I. J. Kim et al. / Bioorg. Med. Chem. 12 (2004) 4543–4550
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the residual material was diluted with ethyl acetate and
NH4OH. The aqueous layer was extracted with ethyl
acetate (3 · 200 mL), washed with water and brine, dried
over sodium sulfate, and concentrated to dryness. Col-
umn chromatography of the crude material with 10%
ethyl acetate in hexanes gave 4 (15.6 g, 71% over two
steps) as a colorless oil. The HCl salt was prepared; mp
at 60 ꢁC for 2 h in a hydrogen atmosphere while vigor-
ously stirring. It was cooled to room temperature and
the mixture basified with NH4OH (pH ꢀ8) and stirred
for 10 min, filtered through a pad of Celite, washed with
MeOH, and the solvent was evaporated in vacuo. Col-
umn chromatography of the crude material with
CH2Cl2–MeOH–NH4OH (91:9:1) gave N-methylated 8
(390 mg, 85%) as a pale yellow oil; 8ÆHCl: mp 196 ꢁC
1
184–185 ꢁC; H NMR (free base) d 7.41–7.15 (m, 7H),
1
6.93–6.84 (m, 2H), 5.79–5.76 (m, 1H), 3.80 (s, 3H), 3.65
(s, 2H), 3.17–3.16 (m, 2H), 2.70–2.66 (m, 2H), 2.57–2.53
(m, 2H); MS m=z 279 (M+H)þ; HRMS (FAB) calcd for
C19H21NO (M+H)þ 279.1623, found 279.1622. Anal.
Calcd for C19H22ClNO: C, 72.25; H, 7.02; N, 4.43.
Found: C, 72.04; H, 7.12; N, 4.36.
(dec); H NMR (free base) d 7.21–7.15 (m, 2H), 6.94–
6.87 (m, 2H), 3.83 (s, 3H), 3.10–3.05 (m, 1H), 3.02–2.92
(m, 1H), 2.79–2.71 (m, 1H), 2.65–2.57 (m, 1H), 2.54–
2.47 (m, 1H), 2.45 (s, 3H), 2.17–2.05 (m, 2H), 1.97–1.73
(m, 3H), 1.64–1.55 (m, 3H), 1.52–1.31 (m, 2H); MS m=z
245 (M+H)þ; HRMS (FAB) calcd for C16H23NO
(M+H)þ 245.1780, found 245.1763; Anal. Calcd for
C16H24ClNOÆ0.1H2O: C, 67.76; H, 8.60; N, 4.94. Found:
C, 67.77; H, 8.60; N, 4.89.
4.2. 2-Benzyl-5-(2-methoxyphenyl)-2-azabicyclo[3.3.1]-
nonane (7)
sec-BuLi (1.4 M) in cyclohexane (1.41 mL, 1.98 mmol)
was added dropwise to a solution of 4 (542 mg,
1.94 mmol) in THF (15 mL) at )50 ꢁC and the mixture
was allowed to warm to )20 ꢁC over 1 h. After cooling
to )50 ꢁC, allyl bromide (171 lL, 1.98 mmol) was added,
and the mixture was allowed to warm slowly to 0 ꢁC
over 2 h. The reaction was quenched by addition of
water, diluted with ethyl acetate, washed with water and
brine, dried over sodium sulfate, filtered, and concen-
trated to give a crude endocyclic enamine 5, which was
used directly for the next reaction. The crude 5 was di-
luted with HCO2H–H3PO4 (5 mL:5 mL) and stirred at
room temperature for 88 h. The reaction mixture was
poured into ice water, treated with 40% NaOH solution
(to pH ꢀ8) and extracted with ethyl acetate (3 · 50 mL).
The organic layer washed with water and brine, dried
over sodium sulfate, and concentrated to provide crude
enamine 6. At 0 ꢁC, NaBH4 (147 mg, 3.88 mmol) was
added to a solution of 6 in MeOH (10 mL). The mixture
was allowed to warm to room temperature and stirred
for 1.5 h. After removal of MeOH, the residue was di-
luted with water, neutralized with 2 N HCl solution
(pH ꢀ8), extracted with ethyl acetate (3 · 20 mL), wa-
shed with water and brine, dried over sodium sulfate,
and concentrated to dryness. Column chromatography
of the crude material with 3% acetone in hexanes
afforded 7 (413 mg, 66% over three steps) as a colorless
4.4. 2-(2-Methyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (2a)
A 48% HBr solution (0.7 mL) was added to a solution of
8 (37.6 mg, 0.153 mmol) in AcOH (0.7 mL), and the
mixture was refluxed for 21 h, cooled to 0 ꢁC, diluted
with water, and basified with 40% NaOH solution
(pH ꢀ10).
The mixture was extracted with ethyl acetate–CHCl3–
MeOH (8:1:1, 3 · 10 mL), and the organic solution was
washed with water and brine, dried over sodium sulfate,
and concentrated to give crude 2a. Column chroma-
tography of crude 2a with CHCl3–MeOH–NH4OH
(80:20:1) provided 2a (24.4 mg, 69%) as a pale-yellow
1
oil; 2aÆHCl: mp 232–233 ꢁC; H NMR (free base) d 7.17
(dd, J ¼ 8 and 2 Hz, 1H), 7.05 (dt, J ¼ 8 and 2 Hz, 1H),
6.85 (dt, J ¼ 8 and 2 Hz, 1H), 6.67 (dd, J ¼ 8 and 2 Hz,
1H), 3.14–3.09 (m, 1H), 3.03 (dt, J ¼ 12 and 5 Hz, 1H),
2.86–2.79 (m, 1H), 2.52–2.42 (m, 2H), 2.49 (s, 3H), 2.17–
2.04 (m, 2H), 1.97–1.87 (m, 2H), 1.70–1.57 (m, 2H),
1.48–1.36 (m, 2H); MS m=z 232 (M+H)þ; HRMS (FAB)
calcd for C15H22NO (M+H)þ 232.1701, found 232.1706.
Anal. Calcd for C15H22ClNOÆ0.25H2O: C, 66.16; H,
8.33; N, 5.14. Found: C, 66.25; H, 8.25; N, 5.04.
4.5. 5-(2-Methoxyphenyl)-2-azabicyclo[3.3.1]nonane (9)
1
solid; mp 99–100 ꢁC (recrystallized from hexanes); H
NMR (free base) d 7.39–7.14 (m, 7H), 6.93–6.86 (m,
2H), 3.81 (s, 3H), 3.71 (q, J ¼ 13 and 6 Hz, 2H), 3.11 (br
s, 1H), 2.96–2.88 (m, 1H), 2.75–2.67 (m, 1H), 2.57–2.45
(M, 2H), 2.20–2.16 (m, 1H), 2.06–1.97 (m, 3H), 1.86–
1.70 (m, 3H), 1.64–1.56 (m, 1H); MS m=z 322 (M+H)þ;
HRMS (FAB) calcd for C22H27NO (M+H)þ 321.2093,
found 321.2102. Anal. Calcd for C22H27NO: C, 82.20;
H, 8.47; N, 4.36. Found: C, 82.03; H, 8.52; N, 4.35.
A mixture of 7 (586 mg, 1.82 mmol), 10% Pd–C
(100 mg), and AcOH (10 drops) in MeOH (30 mL) was
heated at 60 ꢁC for 2.5 h in a hydrogen atmosphere.
After cooling to room temperature, it was basified with
NH4OH (pH ꢀ10), filtered through a pad of Celite,
washed with MeOH, and concentrated to provide the
crude product. Column chromatography of crude
product with H2Cl2–MeOH–NH4OH (91:9:1) afforded 9
(390 mg, 85%) as a pale yellow oil; 9ÆHCl: mp 181–
1
182 ꢁC; H NMR (free base) d 7.22–7.16 (m, 2H), 6.95–
4.3. 5-(2-Methoxyphenyl)-2-methyl-2-azabicyclo[3.3.1]-
nonane (8)
6.87 (m, 2H), 3.83 (s, 3H), 3.47–3.45 (m, 1H), 3.37–3.28
(ddd, J ¼ 14, 10, and 5 Hz, 1H), 2.97 (dt, J ¼ 13 and
6 Hz, 1H), 2.50–2.41 (m, 2H), 2.16–2.20 (m, 3H), 1.82–
1.59 (m, 4H), 1.53–1.42 (m, 1H); MS (DEI) m=z 231
(M)þ; HRMS (DEI) calcd for C15H21NO (M)þ
231.1623, found 231.1626; Anal. Calcd for C15H22ClNO:
A mixture of 7 (598 mg, 1.86 mmol), 10% Pd–C
(100 mg), AcOH (10 drops), and 37% formaldehyde in
H2O (154 lL, 1.9 mmol), in MeOH (25 mL) was heated