The Journal of Organic Chemistry
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dried over Na2SO4. The crude mixture (LC shows a single product) was
purified by SiO2 column EtOAc/hexanes (0À40%) to give the desired
product 19 as a colorless liquid (930 mg, 93%). 1H NMR (400 MHz,
chloroform-d) δ ppm 1.86 (br s, 1 H) 2.50 (s, 3 H) 3.70 (br s, 1 H)
3.80À3.93 (m, 1 H) 4.29 (dd, J = 11.87, 6.06 Hz, 1 H) 7.19À7.39
(m, 3 H) 7.49 (s, 1 H).
(S)-2-(3-(Methylthio)phenyl)-2-(trifluoromethyl)oxirane (20).
To a solution of 19 (252 mg, 1 mmol) in THF (5 mL) was added NaH (60%
in mineral oil, 100 mg, 2.5 mmol) at 0 °C. The resultant mixture was stirred
for 5 min. TsCl was added in one portion (be careful of gas formation!). After
3 h, 1 N NaOH (5 mL) was added, and the mixture was stirred for 5 min and
then extracted with DCM (3 Â 10 mL). The organic layer was dried over
Na2SO4. The crude product (one product by LC) was purified by SiO2
column eluted with EtOAc/hexanes (0À10%) to give the desired product 4
as a colorless liquid (229 mg, 98%). 1H NMR (400 MHz, chloroform-d) δ
ppm 2.50 (s, 3 H) 2.92 (dq, J = 5.34, 1.59 Hz, 1 H) 3.40 (d, J = 5.31 Hz, 1 H)
7.24À7.36 (m, 3 H) 7.39 (s, 1 H). HRMS: calcd for C10H9F3OS + NH4+,
252.0664; found (ESI-FTMS, [M + NH4]+), 252.0664.
concentrated by atmospheric distillation to a volume of 0.75 L. To the
concentrate was added EtOH (1.3 L), the solution was concentrated by
atmospheric distillation to a volume of 1.3 L, to the concentrate was
added EtOH (1.3 L), and the solution was concentrated once again by
atmospheric distillation to a volume of 1.3 L. The concentrated solution
was cooled to 20 °C, and the resulting suspension was stirred at 20 °C for
1 h, cooled to 0 °C, stirred at 0 °C for 1 h, and filtered. The filter cake was
rinsed cold EtOH (2 Â 0.25 L) and dried in a vacuum oven at 40 °C for
12 h to afford boronate 23 (243 g, 89%, HPLC purity 95.3%) as a white
solid. Mp: 158À160 °C. 1H NMR (500 MHz, chloroform-d) δ
ppm 1.23 (d, J = 6.71 Hz, 3 H) 1.38 (s, 12 H) 2.69À2.82 (m, 2 H)
2.86À2.93 (m, 1 H) 2.99À3.07 (m, 1 H) 3.33À3.42 (m, 1 H)
3.72À3.82 (m, 1 H) 4.21À4.31 (m, 1 H) 7.18À7.26 (m, 2 H) 7.29
(s, 1 H) 7.31À7.35 (m, 2 H) 7.54 (t, J = 7.63 Hz, 1 H) 7.90À7.96 (m, 1
H) 8.02 (d, J = 7.32 Hz, 3 H) 8.30 (s, 3 H); 13C NMR (126 MHz,
chloroform-d) δ ppm 14.6 (s, 1 C) 24.9 (d, 4 C) 40.7 (s, 1 C) 49.8 (s, 1
C) 54.1 (s, 1 C) 58.1 (s, 1 C) 84.4 (s, 1 C) 114.5 (s, 1 C) 119.6 (s, 1 C)
122.9 (s, 1 C) 126.4 (s, 1 C) 128.5 (s, 1 C) 129.4 (s, 1 C) 129.6 (s, 1 C)
130.6 (br s, 1 C) 133.2 (s, 1 C) 138.7 (s, 1 C) 140.3 (s, 1 C) 148.0 (s, 1
C) 159.5 (s, 1 C). HRMS: calcd for C24H29BF4N2O4S + H+, 529.1957;
found (ESI-FTMS, [M + H]+), 529.1965.
(R)-4-(4-Fluoro-2-(trifluoromethyl)phenyl)-2-methyl-1-(3-
(3,3,3-trifluoroprop-1-en-2-yl)phenylsulfonyl)piperazine (24).
Method 1: A flask containing 5 (3.3 g, 6.25 mmol), Na2CO3, (2.0 g,
18.8 mmol), and Pd(PPh3)4 (256 mg, 0.31 mmol) was sealed and purged
with nitrogen. Aqueous THF (40 mL, 3:1 vol) was then added, followed by
the careful addition of the vinyl bromide, (3.3 g, 18.8 mmol) which was
cooled to 0 °C before dispensation, as it is an extremely volatile liquid, and
the reaction was heated to 60 °C under thermal conditions for 16 h, after
which it was judged complete by LCÀMS. The reaction was cooled to rt,
diluted with EtOAc (300 mL), and washed with saturated aq NaHCO3
(3 Â 300 mL). The organic layer was dried over Na2SO4 and concentrated
in vacuo. The crude oil was purified via normal phase SiO2 chromatography
(2À20% EtOAc/hexanes gradient), affording the desired olefin 24 (2.3 g,
75%, HPLC purity >95% purity) as a colorless syrup. Method 2: A
suspension of 23 (350 g, 0.66 mol), vinyl bromide 17 (170 g, 0.99 mol),
Pd(OAc)2 (1.5 g, 0.0066 mol), PPh3 (7.0 g, 0.027 mol), and Na2CO3 (84 g,
0.79 mol) in THF/water (v/v 1/1, 2.8 L) was heated in a sealed pressure
reactor to 60 °C for 24 h. The pressure reached 16 psi. The reaction
was cooled to 20 °C, and filtered through a 0.2 μm filter cartridge, and
the reactor and cartridge were rinsed with THF/water (v/v 1/1, 0.60 L)).
The filtrate was washed with 20% NaCl solution (3 Â 0.75 L) and
concentrated by vacuum distillation to a volume of 0.50 L. To the
concentrate was added i-PrOH (3.0 L), and the solution was concentrated
by vacuum distillation to a volume of 1.4 L. The concentrate was warmed
to 35 °C, stirred for 30 min, and filtered through Celite, and the filter
cake was rinsed with i-PrOH (0.30 L). The filtrate was cooled to 5 °C,
stirred for 1 h, and treated dropwise over 1 h with water (1.7 L). The
resulting suspension was stirred at 5 °C for 1 h and filtered, and the filter
cake was rinsed with cold i-PrOH/water (v/v 1/1, 2 Â 0.60 L) and
dried in a vacuum oven at 40 °C for 12 h to afford of 24 (299 g, 91%;
HPLC purity 99.4%) as a colorless syrup. 1H NMR (500 MHz, chloro-
form-d) δ ppm 1.23 (d, J = 7.02 Hz, 3 H) 2.68À2.80 (m, 2 H) 2.89
(d, J = 11.29 Hz, 1 H) 2.99 (dd, J = 11.14, 3.20 Hz, 1 H) 3.38 (td,
J = 12.21, 3.05 Hz, 1 H) 3.76 (d, J = 12.82 Hz, 1 H) 4.14À4.34 (m, 1
H) 5.89 (d, J = 1.53 Hz, 1 H) 6.09 (s, 1 H) 7.16À7.23 (m, 1 H) 7.23À7.32
(m, 2 H) 7.53À7.64 (m, 1 H) 7.68 (d, J = 7.93 Hz, 1 H) 7.89 (d, J =
7.63 Hz, 1 H) 7.96 (s, 1 H). 13C NMR (126 MHz, 1H/19F decoupling,
chloroform-d) δ ppm 14.6 (s, 1 C) 40.8 (s, 1 C) 50.0 (s, 1 C) 54.0 (s, 1 C)
57.9 (s, 1 C) 114.4 (s, 1 C) 119.7 (s, 1 C) 122.3 (s, 1 C) 122.9 (s, 1 C) 123.0
(s, 1 C) 125.9 (s, 1 C) 126.4 (s, 1 C) 127.4 (s, 1 C) 129.3 (s, 1 C) 129.6
(s, 1 C) 131.4 (s, 1 C) 134.8 (s, 1 C) 137.6 (s, 1 C) 141.6 (s, 1 C) 147.8
(s, 1 C) 159.5 (s, 1 C). HRMS: calcd for C21H19F7N2O2S + H+, 497.1135;
found (ESI-FTMS, [M + H]+), 497.1143.
(R)-1,1,1-Trifluoro-2-(3-(methylthio)phenyl)propan-2-ol
(21). To a solution of 20 (69 mg, 0.3 mmol) in ether (2 mL) was added
LAH (1.0 M in Et2O, 0.3 mL, 0.3 mmol) at 0 °C. The resultant mixture
was stirred for 30 min and then diluted with Et2O (10 mL), and aq Na, K
tartrate solution (10 mL) was added. After stirring for 2 h at rt, the organic
layer was separated, and the aq layer was back extracted with Et2O (2 Â
10 mL). The combined organic layer was dried over MgSO4. The crude
product (one product by LC) was purified by SiO2 gel column eluted with
EtOAc/hexanes (0À35%) to give the desired product 5 as a colorless
1
liquid (59 mg, 85%). H NMR (400 MHz, chloroform-d) δ ppm 2.45
(s, 1 H) 2.50 (s, 3 H) 7.22À7.27 (m, 1 H) 7.30À7.35 (m, 2 H) 7.50 (d,
J = 0.51 Hz, 1 H).
(R)-1,1,1-Trifluoro-2-(3-mercaptophenyl)propan-2-ol (22).
To a solution of 5 in liquid NH3 at À78 °C was added a small piece of
sodiummetal. The dark bluesolution wasstirredfor∼3 min. SolidNH4Cl
was added, followed by addition of MeOH (2 mL), then Et2O (10 mL),
and then aq NH4Cl (∼5 mL). Once the temperature of the crude mixture
was brought to rt, the organic layer was separated, and the aq layer was
back extracted with DCM (2 Â 10 mL). The organic layer was dried with
MgSO4. The crude product (one product by LC) was purified by SiO2 gel
column eluted with EtOAc/hexanes (0À50%) to give the desired product
22 as a colorless oil/liquid (43 mg, 83%). 1H NMR (400 MHz, chloro-
form-d) δ ppm 1.76 (d, J = 1.01 Hz, 3 H) 2.39 (s, 1 H) 3.52 (s, 1 H)
7.25À7.32 (m, 2 H) 7.32À7.40 (m, 1 H) 7.52 (s, 1 H).
(R)-4-(4-Fluoro-2-(trifluoromethyl)phenyl)-2-methyl-1-(3-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylsulfonyl)-
piperazine (23). Method 1: A flask containing 7 (3.0 g, 6.25 mmol),
pinnacoldiboron (1.63 g, 6.88 mmol), KOAc (1.84 g, 18.72 mmol), and
PdCl2(dppf)2 (256 mg, 0.31 mmol) was sealed and purged with
nitrogen. Anhydrous DMSO (15 mL) was then added, and the reaction
was heated to 100 °C under thermal conditions for 16 h, after which it
was judged complete by LCÀMS. The reaction was cooled to rt, diluted
with EtOAc (300 mL), and washed with saturated aq NaHCO3 (3 Â
300 mL). The organic layer was dried over Na2SO4 and concentrated in
vacuo. The crude oil was purified via normal phase SiO2 chromatogra-
phy (2À30% EtOAc/hexanes gradient), affording the desired boronic
ester 23 (3.3 g, quantitative yield) in >95% purity (white fluffy solid).
Method 2: A suspension of bis(pinacolato)diboron(150 g, 0.57 mol),
KOAc (160 g, 1.6 mol), and PdCl2(dppf) CH2Cl2 (4.4 g, 0.0052 mol)
3
in DMF (0.70 L) was heated to 80 °C and treated dropwise over 2 h with
a solution of 7 (250 g, 0.52 mol) in DMF0 (50 L). The reaction was
stirred at 80 °C for 18 h, cooled to 20 °C, and treated with Darco KB (75 g),
EtOAc (1.4 L), and water (1.3 L). The biphasic mixture was stirred at
20 °C for 2 h and filtered through Celite, and the cake was rinsed with
EtOAc (1.0 L). The lower aqueous layer was discarded, and the upper
organic layer was washed with 5% NaCl solution (2 Â 1.3 L), and
7053
dx.doi.org/10.1021/jo200958a |J. Org. Chem. 2011, 76, 7048–7055