W. Chu et al. / Bioorg. Med. Chem. 17 (2009) 1222–1231
1229
The crude product was purified by flash column chromatography
5.1.19. 9-(4-(2-Fluoroethyl)benzyl)-9-azabicyclo[3.3.1]nonan-
with hexane–ether (1:1) to obtain 11f (245 mg, 81%) as a colorless
oil. The HCl salt of 11f is a white solid, mp 179.3–180.8 °C. 1H NMR
(CDCl3) d: 8.01 (s, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz,
2H), 7.21 (s, 1H), 6.76 (m, 2H), 5.27 (m, 1H), 3.83 (s, 3H), 3.78 (s,
2H), 3.07 (m, 2H), 2.48 (s, 3H), 2.46 (m, 2H), 2.32 (s, 3H), 2.17
(m, 1H), 1.96 (m, 2H), 1.58 (m, 3H), 1.21 (m, 2H). Anal. Calcd for
C25H32N2O3SÁHCl: C, 62.94; H, 6.97; N, 5.87. Found: C, 62.58; H,
7.02; N, 5.42.
3-yl-2-methoxy-5-methyl-phenylcarbamate (WC-59)
WC-59 was prepared from 14 in a manner similar to that de-
scribed for 11a. The crude product was purified by flash column
chromatography with hexane–ether (1:2) to obtain WC-59
(212 mg, 87%) as a colorless oil. The HCl salt of WC-59 is a white
solid, mp 134.7–135.8 °C. 1H NMR (CDCl3) d: 8.01 (s, 1H), 7.33 (d,
J = 8.1 Hz, 2H), 7.20 (s, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.76 (m, 2H),
5.28 (m, 1H), 4.64 (dt, J = 47.1, 6.6 Hz, 2H), 3.84 (s, 3H), 3.80 (s,
2H), 3.07 (m, 2H), 3.01 (dt, J = 22.8, 6.6 Hz, 2H), 2.50 (m, 2H),
2.33 (s, 3H), 2.17 (m, 1H), 1.97 (m, 2H), 1.55 (m, 3H), 1.18 (m,
2H). Anal. Calcd for C26H34ClFN2O3ÁHClÁ0.25H2O: C, 64.85; H,
7.22; N, 5.82. Found: C, 65.03; H, 7.45; N, 5.33.
5.1.15. 9-(4-Methoxybenzyl)-9-azabicyclo[3.3.1]nonan-3-yl-2-
methoxy-5-methyl-phenylcarbamate (11g)
Compound 11g was prepared from 1-chloromethyl-4-methoxy-
benzene in a manner similar to that described for 11a. The crude
product was purified by flash column chromatography with hex-
ane–ether (1:2) to obtain 11g (221 mg, 72%) as a colorless oil.
The HCl salt of 11g is a white solid, mp 203.9–204.8 °C. 1H NMR
(CDCl3) d: 7.99 (s, 1H), 7.28 (d, J = 8.7 Hz, 2H), 7.17 (s, 1H), 6.86
(d, J = 8.7 Hz, 2H), 6.76 (m, 2H), 5.26 (m, 1H), 3.85 (s, 3H), 3.81 (s,
3H), 3.75 (s, 2H), 3.05 (m, 2H), 2.47 (m, 2H), 2.31 (s, 3H), 2.16
(m, 1H), 1.95 (m, 2H), 1.53 (m, 3H), 1.19 (m, 2H). Anal. Calcd for
C25H32N2O4ÁHClÁ0.25H2O: C, 64.50; H, 7.25; N, 6.02. Found: C,
64.54; H, 7.28; N, 5.65.
5.1.20. 9-(4-(Dimethylamino)benzyl)-9-azabicyclo[3.3.1]nonan-
3-yl-2-methoxy-5-methyl-phenylcarbamate (WC-26)
NaBH3CN (57 mg, 0.91 mmol) was added to a solution of 10
(260 mg, 0.85 mmol) and 4-(dimethylamino)benzaldehyde (127 mg,
0.85 mmol) in methanol (10 mL), and the reaction mixture was
stirred for 3 days. After evaporation of methanol and addition of
ethyl acetate (50 mL), the mixture was washed with water
(30 mL), then with saturated NaCl solution (30 mL), and finally
the organic layer was dried over Na2SO4. The crude product was
purified by flash column chromatography with hexane–ether
(1:2) to obtain WC-26 (185 mg, 50%) as a colorless oil. The HCl salt
of WC-26 is a white solid, mp 192.2–193.1 °C. 1H NMR (CDCl3) d:
8.00 (s, 1H), 7.25 (d, J = 8.7 Hz, 2H), 7.18 (s, 1H), 6.76 (m, 2H),
6.73 (d, J = 8.4 Hz, 2H), 5.27 (m, 1H), 3.85 (s, 3H), 3.74 (s, 2H),
3.08 (m, 2H), 2.95 (s, 6H), 2.49 (m, 2H), 2.32 (s, 3H), 2.17 (m,1H),
1.97 (m, 2H), 1.54 (m, 3H), 1.19 (m, 2H). Anal. Calcd for
C26H35N3O3Á2HClÁ0.5H2O: C, 60.11; H, 7.37; N, 8.09. Found: C,
59.99; H, 7.50; N, 7.74.
5.1.16. 9-(4-Methoxyphenethyl)-9-azabicyclo[3.3.1]nonan-3-yl-
2-methoxy-5-methyl-phenylcarbamate (11h)
Compound 11h was prepared from 1-(2-bromoethyl)-4-
methoxybenzene in a manner similar to that described for 11a.
The crude product was purified by flash column chromatography
with ether to obtain 11h (86 mg, 29%) as a colorless oil. The HCl
salt of 11h is a white solid, mp 209.8–210.9 °C. 1H NMR (CDCl3)
d: 7.96 (s, 1H), 7.16 (s, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.84 (d,
J = 8.7 Hz, 2H), 6.76 (m, 2H), 5.14 (m, 1H), 3.85 (s, 3H), 3.79 (s,
3H), 3.10 (m, 2H), 2.79 (m, 2H), 2.64 (m, 2H), 2.46 (m, 2H), 2.30
(s, 3H), 2.17 (m, 1H), 1.89 (m, 2H), 1.53 (m, 3H), 1.22 (m, 2H). Anal.
Calcd for C26H34N2O4ÁHCl: C, 65.74; H, 7.43; N, 5.90. Found: C,
65.91; H, 7.57; N, 5.64.
5.1.21. 4-[2-(t-Butyl-diphenyl-silyloxy)ethyl]benzoic acid
methyl ester (20)
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (2 mL) was added to
a solution of 4-(2-hydroxyethyl)benzoic acid methyl ester 19
(721 mg, 4.0 mmol) and t-butyldiphenylsilyl chloride (TBDPSCl)
(2.20 g, 8.0 mmol) in CH2Cl2 (15 mL), and the reaction mixture
was stirred overnight. After evaporation of CH2Cl2 under vacuum,
ether (75 mL) was added and the mixture was washed with water
(2 Â 50 mL), then with saturated NaCl solution (50 mL), and finally
the organic layer was dried over Na2SO4. The crude product was
purified by flash column chromatography with hexane–ether
(10:1) to obtain 20 (1.64 g, 98%) as a colorless oil. 1H NMR (CDCl3)
5.1.17. 9-(4-(2-Fluoroethyl)phenethyl)-9-azabicyclo[3.3.1]-
nonan-3-yl-2-methoxy-5-methyl-phenylcarbamate (11i)
Compound 11i was prepared from 18 in a manner similar to
that described for 11a. The crude product was purified by flash
column chromatography ether to obtain 11i (162 mg, 53%) as a
colorless oil. The HCl salt of 11i is a white solid, mp 202.2–
203.7 °C. 1H NMR (CDCl3) d: 7.91 (s, 1H), 7.10 (s, 5H), 6.68 (m,
2H), 5.08 (m, 1H), 4.55 (dt, J = 46.8, 6.6 Hz, 2H), 3.77 (s, 3H),
3.04 (m, 2H), 2.92 (dt, J = 22.8, 6.6 Hz, 2H), 2.74 (m, 2H), 2.64
(m, 2H), 2.40 (m, 2H), 2.24 (s, 3H), 2.09 (m, 1H), 1.83 (m, 2H),
1.46 (m, 3H), 1.18 (m, 2H). Anal. Calcd for C27H36ClFN2O3Á
HCl: C, 66.04; H, 7.39; N, 5.70. Found: C, 66.18; H, 7.54; N,
5.61.
d: 7.97 (d, J = 7.2 Hz, 2H), 7.59 (d, J = 6.6 Hz, 4H), 7.47–7.35 (m, 6H),
7.27 (d, J = 7.8 Hz, 2H), 3.95 (s, 3H), 3.89 (t, J = 6.6 Hz, 2H), 2.92 (t,
J = 6.6 Hz, 2H), 1.04 (s, 9H).
5.1.22. [4-[2-(t-Butyl-diphenyl-silyloxy)ethyl]phenyl]-
methanol (21)
Compound 21 was prepared from 20 in a manner similar to that
described for 13. The crude product was purified by flash column
chromatography with hexane–ether (1:1) to obtain 21 (540 mg,
35%) as a colorless oil. 1H NMR (CDCl3) d: 7.64 (m, 4H), 7.45–7.36
(m, 6H), 7.30 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 4.69 (s,
2H), 3.88 (t, J = 6.9 Hz, 2H), 2.90 (t, J = 6.9 Hz, 2H), 1.08 (s, 9H).
5.1.18. 9-(4-(Dimethylamino)phenethyl)-9-azabicyclo[3.3.1]-
nonan-3-yl-2-methoxy-5-methyl-phenylcarbamate (11j)
Compound 11j was prepared from 4-(2-bromoethyl)-N,N-
dimethylaniline in a manner similar to that described for 11a.
The crude product was purified by flash column chromatography
with ether to obtain 11j (131 mg, 44%) as a pale yellow oil. The
HCl salt of 11j is a white solid, mp 253.6–255.2 °C. 1H NMR (CDCl3)
5.1.23. [2-(4-Bromomethyl-phenyl)ethoxy]-t-butyl-diphenyl-
silane (22)
d: 7.96 (s, 1H), 7.14 (s, 1H), 7.10 (d, J = 9.0 Hz, 2H), 6.76 (m, 2H),
Compound 22 was prepared from 21 in a manner similar to that
described for 14. The crude product was purified by flash column
chromatography with hexane–ether (10:1) to obtain 22 (148 mg,
65%) as a colorless oil. 1H NMR (CDCl3) d: 7.60 (m, 4H), 7.45–7.34
(m, 6H), 7.30 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 4.50 (s, 2H),
3.84 (t, J = 6.9 Hz, 2H), 2.85 (t, J = 6.9 Hz, 2H), 1.06 and 1.04 (s, 9H).
6.71 (d, J = 8.7 Hz, 2H), 5.15 (m, 1H), 3.85 (s, 3H), 3.13 (m, 2H),
2.92 (s, 6H), 2.79 (m, 2H), 2.64 (m, 2H), 2.45 (m, 2H), 2.30 (s,
3H), 2.17 (m, 1H), 1.91 (m, 2H), 1.52 (m, 3H), 1.22 (m, 2H). Anal.
Calcd for C27H37N3O3Á2HCl: C, 61.83; H, 7.49; N, 8.01. Found: C,
61.99; H, 7.51; N, 7.84.