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C. Yuan et al. / Journal of Fluorine Chemistry 127 (2006) 44–47
evaporation of solvent, crystalline pale yellow product was
obtained. When the mother liquid was treated with petroleum
ether, additional crystalline product was obtained. 18.5 g or
70% yield. As demonstrated by spectroscopic data, the product
is a mixture of 1 and 2 in 1:7 ratio. 1H NMR (300 MHz, CDCl3):
d: 1.34–1.39 (6H, m, P(OCH2CH3)2), 2.29–2.36 (2H, d,
C(OH)2CH2P), 3.35–3.42 (2H, d, COCH2P), 4.15–4.25 (4H, m,
P(OCH2CH3)2), 5.8 (2H, b, C(OH)2CH2P). 19F NMR
(282 MHz, CDCl3) d: 4.6 (1) and 10.2 (2).
For the preparation of 3, a mixture of 1 and 2 (0.744 g,
2.8 mmol) was added to 10 mL aqueous ethanol (1:1). After
the cooling down by ice, added graduately NaBH4 (0.12 g,
3.2 mmol) and the mixture was stirring overnight. The reaction
mixture was filtered and then diluted with brine (30 mL),
extracted with ether (50 mL ꢁ 2). The combined ether was
evaporated. Flash column chromatography on silica gel
using petroleum ether:ethyl acetate (2:1) as eluent afforded
0.68 g 3 as colorless oily liquid, yield 97.5%. 1H NMR
(300 MHz, CDCl3): d: 1.26–1.38 (6H, m, P(OCH2CH3)2),
2.06–2.19 (2H, m, CH(OH)CH2P), 4.09–4.21 (4H, m,
P(OCH2CH3)2), 4.36–4.42 (1H, m, CH(OH)CH2P). 19F
NMR (282 MHz, CDCl3) d: 4.0 (s). 31P NMR (120 MHz,
CDCl3) d: 30.1 (s). Anal Calcd. for C7H14O4F3P: C, 33.01; H,
5.60. Found C, 33.46; H, 5.63.
3.4. Diethyl 1,2-di(b-chloroacetyloxy)-3,3,3-
trifluoropropanephosphonate (6)
A mixture of 5 (5 mmol), chloroacetic acid (0.95 g,
10 mmol) DCC (2.45 g, 12 mmol) in 10 mL CH2Cl2 was
cooled down to 0 8C then DMAP (50 mg) was introduced and
stirring was continued for 2 h. The reaction mixture was stirring
overnight at room temperature. Remove the precipate formed
by filtration and washed with CH2Cl2 (5 mL). The organic
solution was dried over Na2SO4 and evaporated under reduced
pressure to give a crude product, which was subject to flash
chromatography on silica gel using petroleum ether:ethyl
acetate (3:1) as eluent. 6 was obtained as colorless liquid
1.93 g, yield 90%. FT-IR (KBr, cmꢀ1) 2960, 1755, 1413,
1193, 1146, 960, 794, 544 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d: 1.32–1.39 (6H, q, P(OCH2CH3)2), 4.10–4.31 (8H, m,
2 ꢁ CHOCOCH2Cl + P(OCH2CH3)2), 5.77–5.92 (2H, m,
CF3CHCH). EIMS m/z (rel, intensity): 419 (M+ + 1)(2.58),
265 (27.40), 155 (100, base), 109 (65.15). Anal Calcd. for
C15H15N3O2P: C, 31.52; H, 3.58. Found C, 31.61; H, 4.14.
3.5. Enzymatic resolution of 6 using CALB
To 210 mg (0.5 mmol) of 6, was added a benzene (2 mL)
solution of CALB (100 mg) followed by 0.4 mL n-BuOH. The
mixture was stirred constantly at 30 8C for 40 h. The residue
CALB was removed by filtration and washed with acetone
(5 mL). The combined organic solution was evaporated and
the residue subject to flash chromatography on silica gel
using petroleum ether:EtOAc (2:1) as eluent. Chiral diethyl
1-chloroacetyloxy-2-hydroxy-3,3,3-trifluoropropane phospho-
nate 7 was obtained as colorless liquid, 65 mg (38% yield),
3.2. Diethyl 3,3,3-trifluoropropenylphosphonates (4)
To an ice chilled mixture of 3 (7.5 g, 0.03 mol) and
triethylamine (8.1 g, 0.03 mol) in dichloromethane (20 mL)
was added dropwisely mesyl chloride (4.6 g, 0.04 mol). After
the reaction mixture was warmed up to room temperature
stirring overnight. Flash column chromatography on silica gel
using petroleum ether:ethyl acetate (3:1) as eluent gave 4 as
colorless liquid 4.8 g or 69% yield. 1H NMR (300 MHz,
CDCl3): d: 1.26–1.38 (6H, m, P(OCH2CH3)2), 4.11–4.21 (4H,
m, P(OCH2CH3)2), 6.42–6.71 (2H, m, CH CHP). 19F NMR
(282 MHz, CDCl3) d: ꢀ9.7 (s). 31P NMR (120 MHz, CDCl3) d:
12.5 (s).
20
½aꢂD ¼ ꢀ11:6 (c = 2.5, CHCl3).
Chiral diethyl 1,2-bis(chloroacetyloxy)-3,3,3-trifluoropro-
pane phosphonate (8) was resulted as colorless liquid, 82 mg
20
(39% yield), ½aꢂD ¼ ꢀ19:1 (c = 0.5, CHCl3).
3.6. Enzymatic resolution of 6 using IM
3.3. Diethyl 1,2-dihydroxy-3,3,3-
trifluoropropanephosphonate (5)
Analogously, 6 was enzymatic resolution by IM in the same
manner. 7 was obtained as colorless liquid, 60 mg (35% yield),
20
½aꢂD ¼ ꢀ11:9 (c = 1.5, CHCl3).
To an ice-cold suspension of 4 (1.57 g, 6.78 mmol) in water
(20 mL) was added dropwisely under stirring an aqueous
(30 mL) solution of KMnO4 (1.12 g, 7.1 mmol). After that the
mixture was stirred additionally hours at room temperature.
The reaction mixture was extracted with ethyl acetate
(4 ꢁ 50 mL), washed with brine and dried over Na2SO4. Flash
column chromatography on silica gel using petroleum
ether:ethyl acetate (1:1) as eluent gave product 5 as colorless
Chiral diethyl 1,2-bis(chloroacetyloxy)-3,3,3-trifluoropro-
pane phosphonate (8) was collected as colorless liquid, 78 mg
20
(37% yield), ½aꢂD ¼ ꢀ22:1 (c = 1.3, CHCl3).
3.7. Diethyl (R,R)-1,2-dihydroxy-3,3,3-trifluoropropane
phosphonate (9)
7 (50 mg, 0.2 mmol) was dissolvent in methanol (10 mL)
followed by addition of aqueous ammonia solution (0.5 mL).
The mixture was stirred at room temperature. The hydrolysis
was completed in 3 h as monitored by TLC. The reaction
mixture was evaporated under diminished pressure to remove
solvent. The resultant residue was extracted with EtOAc
(2 ꢁ 20 mL) and then the extract was washed with brine and
dried over Na2SO4. The mixture was then subjected to flash
1
solid, mp 39 8C. Yield 0.79 g or 48% of theoretical. H NMR
(300 MHz, CDCl3): d: 1.34–1.39 (6H, t, P(OCH2CH3)2), 4.19–
4.29 (6H, m, CF3CHOHCHOH + CH(OH)CH2P), 4.89 (1H, b,
CHOHP), 5.56 (1H, b, CH3CHOH). 19F NMR (282 MHz,
CDCl3) d: ꢀ0.5 (d, J = 12 Hz, 3F). 31P NMR (120 MHz,
CDCl3) d: 20.6 (s). Anal Calcd. for C7H14O5F3P: C, 31.59; H,
5.30. Found C, 31.51; H, 5.52.