pentylphenol and 4-cyclopentylphenol was chromatographed
over silica gel (60–120 mesh) using petroleum ether as eluent
to give pure 2-cyclopentyl phenol (2.1 g, 62%) as a colorless
oil.
ated to dryness. The crude product was purified by flash column
chromatography using EtOH–petroleum ether (1:1) to yield the
diol 4 as a colorless liquid (0.74 g, 90%); [α]D Ϫ12.3 (c 0.8,
MeOH); IR (neat, cmϪ1) 3300–3550, 1600, 1492, 1452, 1242,
1
1112, 1046; H NMR (200 MHz; CDCl3) δ 1.4–1.9 (m, 6H),
2-Cyclopentylphenol 2a. Viscous liquid (yield 62%), IR (neat,
cmϪ1) 3400, 2910, 1600, 1480, 1290; 1H NMR (200 MHz;
CDCl3) δ 1.5–2.0 (m, 6H), 2.0–2.2 (m, 2H), 3.15–3.3 (m, 1H),
4.9 (s, 1H), 6.8 (d, J 8.1 Hz, 2H), 6.95 (t, J 8.1 Hz, 1H), 7.1 (t,
J 8.1 Hz, 1H), 7.25 (d, J 8.1 Hz, 1H); 13C NMR (50.3 MHz;
CDCl3) δC 25.5, 33.1, 39.05, 115.5, 121.04, 126.8, 127.8, 132.42,
153.43; MS (m/z, % rel. intensity) 162 (Mϩ, 42), 147 (31), 133
(100), 120 (65), 115 (22), 107 (97), 91 (54), 77 (16).
1.9–2.15 (m, 2H), 2.3 (br s, 1H), 2.7 (br s, 1H), 3.2–3.35 (m, 1H),
3.7–3.9 (m, 2H, CH2), 4.05 (d, J 5.4 Hz, 2H, OCH2), 4.1–4.25
(m, 1H, CH), 6.85 (d, J 8.1 Hz, 1H), 7.0 (t, J 8.2 Hz, 1H), 7.15
(t, J 8.1 Hz, 1H), 7.25 (d, J 8.1 Hz, 1H); 13C NMR (50.3 MHz;
CDCl3) δC 25.85, 33.35, 39.35, 64.29, 69.58, 71.18, 112.08,
121.49, 126.96, 127.17, 135.16, 156.58; MS (% rel. intensity) 236
(Mϩ, 11), 162 (60), 133 (100), 120 (43.1), 107 (47), 91 (21), 77
(4).
4-Cyclopentylphenol 2b. Viscous liquid (yield 28%), IR (neat,
cmϪ1) 3400, 2920, 1600, 1480, 1290; 1H NMR (200 MHz;
CDCl3) δ 1.2–1.9 (m, 6H), 1.9–2.2 (m, 2H), 3.15 (m, 1H), 4.8
(s, 1H), 6.95 (m, 2H), 7.05 (m, 2H).
Procedure for the preparation of cyclic sulfite 5
The diol 4 (0.5 g, 2.1 mmol) was dissolved in dry pyridine (2 ml)
and cooled to 0 ЊC in an ice-bath under argon atmosphere.
Freshly distilled thionyl dichloride (0.46 g, 0.19 ml, 2.2 mmol)
was added dropwise and the reaction mixture was stirred for
3 h. Ice-cold water was added to the reaction mixture, which
was then extracted with ether. The ethereal layer was washed
successively with dil. HCl, saturated aq. sodium bicarbonate
and brine. The ether extract was dried over anhydrous sodium
sulfate and evaporated to dryness. The crude product was
dissolved in 10 ml of dichloromethane and a 2.5 ml aliquot
was purified by flash column chromatography using EtOAc–
petroleum ether (1:9) to furnish a light yellow oil (0.138 g, 93%);
[α]D ϩ12.05 (c 0.8, MeOH); IR (neat, cmϪ1) 2930, 1440, 1390,
2-Cyclohexylphenol. Viscous liquid (yield 38%), IR (neat,
cmϪ1) 3300, 2910, 1610, 1495, 1270; 1H NMR (200 MHz;
CDCl3) δ 1.1–1.6 (m, 6H), 1.6–2.1 (m, 4H), 2.3 (m, 1H), 4.9 (s,
1H), 6.8 (d, J 8.1 Hz, 1H), 6.95 (t, J 8.1 Hz, 1H), 7.1 (t, J 8.1 Hz,
1H), 7.2 (d, J 8.1 Hz, 1H).
4-Cyclohexylphenol. Viscous liquid (yield 41%), IR (neat,
cmϪ1) 3300, 2910, 1610, 1480, 1285; 1H NMR (200 MHz;
CDCl3) δ 1.2–1.55 (m, 6H), 1.55–1.8 (m, 4H), 4.1 (m, 1H), 4.8
(s, 1H), 6.9 (m, 2H ), 7.3 (m, 2H).
1
1235, 1195; H NMR (200 MHz; CDCl3) δ 1.5–1.9 (m, 6H),
1.9–2.1 (m, 2H), 3.3 (m, 1H), 4.1 (m, 1H), 4.4 (m, 2H), 4.7 (d,
J 6.4 Hz, 1H), 4.9 (m, 1H), 5.35 (m, 1H), 6.85 (d, J 8.1 Hz, 1H),
7.0 (d, J 8.1 Hz, 1H), 7.2 (t, J 8.1 Hz, 1H), 7.3 (d, J 8.1 Hz, 1H);
13C NMR (50.3 MHz; CDCl3) δC 25.78, 33.13, 33.19, 39.51,
67.09, 69.01, 78.70, 121.95, 127.02, 127.36, 135.12, 156.07; MS
(% rel. intensity) 282 (12), 218 (2), 160 (78), 145 (50), 131 (56),
121 (100), 107 (41), 91 (94), 77 (6) (Calc. for C14H18O4S: C,
59.57; H, 6.38; S, 11.35. Found: C, 59.94; H, 6.42; S, 11.31%).
4-Chloro-2-cyclopentylphenol (dowicide). Viscous liquid (yield
78%), IR (neat, cmϪ1) 3400, 2940, 2855, 1600, 1480, 1420, 1325,
1
1255, 1185, 1120; H NMR (200 MHz; CDCl3) δ 1.5–2.0 (m,
6H), 2.0–2.2 (m, 2H), 3.2 (m, 1H), 4.95 (s, 1H), 6.7 (d, J 8.1 Hz,
1H), 7.05 (d, J 8.1 Hz, 1H), 7.2 (s, 1H); 13C NMR (50.3 MHz;
CDCl3) δC 25.60, 33.06, 39.33, 116.74, 125.93, 126.67, 127.34,
134.40, 152.28.
Preparation of allyl 2-cyclopentylphenyl ether 3
Preparation of cyclic sulfate 6
A mixture of 2-cyclopentylphenol (1.5 g, 9.3 mmol), allyl
bromide (2.24 g, 18.5 mmol) and potassium carbonate (3.2 g, 23
mmol) in acetone (50 ml) was stirred at room temperature for
12 h (TLC). The mixture was filtered through a sintered-glass
funnel and the filtrate was evaporated to dryness. The residue
was purified by flash chromatography using 1% EtOAc in
petroleum ether to furnish the title allyl phenyl ether as light
yellow liquid (1.7 g, 91%), IR (neat, cmϪ1) 2920, 1630, 1390,
1225; 1H NMR (200 MHz; CDCl3) δ 1.4–1.9 (m, 6H), 1.9–2.15
(m, 2H), 3.35 (m, 1H), 4.5 (br d, 2H), 5.15–5.5 (dd, J 8.1 Hz
each, 2H), 6.1 (m, 1H), 6.7–7.05 (m, 2H), 7.05–7.3 (m, 2H);
13C NMR (50.3 MHz; CDCl3) δC 25.76, 33.17, 35.17, 39.59,
69.14, 112.03, 116.89, 120.93, 126.65, 127.0, 134.05, 135.21,
156.73; MS (% rel. intensity) 202 (Mϩ, 4), 161 (27), 145 (17), 133
(28), 107 (100), 91 (54), 77 (8).
The crude cyclic sulfite 5 (0.41 g, 1.5 mmol) was dissolved in a
mixture of 2 ml of acetonitrile and 2 ml of CCl4 and the solu-
tion was cooled to 0 ЊC in an ice-bath. Sodium periodate (0.47
g, 2.2 mmol) was added to the cold solution followed by RuCl3
(3 mg, 0.014 mmol) and 3 ml of water. The reaction mixture
was filtered through a pad of Celite and evaporated. The
residual mixture was extracted with ether, and this extract was
dried over anhydrous sodium sulfate and evaporated to dryness.
Purification by flash column chromatography of the crude
product with EtOAc–petroleum ether (1:9) afforded a white
solid (0.4 g, 91%), mp 89 ЊC; [α]D ϩ5.6 (c 1, MeOH); IR (Nujol,
cmϪ1) 2900, 1445, 1370, 1235, 1195; 1H NMR (200 MHz;
CDCl3) δ 1.5–1.95 (m, 6H), 1.95–2.1 (m, 2H), 3.25–3.4 (m, 1H),
4.35 (d, J 6.4 Hz, 2H), 5.75–5.95 (m, 2H), 5.3 (m, 1H), 6.75 (d,
J 8.1 Hz, 2H), 7.0 (t, J 8.1 Hz, 1H), 7.15 (t, J 8.1 Hz, 1H), 7.25
(d, J 8.1 Hz, 1H); 13C NMR (75 MHz; CDCl3) δC 25.29, 32.88,
38.73, 65.95, 69.35, 79.00, 111.44, 122.03, 126.53, 127.03,
135.08, 155.14; MS (% rel. intensity) 298 (Mϩ, 15), 161 (26), 145
(100), 131 (150), 115 (23), 107 (12), 91 (18), 77 (10).
Procedure for asymmetric dihydroxylation of 3 to afford diol 4
A 250 ml round-bottomed flask was charged with K3Fe(CN)6
(3.4 g, 10 mmol), K2CO3 (1.43 g, 10 mmol), (DHQ)2PHAL (54
mg, 0.07 mmol) and t-BuOH–H2O (1:1; 80 ml) and the mixture
was stirred for 5 min at room temperature. The flask was cooled
to 0 ЊC and a solution of OsO4 (0.17 ml of a 0.2 M solution in
toluene, 0.03 mmol) was added followed by the allyl 2-cyclo-
pentylphenyl ether 3 (0.7 g, 3.5 mmol). The reaction mixture
was stirred for 24 h at room temperature (TLC). Ethyl acetate
(20 ml) and sodium metabisulfite (1 g) were added to the
mixture, which was stirred for 1 h. Two layers separated out.
The organic layer was separated and the aqueous layer was
extracted with EtOAc (3 × 20 ml). The combined organic layer
was washed with brine, dried over sodium sulfate, and evapor-
Procedure for the opening of cyclic sulfate 6 to give 1-(2-cyclo-
pentylphenoxy)-3-[(1,1-dimethylethyl)amino]propan-2-ol
[(S)-penbutolol] 1
A 25 ml round-bottomed flask was charged with cyclic sulfate
6 (200 mg, 0.67 mmol) in dry THF (10 ml) and freshly distilled
t-butylamine in excess (5 ml) under nitrogen atmosphere. The
reaction mixture was refluxed for 8 h. The solvent was evapor-
ated under reduced pressure to give a wine-red, viscous residue.
This residue was treated with 5 ml of 20% H2SO4 and 10 ml of
J. Chem. Soc., Perkin Trans. 1, 1999, 3015–3018
3017