7.84 (s, 1H), 7.89 (d, J ) 8 Hz, 1H). Anal.
(C19H22N2O2S‚HCl), C, H, N.
(R)-3′-(2-Chlorobenzo[b]thiophen-5-yl)spiro[1-azabicyclo-
[2.2.2]octane-3,5′-oxazolidin]-2′-one HCl (22). This compound
was prepared from compound 2 (910 mg, 5.0 mmol) and 5-bromo-
2-chlorobenzo[b]thiophene (2.0 g, 8.0 mmol) using the same
procedure described for the preparation of compound 7 to yield
compound 22, which was then converted to the HCl salt (278 mg,
1
yellow crystals; mp >270 °C. H NMR (DMSO-d6) δ 1.75-1.93
(m, 3H), 2.00-2.10 (m, 1H), 2.35-2.40 (m, 1H), 3.10-3.40 (m,
6H), 3.50-3.62 (m, 2H), 4.06 (d, J ) 9 Hz, 1H), 4.20 (d, J ) 9
Hz, 1H), 4.53 (t, J ) 8 Hz, 2H), 6.94 (d, J ) 7 Hz, 1H), 7.04 (s,
1H), 7.22 (d, J ) 8 Hz, 1H), 10.97 (brs, 1H). Anal. (C17H20N2O3‚
HCl‚0.2H2O), C, H, N.
1
14%) as pale yellow crystals; mp >270 °C. H NMR (DMSO-d6)
δ 1.76-1.98 (m, 3H), 2.05-2.15 (m, 1H), 2.45 (s, 1H), 3.17-
3.40 (m, 4H), 3.58-3.67 (m, 2H), 4.17 (d, J ) 9 Hz, 1H), 4.35 (d,
J ) 9 Hz, 1H), 7.58 (s, 1H), 7.66 (dd, J ) 2 Hz, 9 Hz, 1H), 7.95
(d, J ) 2 Hz, 1H), 7.99 (d, J ) 9 Hz, 1H), 10.41 (brs, 1H). Anal.
(C17H17ClN2O2S‚HCl), C, H, N.
(R)-3′-(Benzo[b]thiophen-5-yl)spiro[1-azabicyclo[2.2.2]octane-
3,5′-oxazolidin]-2′-one HCl (18). This compound was prepared
from compound 2 (550 mg, 3.0 mmol) and 5-bromobenzo[b]-
thiophene (1.6 g, 7.5 mmol) using the same procedure described
for the preparation of compound 7 to yield compound 18, which
was then converted to the HCl salt (610 mg, 58%) as pale brown
crystals; mp >280 °C. 1H NMR (DMSO-d6) δ 1.83-2.00 (m, 3H),
2.06-2.15 (m, 1H), 2.44 (brs, 1H), 3.16-3.36 (m, 4H), 3.65 (dd,
J ) 14 Hz, 33 Hz, 2H), 4.20 (d, J ) 9 Hz, 1H), 4.35 (d, J ) 9 Hz,
1H), 7.46 (d, J ) 5 Hz, 1H), 7.67 (dd, J ) 3 Hz, 9 Hz, 1H), 7.82
(d, J ) 5 Hz, 1H), 7.99 (d, J ) 2 Hz, 1H), 8.03 (d, J ) 9 Hz, 1H),
10.93 (brs, 1H). Anal. (C17H18N2O2S‚HCl‚0.1H2O), C, H, N.
(R)-3′-(2-Methylbenzo[b]furan-5-yl)spiro[1-azabicyclo[2.2.2]-
octane-3,5′-oxazolidin]-2′-one HCl (19). This compound was
prepared from compound 2 (910 mg, 5.0 mmol) and 5-bromo-2-
methylbenzo[b]furan (2.6 g, 12.5 mmol) using the same procedure
described for the preparation of compound 7 to yield compound
19, which was then converted to the HCl salt (1.1 g, 63%) as pale
(R)-3′-(3-Methylbenzo[b]thiophen-5-yl)spiro[1-azabicyclo-
[2.2.2]octane-3,5′-oxazolidin]-2′-one HCl (23). This compound
was prepared from compound 2 (4.00 g, 22.0 mmol) and 5-bromo-
3-methylbenzo[b]thiophene (12.0 g, 52.9 mmol) using the same
procedure described for the preparation of compound 7 to yield
compound 23, which was then converted to the HCl salt (3.5 g,
44%) as colorless crystals; mp 272-274 °C. ee > 99.9%. 1H NMR
(DMSO-d6) δ 1.85-1.96 (m, 3H), 1.90-1.94 (m, 1H), 2.31 (s, 3H),
3.14-3.44 (m, 5H), 3.66-3.67 (m, 2H), 4.20 (d, J ) 8 Hz, 1H),
4.39 (d, J ) 8 Hz, 1H), 7.46 (s, 1H), 7.71 (d, J ) 8 Hz, 1H), 7.79
(s, 1H), 7.98 (d, J ) 8 Hz, 1H). Anal. (C18H20N2O2S‚HCl), C, H,
N.
5-Bromo-3-ethylbenzo[b]thiophene (32). To a solution of
4-bromobenzenethiol 31 (6.2 g, 33.0 mmol) and 1-bromobutan-2-
one (5.0 g, 33.0 mmol) in DMF (150 mL) was added K2CO3 (5.4
g, 39.0 mmol) at 0 °C. After stirring for 2 h at room temperature,
the reaction mixture was added to water and extracted with AcOEt.
The combined organic phases were dried over MgSO4 and
evaporated in vacuo to give the crude intermediate. The obtained
intermediate was heated at reflux with PPA (24 g) in chlorobenzene
(200 mL) for 3 days. The resultant mixture was diluted with CHCl3,
washed with water, and dried over MgSO4. The organic solution
was evaporated and purified by silica gel column chromatography
(eluent: hexane) to give compound 32 (6.8 g, 85%) as a colorless
oil. 1H NMR (CDCl3) δ 1.36 (t, J ) 8 Hz, 3H), 2.82 (q, J ) 8 Hz,
2H), 7.12 (s, 1H), 7.43 (dd, J ) 2 Hz, 8 Hz, 1H), 7.70 (d, J ) 8
Hz, 1H), 7.87 (d, J ) 2 Hz, 1H). Anal. (C10H9BrS), C, H, N.
1
yellow crystals; mp >270 °C. H NMR (DMSO-d6) δ 1.76-1.93
(m, 3H), 2.05-2.15 (m, 1H), 2.44 (s, 3H), 2.35-2.40 (m, 1H),
3.18-3.40 (m, 4H), 3.58-3.70 (m, 2H), 4.16 (d, J ) 9 Hz, 1H),
4.30 (d, J ) 9 Hz, 1H), 6.61 (d, J ) 1 Hz, 1H), 7.42 (dd, J ) 2
Hz, 9 Hz, 1H), 7.52 (d, J ) 9 Hz, 1H), 7.66 (d, J ) 2 Hz, 1H),
10.64 (brs, 1H). Anal. (C18H20N2O3‚HCl), C, H, N.
(R)-3′-(2-Methylbenzo[b]thiophen-5-yl)spiro[1-azabicyclo-
[2.2.2]octane-3,5′-oxazolidin]-2′-one HCl (20). This compound
was prepared from compound 2 (1.1 g, 6.2 mmol) and 5-bromo-
2-methylbenzo[b]thiophene (3.5 g, 15.4 mmol) using the same
procedure described for the preparation of compound 7 to yield
compound 20, which was then converted to the HCl salt (1.21 g,
1
53%) as pale yellow crystals; mp >300 °C. H NMR (DMSO-d6)
δ 1.78-1.94 (m, 3H), 2.05-2.15 (m, 1H), 2.41 (m, 1H), 2.53 (s,