9202
Z. Wang et al. / Tetrahedron 67 (2011) 9199e9203
Calcd for C21H19NO2S: C, 72.18; H, 5.48; N, 4.01; S, 9.18. Found: C,
71.06; H, 5.52; N, 3.95; S, 9.22.
extracted by EA (3ꢄ50 mL), combined, dried over Na2SO4, filtrated,
condensed in vacuum, and purified silica gel with hexane/ethyl
acetate (2:1 to 1:1) to afford aziridinol 12 as a white solid (1.71 g,
4.3. N-(4-(Methylthio)benzylidene)diphenylmethanamine
(16)
95% yield). Mp 193e195 ꢁC. ½a D25
ꢃ
þ166.8 (c 1.06, CHCl3). 1H NMR
(400 MHz, CDCl3):
d
¼2.34 (1H, q, CHCH2OH), 3.04e3.05 (4H, m,
SO2CH3 and ArCH), 3.38 (2H, d, J¼6.4 Hz, CH2OH), 3.92 (1H, s,
Compound 16 was prepared in the same procedure as 4, white
powder, 91% yield. Mp 99e100 ꢁC. 1H NMR (400 MHz, CDCl3):
Ph2CH), 7.19e7.51 (10H, m, Ar), 7.58 (2H, d, J¼8.4 Hz, Ar), 7.85 (2H, d,
J¼8.4 Hz, Ar) ppm. 13C NMR (100 MHz, CDCl3):
¼44.54, 45.94,
d
d
¼2.54 (3H, s, SCH3), 5.64 (1H, s, Ph2CH), 7.28e7.46 (12H, m, Ar),
47.96, 60.34, 78.29, 127.20, 127.28, 127.34, 127.40, 127.70, 128.52,
128.57, 128.83, 139.16, 142.38, 143.05, 143.30 ppm. ESI-MS: (m/z)
(%)¼394 [MþH]þ. FTIR (KBr): nmax¼3478, 3055, 2923, 1597, 1397,
1307, 1293, 1146, 1028, 704, 569 cmꢀ1. Anal. Calcd for C23H23NO3S:
C, 70.20; H, 5.89; N, 3.56; S, 8.15. Found: C, 70.08; H, 5.92; N, 3.49; S,
8.08.
7.80 (2H, d, J¼8.4 Hz, Ar), 8.41 (1H, s, N]CH) ppm. 13C NMR
(100 MHz, CDCl3):
d
¼15.34, 77.92, 125.84, 127.03, 127.75, 128.50,
128.84, 133.16, 142.25, 144.02, 160.18 ppm. ESI-MS: (m/z)¼318
[MþH]þ. FTIR (KBr): nmax¼: 3078, 3021, 2915, 2856, 1637, 1590,
1491, 1024, 809, 755, 699 cmꢀ1. Anal. Calcd for C21H19NS: C, 79.45;
H, 6.3; N, 4.41; S, 10.10. Found: C, 79.32 H, 6.06; N, 4.38; S, 10.06.
4.6. (2S,3S)-1-Benzhydryl-2-(fluoromethyl)-3-(4-(methylsulf-
onyl) phenyl)aziridine (13)
4.4. (2S,3S)-Ethyl 1-benzhydryl-3-(4-(methylsulfonyl)phenyl)
aziridine-2-carboxylate (11)
Compound 12 (1.50 g, 3.82 mmol) and NEt3 (1.06 mL,
7.64 mmol) were dissolved in anhydrous CH2Cl2 (10 mL) under
Ar. Then cooled to ꢀ40 ꢁC, DAST (0.94 mL, 7.64 mmol) was added
dropwise via syringe. After the addition, the reaction mixture
was warmed to room temperature and stirred for 8 h. The re-
action was quenched by adding 5% NaHCO3 (40 mL) and
extracted with ethyl acetate (3ꢄ100 mL). The combined organic
phases were dried over sodium sulfate. The solvent was removed
and the residue was purified by flash column chromatography on
silica gel with hexane/ethyl acetate (2:1 to 1:1) to afford fluo-
roaziridine 13 as white solid (1.40 g, 93% yield). Mp 165e168 ꢁC.
4.4.1. 1 mmol scale. Phenol (56.4 mg, 0.6 mmol), boric acid
(12.4 mg, 0.2 mmol), and molecular sieve (20 mg) were added to
a flame-dried flask cooled under argon and then added 2 mL an-
hydrous toluene. The mixture was stirred and heated to reflux
overnight. Then cooled to room temperature and (R)-VANOL
(21.9 mg, 0.05 mmol) was added. The mixture was heated to 80 ꢁC
for 1 h. After slow evaporation of the solvent, a vacuum (0.5 mmHg)
was applied for 30 min with the temperature maintained at 80 ꢁC.
The resulting catalyst was dissolved in anhydrous toluene (1 mL)
and transferred via syringe to a suspension of imine 4 (349 mg,
1 mmol) in anhydrous toluene (1 mL) under argon. The reaction
mixture was stirred for 10 min at room temperature, and then
½
a 2D5
ꢃ
þ101.7 (c 1.05, CHCl3). 1H NMR (400 MHz, CDCl3):
¼2.44
d
(1H, q, CHCH2F), 3.03 (3H, s, SO2CH3), 3.10 (1H, d, ArCH), 3.96
(1H, s, Ph2CH), 3.97e4.41 (2H, m, CH2F), 7.18e7.50 (10H, m, Ar),
7.56 (2H, d, J¼8.4 Hz, Ar), 7.86 (2H, d, J¼8.4Hz, Ar) ppm. 13C NMR
cooled to ꢀ10 ꢁC, treated with ethyl diazoacetate (110
mL,1.1 mmol).
Some gas was emitted. The reaction was stirred at this temperature
for 18 h, and then warmed up at room temperature for 1 h. After
removal of the toluene, the 1H NMR of the crude product revealed
aziridine 11 with a cis/trans ratio >50:1 and less than 5% of acyclic
side products. Purification by column chromatography on silica gel
with hexane/ethyl acetate (2:1 to 1:1) gave aziridine 11 (405 mg,
93% yield, 85% ee). Recrystallization from hexane: CH2Cl2 gave 11 as
(100 MHz, CDCl3):
d
¼44.47, 44.84 (d, J¼28.4 Hz, CHCH2F), 45.22
(d, J¼3.8 Hz, ArCHCHCH2F), 77.89, 81.19 (d, J¼166 Hz, CH2F),
127.14, 127.29, 127.46, 128.54, 128.58, 139.30, 142.38, 142.55 ppm.
ESI-MS: (m/z) (%)¼396 [MþH]þ. FTIR (KBr): nmax¼3024, 2925,
1600, 1453, 1307, 1146, 993, 706, 570, 535 cmꢀ1. Anal. Calcd for
C23H22FNO2S: C, 69.85; H, 5.61; N, 3.54; S, 8.11. Found: C, 69.77;
H, 5.57; N, 3.50; S, 8.06.
white needles (292 mg, 67% yield, 99.5% ee). Mp 122e123 ꢁC. ½a D25
ꢃ
ꢀ20.9 (c 1.05, CHCl3). 1H NMR (400 MHz, CDCl3):
¼1.00 (3H, t,
d
J¼7.0 Hz, CH2CH3), 2.70 (1H, d, J¼6.4 Hz, CHCOOEt), 3.00 (3H, s,
SO2CH3), 3.24 (1H, d, J¼6.8 Hz, ArCH), 3.95 (2H, q, J¼7.0 Hz,
CH2CH3), 3.98 (1H, s, Ph2CH), 7.19e7.58 (10H, m, Ar), 7.62 (2H, d,
J¼8.4 Hz, Ar), 7.82 (2H, d, J¼8.4 Hz, Ar) ppm. 13C NMR (100 MHz,
4.7. (1R,2S)-2-(Benzhydrylamino)-3-fluoro-1-(4-(methylsulfo-
nyl) phenyl)propan-1-ol (14)
CDCl3):
d
¼14.03, 44.50, 46.86, 47.25, 60.94, 77.63, 126.95, 127.11,
Compound 13 (2.00 g, 5.06 mmol) and PTSA (0.96 g,
5.06 mmol) were dissolved in MeCN (10 mL) and H2O (10 mL). The
mixture was stirred at 40 ꢁC for 24 h, then cooled to room tem-
perature and evaporated the solvent. The residue was dissolved in
100 mL CH2Cl2 and washed by 1% aq NaHCO3 (100 mL) and brine
(50 mL). The organic solvent was dried over Na2SO4, condensed in
vacuum and purified silica gel with hexane/ethyl acetate (2:1 to
1:1) to afford protected fluoroalkamine 14 as a white solid (1.86 g,
127.46, 127.69, 128.64, 128.68, 128.92, 139.51, 141.52, 141.93, 142.16,
167.07 ppm. ESI-MS: (m/z) (%)¼436 [MþH]þ. FTIR (KBr):
nmax¼3026, 2918, 1736, 1600, 1453, 1314, 1299, 1210, 1149, 747,
560 cmꢀ1. Anal. Calcd for C25H25NO4S: C, 68.94; H, 5.79; N, 3.22; S,
7.36. Found: C, 68.80; H, 5.73; N, 3.19; S, 7.31.
4.4.2. 10 mmol scale. 10 mmol scale procedure for 4 was same as
1 mmol scale one, except for the workup. The crude product was
recrystallized from hexane: CH2Cl2 for two times to furnish 11 as
white needles (2.82 g, 65% yield, 100% ee).
89% yield). Mp 142e144 ꢁC. ½a D25
ꢃ
þ70.6 (c 1.05, CHCl3). 1H NMR
(400 MHz, CDCl3):
d
¼2.70e2.83 (1H, m, NCHCH2F), 3.04 (3H, s,
SO2CH3), 4.11e4.26 (1H, m, CHaHbF), 4.48e4.68 (1H, m, CHaHbF),
4.74 (1H, d, J¼7.6 Hz, ArCHOH), 4.92 (1H, s, Ph2CH), 7.22e7.36
(10H, m, Ar), 7.51 (2H, d, J¼8.4 Hz, Ar), 7.89 (2H, d, J¼8.4 Hz, Ar).
4.5. ((2S,3S)-1-Benzhydryl-3-(4-(methylsulfonyl)phenyl)aziri-
din-2-yl)methanol (12)
13C NMR (100 MHz, CDCl3):
d
¼44.54, 61.06 (d, J¼18.2 Hz, CHCH2F),
64.53, 71.72 (d, J¼4.3 Hz, ArCHCHCH2F), 80.21 (d, J¼168 Hz, CH2F),
127.03, 127.45, 127.51, 127.66, 127.69, 127.85, 128.84, 139.99, 141.96,
143.30, 147.95. ESI-MS: (m/z) (%)¼414 [MþH]þ. FTIR (KBr):
nmax¼3479, 3372, 3023, 2923, 2850, 1597, 1493, 1453, 1290, 1143,
KBH4 (745 mg, 13.8 mmol) and LiCl (584 mg, 13.8 mmol) were
stirred and refluxed in anhydrous THF (20 mL) under N2 for 2 h.
Then cooled to room temperature, and the THF solution of aziridine
11 (2.00 g, 4.6 mmol, >99% ee) was added dropwise. After the
addition, the mixture was heated at 50 ꢁC overnight. Then cooled to
room temperature, 30 mL H2O was added and stirred for 1 h. Then
1085, 957, 772, 752, 706, 698, 563 cmꢀ1
. Anal. Calcd for
C23H24FNO3S: C, 66.81; H, 5.85; N, 3.39; S, 7.75. Found: C, 66.68; H,
5.89; N, 3.41; S, 7.71.