S. P. Panchgalle et al. / Tetrahedron: Asymmetry 20 (2009) 1767–1770
1769
0
0
4
.2. 3-(1 -Naphthoxy)propanol 4
4.5. (S)-2-((1 -Naphthoxy)-methyl)oxirane 7
To a stirring solution of
aqueous NaOH solution (20 mL) was added 3-bromopropanol
3.056 g, 22 mmol). After refluxing for 6 h, the reaction mixture
was extracted with CH Cl
(2 ꢁ 50 mL). The combined organic layer
was washed with water (1 ꢁ 50 mL), brine, dried over anhydrous
Na SO , filtered, and concentrated on a rotary evaporator under re-
duced pressure. The resulting residue was purified by flash column
chromatography (silica gel) using EtOAc–petroleum ether (15:85)
as an eluent, to afford alcohol 4. Yield: 2.706 g (67%); yellow oil; IR
a
-naphthol 3 (2.880 g, 20 mmol) in 10%
To a stirred solution of diol 6 (1.500 g, 6.88 mmol) in anhydrous
1,4-dioxane (25 mL) was added PPh (2.703 g, 10.32 mmol, 1.5
3
(
equiv) at 70 °C for 10 min. Diisopropyl azodicarboxylate (2.084 g,
10.32 mmol, 1.5 equiv) diluted in 20 mL of anhydrous 1,4-dioxane
was added dropwise and the reaction mixture was stirred at the
same temperature for further 40 min. The reaction mixture was
cooled to room temperature, washed with water, brine, dried over
2
2
2
4
2 4
anhydrous Na SO , filtered, and concentrated on a rotary evaporator
under reduced pressure. Purification by flash column chromatogra-
(
CHCl
3
)
m
max 3461, 3059, 3011, 2889, 2580, 1657, 1641, 1589,
phy (silica gel) using EtOAc–petroleum ether (15:85) as an eluent
ꢀ
1
1
25
7
35 cm ; H NMR (200 MHz, CDCl
m, 2H), 3.97 (t, J = 5.94 Hz, 2H), 4.30 (t, J = 5.94 Hz, 2H), 6.83 (d,
J = 8.46 Hz, 1H), 7.32–7.52 (m, 4H), 7.76–7.84 (m, 1H), 8.18–8.26
3
): d = 1.64 (br s, 1H), 2.13–2.25
afforded epoxide 7. Yield: 0.921 g (67%); yellow oil; ½
a
ꢂ
¼ ꢀ34:0
D
7
i
25
D
(
(c 1.52, MeOH) {Lit.
½
aꢂ
¼ ꢀ33:9 (c 1.55, MeOH)}; IR (CHCl
3 max
) m
ꢀ1 1
3
3443, 3420, 3031, 1265 cm ; H NMR (200 MHz, CDCl ): d = 2.84–
1
3
(
m, 1H); C NMR (50 MHz, CDCl
3
): d = 31.8, 59.7, 64.9, 104.5,
2.88 (dd, J = 2.6, 4.9 Hz, 1H), 2.95–2.99 (m, 1H), 3.46–3.54 (m, 1H),
4.10–4.18 (dd, J = 5.5, 11.1 Hz, 1H), 4.37–4.44 (dd, J = 3.1, 10.9 Hz,
1
20.1, 121.6, 125.0, 125.3, 125.7, 126.2, 127.3, 134.3, 154.3 ppm.
1
H), 6.80 (d, J = 7.3 Hz, 1H), 7.32–7.53 (m, 4H), 7.76–7.84 (m, 1H),
0
13
4
.3. 3-(1 -Naphthoxy)propanal 5
8.26–8.34 (m, 1H); C NMR (50 MHz, CDCl
3
): d = 44.4, 50.0, 68.7,
1
04.8, 120.6, 121.9, 125.1, 125.4, 125.6, 126.3, 127.3, 134.3,
To solution of alcohol 4 (2.500 g, 12.37 mmol) in anhydrous di-
154.0 ppm.
methyl sulfoxide (16 mL) was added IBX (5.343 g, 18.55 mmol,
.5 equiv). After stirring at room temperature for 2 h, the reaction
mixture was diluted with water (10 mL), and then with diethyl ether
100 mL). The diethyl ether layer was filtered through bed of Celite.
The filtrate was washed with water (50 mL), brine, dried over anhy-
drous Na SO , filtered, and concentrated on rotary evaporator under
reduced pressure to afford aldehyde 5. Yield: 2.202 g (89%); yellow
oil; IR (CHCl max 3061, 3011, 2957, 2837, 2356, 2045, 1721, 1587,
1
4.6. (S)-(ꢀ)-Propranolol 1
(
To a stirred solution of epoxide 7 (0.500 g, 2.5 mmol) in 10 mL
dichloromethane was added slowly isopropylamine (1.475 g,
25 mmol). The reaction mixture was stirred for 30 h at room
temperature, and then excess isopropylamine was removed under
reduced pressure. The residue was diluted with water and ex-
tracted with EtOAc (2 ꢁ 25 mL). The combined organic layer was
2
4
3
) m
ꢀ1 1
1
2
4
3
511, 1257, 749 cm ; H NMR (200 MHz, CDCl ): d = 2.99–3.06 (m,
H), 4.48 (t, J = 6.07 Hz, 2H), 6.84 (d, J = 8.47 Hz, 1H), 7.33–7.53 (m,
H), 7.76–7.84 (m, 1H), 8.14–8.22 (m, 1H), 9.94 (t, J = 1.64 Hz, 1H);
2 4
washed with brine, dried over anhydrous Na SO , filtered, and
concentrated on rotary evaporator under reduced pressure. Purifi-
cation by flash column chromatography (silica gel) using EtOAc–
petroleum ether (75:25) as an eluent afforded (S)-propranolol 1.
1
3
3
C NMR (50 MHz, CDCl ): d = 43.0, 61.7, 104.6, 120.6, 121.7, 125.2,
125.3, 125.6, 126.4, 127.3, 134.3, 153.9, 200.1 ppm.
7
p
Yield: 0.537 g (83%), white solid; mp 71–72 °C {Lit. mp 72–
0
25
D
7p
25
D
4
.4. (S)-3-(1 -Naphthoxy)propane-1,2-diol 6
73 °C}; ½
IR (CHCl
(200 MHz, CDCl
a
ꢂ
¼ ꢀ9:8 (c 0.55, EtOH) {Lit.
½
aꢂ
¼ ꢀ9:9 (c 0.5, EtOH)};
ꢀ1 1
3
)
m
max 3410, 3281, 3011, 2989, 1271 cm
;
H NMR
To a solution of aldehyde 5 (2.0 g, 10 mmol) and nitrosobenzene
3
): d = 1.23 (d, J = 6.2 Hz, 6 H), 2.90–3.13 (m, 3H),
(
3
1.070 g, 10 mmol) in CH CN (50 mL) was added
L-proline (0.230 g,
4.05–4.21 (m, 2H), 4.35–4.46 (m, 1H), 5.14 (br s, 2H), 6.73 (d,
2
mmol, 20 mol %) at ꢀ20 °C. The reaction mixture was allowed to
J = 7.2 Hz, 1H), 7.25–7.50 (m, 4H), 7.74–7.81 (m, 1H), 8.20–8.26
1
3
stir at the same temperature for 24 h followed by addition of
MeOH (25 mL) and NaBH (0.570 g, 15 mmol) to the reaction mix-
ture, which was stirred for 10 min. After addition of phosphate buf-
3
(m, 1H); C NMR (50 MHz, CDCl ): d = 21.4, 49.0, 49.5, 67.4,
4
70.3, 104.8, 120.4, 121.7, 125.1, 125.3, 125.6, 126.2, 127.3, 134.2,
+
+
154.0 ppm; LC–MS: m/z = 260.17 (M +1), 282.20 (M +Na).
fer, the resulting mixture was extracted with EtOAc (3 ꢁ 50 mL)
2 4
and the combined organic phases were dried over Na SO , filtered,
4.7. (S)-(ꢀ)-Propranolol hydrochloride 8
and concentrated on a rotary evaporator under reduced pressure to
afford crude aminoxy alcohol. To a solution of crude aminoxy alco-
hol in MeOH was added 10% Pd/C (100 mg) carefully. The reaction
mixture was then stirred under a hydrogen atmosphere (1 atm of
(S)-Propranolol 1 (0.500 g, 1.93 mmol) was dissolved in diethyl
ether (20 mL) and treated with HCl gas. The resultant solid was fil-
tered and recrystallization from methanol–ether afforded (S)-pro-
pranolol hydrochloride 8. Yield: 0.490 g (86%), white crystals; mp
2
H ) for 6 h. After completion of the reaction (monitored by TLC),
7
f
25
D
the reaction mixture was filtered through a Celite pad and then
concentrated to near dryness. Purification by flash column chroma-
tography (silica gel) using EtOAc–petroleum ether (40:60) as an
eluent afforded diol 6. Yield: 1.722 g (79%); white solid; mp 113–
192–193 °C {Lit. mp 192–193.5 °C}; ½
a
ꢂ
¼ ꢀ25:8 (c 1.25, EtOH)
7
f
25
D
1
{Lit.
½
aꢂ
¼ ꢀ25:7 (c 1.23, EtOH)}; H NMR (200 MHz, D
2
O):
d = 1.35 (d, J = 6.2 Hz, 6H), 3.29–3.42 (m, 2H), 3.45–3.55 (dd,
J = 6.2, 12.2 Hz, 1H), 4.21–4.36 (m, 2H), 4.41–4.50 (m, 1H), 7.01 (d,
J = 7.4 Hz, 1H), 7.47 (m, 1H), 7.52–7.63 (m, 3H), 7.92 (d, J = 7.4 Hz,
7
p
25
D
7g
1
[a
15 °C {Lit. mp 113–114 °C}; ½
aꢂ
¼ þ6:7 (c 1.05 MeOH). {Lit.
1
3
]
D
= +6.7 (c 1.1 MeOH)}; ee >98% [Chiral HPLC analysis: Kromasil 5-
Cellucoat (250 ꢁ 4.6 mm) column; eluent: ethanol–hexane 20:80; flow
rate: 0.5 mL/min, detector: 254 nm t = 15.13 min, t = 16.85 min]; IR
CHCl max 3443, 3024, 2887, 2589, 1647, 1635, 1597, 735 cm
H NMR (400 MHz, CDCl ): d = 2.34 (br s, 2H), 3.84–3.97 (m, 2H),
.22–4.24 (m, 2H), 4.26–4.31 (m, 1H), 6.83 (d, J = 7.53 Hz, 1H),
.36–7.40 (m, 1H), 7.46–7.53 (m, 4H), 7.81–7.83 (m, 1H), 8.21–
1H), 8.28 (d, J = 7.4 Hz, 1H); C NMR (50 MHz, D
49.6, 68.7, 70.7, 104.8, 120.5, 121.8, 125.1, 125.5, 126.3, 126.8,
127.4, 134.5, 154.2 ppm. Elemental Anal. Calcd for C16 22ClNO : C,
2
O): d = 22.9, 48.9,
R
S
H
2
ꢀ1
(
3
)
m
;
64.96; H, 7.50; N, 4.74. Found: C, 64.71; H, 7.66; N, 4.61.
1
3
4
7
8
1
1
4.8. (S)-(+)-Naftopidil 2
1
3
.23 (m, 1H); C NMR (100 MHz, CDCl
05.0, 120.9, 121.5, 125.3, 125.4, 125.7, 126.5, 127.6, 134.5,
54.0 ppm. Elemental Anal. Calcd for C13 : C, 71.54; H, 6.47.
3
): d = 63.8, 69.2, 70.5,
To a solution of epoxide 7 (0.400 g, 2 mmol) in anhydrous
2-propanol (10 mL) was added 1-(2-methoxyphenyl) piperazine
(0.384 g, 2 mmol, 1 equiv) and the reaction mixture was refluxed
for 32 h. After completion of the reaction, the solvent was removed
14 3
H O
Found: C, 71.47; H, 6.39.