Kuethe et al.
of 17 in 7.5 mL of CH2Cl2 was added 143 mg (1.42 mmol) of
NEt3 followed by 332 mg (1.20 mmol) of bistrifluoromethyl benzoyl
chloride (18). The resulting mixture was stirred at room temperature
for 30 min and quenched with 20 mL of water. The organic layer
was dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by silica gel chromatography to give 616
mg (100%) of 19 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
δ 0.02 (s, 6H), 0.89 (s, 9H), 1.94 (m, 3H), 2.25 (m, 1H), 2.37 (m,
1H), 3.19 (dd, 1H, J ) 10.0 and 7.2 Hz), 3.54 (dd, 1H, J ) 10.0
and 5.3 Hz), 3.64 (dd, 1H, J ) 10.0 and 4.2 Hz), 5.42 (m, 1H),
7.03 (m, 2H), 7.23 (m, 2H), 8.05 (s, 1H), 8.42 (s, 2H); 13C NMR
(CDCl3, 100 MHz) δ -5.3, 18.5, 25.9, 26.0, 31.5, 48.3, 52.8, 63.9,
84.4, 115.7 (d, J ) 20 Hz), 125.9 (q, J ) 190 Hz), 126.4, 129.3
(d, J 10 Hz), 129.8, 132.4, (q, J ) 30 Hz), 132.8, 137.5, 162.4 (d,
J ) 240 Hz), 163.8. Anal. Calcd for C27H31F7O3Si: C, 57.44; H,
5.53. Found: C, 57.75; H, 5.66.
Preparation of [(1R,2R,3S)-3-{1-(3,5-Bistrifluoromethylphen-
yl)-vinyloxy}-2-(4-fluorophenyl)-cyclopentylmethoxy]-tert-butyl-
dimethylsilane (20). To a solution of 730 mg (2.93 mmol) of
dichlorotitanocene in 25 mL of toluene at -5 °C was added 4.6
mL (7.33 mmol) of a 1.6 M solution of MeLi. The resulting mixture
was stirred at 0 °C for 1 h and was quenched with 10 mL of 6%
NH4Cl. The layers were separated, and the organic layer was dried
over MgSO4 and concentrated to a final volume of 7 mL. To the
solution of dimethyltitanocene was added 550 mg (0.974 mmol)
of 19 in 1 mL of toluene, and the mixture was heated to 80 °C for
4 h and cooled to room temperature. The reaction mixture was
quenched with 3 mL of 5% MeOH in water, stirred at room
temperature for 15 min, and diluted with 10 mL of water and 15
mL of EtOAc. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography to afford 486 mg (89%) of 20 as a
colorless oil: 1H NMR (CDCl3, 400 MHz) δ -0.01 (s, 6H), 0.88
(s, 9H), 2.01 (m, 2H), 2.19 (m, 3H), 3.12 (dd, 1H, J ) 10.0 and
5.8 Hz), 3.53 (dd, 1H, J ) 10.0 and 5.8 Hz), 3.63 (dd, 1H, J )
10.0 and 4.4 Hz), 4.19 (d, 1H, J ) 3.3 Hz), 4.54 (m, 1H), 4.74 (d,
1H, J ) 3.3 Hz), 7.03 (m, 2H), 7.22 (m, 2H), 7.80 (s, 1H), 7.97 (s,
2H); 13C NMR (CDCl3, 100 MHz) δ -5.3, 18.4, 26.0, 27.5, 31.7,
49.1, 53.9, 64.4, 86.9, 115.6 (d, J ) 20 Hz), 122.1, 122.3 (q, J )
190.0 Hz), 125.7, 129.3, 129.4, 131.7 (q, J ) 30 Hz), 138.9, 139.0,
156.3, 162.4 (d, J ) 240 Hz). Anal. Calcd for C28H33F7O2Si: C,
59.77; H, 5.91. Found: C, 60.10; H, 6.01.
Palladium-Catalyzed Hydrogenation of Vinyl Ether 20. To a
solution of 263 mg (0.467 mmol) of 20 in 8 mL of EtOAc was
added 25 mg of 5% Pd/C. The resulting mixture was stirred under
an atmosphere of 40 psi hydrogen for 5 h, filtered through a pad
of Celite, and concentrated under reduced pressure to afford 245
mg (93%) of a 1:4 mixture of 21:22 which could not be separated.
The above crude product was redissolved in 10 mL of THF,
and 0.51 mL of a 1 M solution of TBAF in THF was added. The
mixture was stirred at room temperature for 30 min and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography using a 25% solution of EtOAc in hexane. The
first product to elute from the column (158 mg, 75%) was identified
as [(1R,2R,3S)-3-{(S)-1-(3,5-bis-trifluoromethyl-phenyl)-ethoxy}-
2-(4-fluorophenyl)-cyclopentyl]-methanol (23) and was obtained as
a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.27 (d, 3H, J )
6.5 Hz), 1.69 (m, 2H), 1.85 (m, 3H), 2.10 (m, 1H), 2.81 (dd, 1H,
J ) 9.9 and 7.2 Hz), 3.48 (dd, 1H, J ) 10.7 and 6.7 Hz), 3.58 (dd,
1H, J ) 10.7 and 4.8 Hz), 3.78 (q, 1H, J ) 7.2 Hz), 4.32 (q, 1H,
J ) 6.5 Hz), 7.01 (m, 2H), 7.16 (m, 2H), 7.52 (s, 2H), 7.75 (s,
1H); 13C NMR (CDCl3, 100 MHz) δ 24.0, 25.9, 31.7, 48.3, 54.9,
65.1, 75.5, 86.1, 115.5 (d, J ) 21 Hz), 121.4, 123.1 (d, J ) 190
Hz), 126.3, 128.9 (d, J ) 10 Hz), 131.5 (q, J ) 30 Hz), 138.9,
147.0, 161.4 (d, J ) 240 Hz); 19F NMR (CDCl3, 75 MHz) δ -63.5,
-116.9. Anal. Calcd for C22H21F7O2: C, 58.67; H, 4.70. Found:
C, 58.54; H, 4.66.
ethoxy}-2-(4-fluorophenyl)-cyclopentyl]-methanol (24) and was
obtained as a colorless solid: mp 39-40 °C; H NMR (CDCl3,
1
400 MHz) δ 1.38 (d, 3H, J ) 6.5 Hz), 1.49 (br s, 1H), 1.77 (m,
2H), 1.95 (m, 1H), 2.10 (m, 2H), 2.76 (dd, 1H, J ) 10.1 and 8.1
Hz), 3.48 (m, 1H), 3.58 (m, 1H), 3.73 (q, 1H, J ) 7.0 Hz), 4.50
(q, 1H, J ) 6.5 Hz), 6.92 (m, 2H), 7.04 (m, 2H), 7.44 (s, 2H), 7.68
(s, 1H); 13C NMR (CDCl3, 100 MHz) δ 24.8, 25.8, 30.3, 47.3,
54.6, 65.3, 75.3, 85.6, 115.4 (d, J ) 20 Hz), 121.3, 122.3 (q, J )
190 Hz), 126.1, 128.8 (d, J ) 10 Hz), 131.4 (q, J ) 30 Hz), 137.7,
146.9, 162.3 (d, J ) 240 Hz); 19F NMR (CDCl3, 75 MHz) δ -63.4,
-117.2. Anal. Calcd for C22H21F7O2: C, 58.67; H, 4.70. Found:
C, 59.01; H, 4.69.
Reductive Etherification of 25. To a 0 °C solution of 180 mg
(0.756 mmol) of 12 in 6.5 mL of CH2Cl2 was added 115 mg (1.13
mmol) of NEt3 followed by 285 mg (1.28 mmol) of TMSOTf. The
reaction mixture containing 25 was cooled to -78 °C, and 840 mg
(3.78 mmol) of TMSOTf, 213 mg (0.832 mmol) of 3′,5′-bis-
(trifluoromethyl)acetophenone 26, and 105.5 mg (0.910 mmol) of
triethylsilane were added. The cooling bath was removed, and the
reaction mixture allowed to slowly warm to room temperature and
was stirred an additional 18 h. HPLC analysis of the crude reaction
mixture indicated 80% conversion to 14 and 15 and 65% combined
assay yield. The reaction mixture was quenched with water and
extracted with EtOAc. The organic layer was washed with brine,
dried over MgSO4, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography employing 15%
EtOAc in hexanes. The first product to elute from the column (56
mg, 16%) was identified as (1R,2R,3S)-3-[(S)-1-(3,5-bistrifluoro-
methylphenyl)-ethoxy]-2-(4-fluorophenyl)-cyclopentanecarboxyl-
1
ic acid methyl ester (15) and was obtained as a colorless oil:: H
NMR (CDCl3, 400 MHz) δ 1.38 (d, 3H, J ) 6.5 Hz), 1.92 (m,
1H), 2.12 (m, 3H), 2.79 (m, 1H), 3.36 (dd, 1H, J ) 10.7 and 8.2
Hz), 3.58 (s, 3H), 3.75 (m, 1H), 4.52 (q, 1H, J ) 6.5 Hz), 6.93 (m,
2H), 7.05 (m, 2H), 7.46 (s, 2H), 7.69 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ 24.6, 26.8, 30.5, 49.5, 51.7, 54.9, 75.6, 84.6, 115.3
(d, J ) 20 Hz), 121.3, 125.1 (q, J ) 190 Hz), 126.1, 128.9 (d, J )
10 Hz), 131.6 (q, J ) 30 Hz), 136.4, 146.8, 162.4 (d, J ) 240 Hz),
174.9; 19F NMR (CDCl3, 75 MHz) δ -62.9, -116.7. Anal. Calcd
for C23H21F7O3: C, 57.74; H, 4.42. Found: C, 57.54; H, 4.29.
The second product to elute from the column (178 mg, 49%)
was identified as (1R,2R,3S)-3-[(R)-1-(3,5-bistrifluoromethylphen-
yl)-ethoxy]-2-(4-fluorophenyl)-cyclopentanecarboxylic acid methyl
ester (14) and was obtained as a colorless oil: 1H NMR (CDCl3,
400 MHz) δ 1.29 (d, 3H, J ) 6.5 Hz), 1.82-2.15 (m, 4H), 2.80
(q, 1H, J ) 8.9 Hz), 3.43 (dd, 1H, J ) 10.1 and 7.3 Hz), 3.61 (s,
3H), 3.80 (q, 1H, J ) 6.9 Hz), 4.36 (q, 1H, J ) 4.6 Hz), 7.01 (m,
2H), 7.18 (m, 2H), 7.54 (s, 2H), 7.75 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ 24.0, 27.1, 32.0, 50.5, 51.8, 55.2, 75.6, 85.2, 115.6
(d, J ) 20 Hz), 121.4, 123.9 (q, J ) 190 Hz), 126.3, 128.9 (d, J )
10 Hz), 131.7 (q, J ) 30 Hz), 137.8, 146.9, 162.5 (d, J ) 240 Hz),
174.9; 19F NMR (CDCl3, 75 MHz) δ -63.5, -116.5. Anal. Calcd
for C23H21F7O3: C, 57.74; H, 4.42. Found: C, 57.67; H, 4.39.
Preparation of (1S)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl-
2,2,2-trichloroethanimidoate (30). To a solution of 8.00 kg (31.0
mol) of 5 in 37 L of a 4:1 mixture of cyclohexane/CH2Cl2 was
added dropwise 4.92 kg (34.1 mol) of trichloroacetoritrile followed
by 92 mL of DBU. The resulting mixture was stirred at room
temperature for 5.5 h. The resulting reaction mixture was then
washed with 27 L of water, 27 L of brine, and then concentrated
under reduced pressure to a final volume of 15 L and a KF < 200
and was used without further purification. HPLC assay of the crude
solution was 12.00 kg (96%) of 30. An analytical sample was
obtained by silica gel chromatography to give 30 as a colorless
oil: 1H NMR (CDCl3, 400 MHz) δ 1.72 (d, 3H, J ) 6.4 Hz), 6.11
(q, 1H, J ) 6.4 Hz), 7.85 (s, 1H), 7.91 (s, 2H), 8.43 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 22.0, 75.5, 91.2, 121.9, 123.3 (q, J )
272 Hz), 126.1, 132.0 (q, J ) 33 Hz), 144.1, 161.2; 19F NMR
(CDCl3, 75 MHz) δ -63.4. Anal. Calcd for C12H8Cl3F6NO: C,
35.80; H, 2.00; N, 3.48. Found: C, 36.19; H, 1.97; N, 3.44.
The second product to elute from the column (32 mg, 15%) was
identified as [(1R,2R,3S)-3-{(R)-1-(3,5-bistrifluoromethylphenyl)-
7388 J. Org. Chem., Vol. 71, No. 19, 2006