Hideo Shimizu et al
COMMUNICATIONS
7.2 Hz), 3.88 (2H, s), 4.18 (2H, q, J 7.2 Hz), 6.95 7.15 (4H,
m); EI-MS: m/z 238 (M) .
()-1-(2-Fluorobenzyl)-2-methylpropyl
Methanesulfonate [()-7]
A mixture of 6 (8.6 g, 47.2 mmol), triethylamine (7.9 mL,
56.6 mmol) and dichloromethane (40 mL) was cooled to 0 8C,
and then methanesulfonyl chloride (4.0 mL, 51.9 mmol) was
added to the mixture. The reaction mixture was stirred
overnight at room temperature, then treated with water and
extracted 3 times with dichloromethane. The combined extract
was washed with brine, dried over Na2SO4 and evaporated
under vacuum. Purification by silica gel column chromatog-
Ethyl 4-(2-Fluorophenyl)-3-hydroxy-2-methylbutyrate
(5)
A 500 mL stainless steel autoclave was charged under a
nitrogen stream with [{RuCl((R)-segphos)}2(m-Cl)3][Me2NH2]
(138 mg, 0.084 mmol), 4 (20 g, 83.9 mmol) and ethanol
(80 mL). Hydrogen (3.0 MPa) was introduced and the mixture
was stirred for 18 h at 80 8C. Evaporation under vacuum and
purification by silica gel chromatography gave 5 as a diaster-
eomeric mixture (ca. 1:1); yield: 18.6 g (93%). The optical
purity of the two diastereomers was 96.9% ee and 98.5% ee,
respectively. The optical purity was determined by GC analysis
raphy gave ()-7; yield: 12.5 g (91%); [a]D24: 30.8 (c 1.0,
1
CHCl3); H NMR (CDCl3): d 1.06 (3H, d, J 7.0 Hz), 1.08
(3H, d, J 7.0 Hz), 2.07 (1H, dqq, J 4.2, 7.0, 7.0 Hz), 2.48 (3H,
s), 2.93 (1H, dd, J 9.0, 14.6 Hz), 3.06 (1H, dd, J 4.4, 14.6 Hz),
4.77 (1H, ddd, J 4.2, 4.4, 9.0 Hz), 6.98 7.15 (2H, m), 7.18
7.32 (2H, m).
(Cp Chirasil DEX-CB). EI-MS: m/z 241 (M 1) .
()-1,2-Bis(2-isopropyl-2,3-dihydro-1H-phosphindol-
1-yl)benzene [()-iPr-BeePHOS] [()-2b]
4-(2-Fluorophenyl)-2-methylbutane-1,3-diol
A solution of 5 (18.0 g, 74.9 mmol) in THF (180 mL) was added
1,2-Bis(phosphino)benzene (300 mL, 2.32 mmol) in THF
(9 mL) was cooled to 0 8C and 1.6 M n-butyllithium in hexane
(2.9 mL, 4.64 mmol) was added dropwise. After stirring for 1 h
at 0 8C, a solution of ()-7 (1.21 g, 4.64 mmol) in THF (12 mL)
was added. The reaction mixture was stirred for 1 h at 0 8C and
then for 1 h at room temperature. The mixture was cooled to
0 8C and 1.6 M n-butyllithium in hexane (4.4 mL, 6.96 mmol)
was added. Subsequently it was stirred overnight at room
temperature. The reaction mixture was treated with water
(1 mL) and evaporated under vacuum. The residue was then
treated with water and extracted 3 times with diethyl ether. The
combined extract was washed with water and evaporated
under vacuum. Purification by silica gel column chromatog-
to
a suspension of lithium aluminum hydride (2.84 g,
74.9 mmol) in THF (30 mL). The reaction mixture was stirred
for 18 h at room temperature, and water (5 mL) and 1 N NaOH
(5 mL) were added. Filtration, evaporation under vacuum and
purification by silica gel chromatography gave the product;
yield: 14.5 g (99%). EI-MS: m/z 199 (M 1) .
4-(2-Fluorophenyl)-3-hydroxy-2-methylbutyl
p-Toluenesulfonate
4-(2-Fluorophenyl)-2-methylbutane-1,3-diol (13.5 g, 68.1 mmol),
triethylamine (14.2 mL, 21.3 mmol), dichloromethane
(70 mL) was cooled to 0 8C and p-toluenesulfonyl chloride
(13.0 g, 68.1 mmol) was added. After stirring overnight at room
temperature, the reaction mixture was treated with water and
extracted 3 times with dichloromethane. The combined extract
was dried over Na2SO4 and evaporated under vacuum.
Purification of the residue by silica gel column chromatog-
raphy gave the product; yield: 21.1 g (88%). EI-MS: m/z 353
raphy gave ()-2b; yield: 227 mg (23%); mp 70 71 8C; [a]D24:
1
186.1 (c 1.0, CHCl3); H NMR (CDCl3): d 1.05 (6H, d, J
6.4 Hz), 1.09 (6H, d, J 6.8 Hz), 2.09 2.21 (2H, m), 2.60 2.69
(2H, m), 2.93 3.01 (2H, m), 3.28 3.36 (2H, m), 6.74 6.80
(2H, m), 7.02 7.06 (2H, m), 7.18 7.40 (8H, m); 31P NMR
(CDCl3): d 0.27 (s); HRMS: calcd. for C28H32P2: 430.1978;
found: 430.1960.
(M 1) .
[Rh(cod)(()-ipr-beephos)]OTf
()-1-(2-Fluorophenyl)-3-methylbutan-2-ol [()-6]
A solution of ()-2b (50.0 mg, 0.116 mmol) in dichlorome-
thane (2.5 mL) was added dropwise to a solution of [Rh-
(cod)2]OTf (54.3 mg, 0.116 mmol) in dichloromethane (5 mL).
After stirring overnight at room temperature, the solvent was
removed under vacuum. The residue was dissolved with
dichloromethane (0.5 mL), and diethyl ether (5 mL) was
slowly added, yielding an orange precipitate. The solution
was then removed and the solid was washed twice with diethyl
A solution of 4-(2-fluorophenyl)-3-hydroxy-2-methylbutyl
p-toluenesulfonate (21.1 g, 60.2 mmol) in THF (210 mL)
was added into a suspension of lithium aluminum hydride
(2.28 g, 60.2 mmol) in THF (25 mL) at room temperature. The
reaction mixture was stirred for 30 min, followed by the
addition of Na2SO4 ¥ 10 H2O. Filtration, evaporation under
vacuum and purification by silica gel chromatography gave
()-6; yield: 9.6 g (88%, 98.1% ee). The ee was determined by
GC analysis (Cp Chirasil DEX-CB); mp 37 38 8C; [a]D24:
27.9 (c 1.0, CHCl3); 1H NMR (CDCl3): d 1.01 (6H, d,
ether and dried under vacuum to afford the product; yield:
1
73.8 mg (81%); H NMR (CD2Cl2): d 1.18 (6H, d, J 6.6 Hz),
1.22 (6H, d, J 6.6 Hz), 2.17 2.36 (8H, m), 2.47 2.55 (2H, m),
J
J
6.6 Hz), 1.76 (1H, dqq, J 5.5, 6.6, 6.6 Hz), 2.63 (1H, dd,
2.88 2.99 (2H, m), 3.11 3.17 (2H, m), 3.68 3.78 (2H, m),
5.03 5.10 (2H, m), 5.14 5.20 (2H, m), 7.11 7.15 (2H, m),
9.63, 13.2 Hz), 2.92 (1H, dd, J
2.7, 13.2 Hz), 3.64
(1H, m), 7.00 7.10 (2H, m), 7.18 7.28 (2H, m); EI-MS:
m/z 182 (M) .
7.32 7.41 (4H, m), 7.47 7.54 (4H, m), 7.58 7.63 (2H, m);
31
P NMR (CD2Cl2): d 73.4 (d, J 151.5 Hz).
188
Adv. Synth. Catal. 2003, 345, 185 189