S.S. Ribeiro et al. / Journal of Fluorine Chemistry 154 (2013) 53–59
57
Table 5
Optical rotations of the organofluorine alcohols 2a–e and acetates 3a–e obtained by kinetic resolution with lipase B from Candida antarctica.
Compounds
½
a DT
ꢃ
experimental
½
a DT
literature
ꢃ
(R)-2,2,2-trifluoro-1-phenylethanol (2a)
½
½
½
½
a 2D6
ꢃ
ꢁ1.77 (c 0.12, CHCl3)
ꢁ13.26 (c 0.021, CHCl3)
ꢁ16.89 (c 0.012, EtOH)
ꢁ1.82 (c 1.654, CHCl3)
½
½
½
½
½
a 2D5
ꢃ
ꢁ20.41 (c 0.48, CHCl3) [21]
ꢁ25.1 (c 2.49, EtOH) [22]
ꢁ27.5 (c 1.06, EtOH) [23]
ꢁ29.9 (c 0.005, CHCl3) [24]
ꢁ23.0 (MeOH) [25]
(R)-1-(3-bromophenyl)-2,2,2-trifluoroethanol (2b)
(R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (2c)
(S)-1-(2,4,5-trifluorophenyl)ethanol (2d)
a 2D5
a 3D2
a 2D6
ꢃ
a 2D5
a 2D0
a 2D0
a 2D5
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
(S)-1-(2-trifluoromethyl)phenyl)ethanol (2e)
(S)-2,2,2-trifluoro-1phenylethyl acetate (3a)
(S)-1-(3-bromophenyl)-2,2,2-trifluoroethyl acetate (3b)
(S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl acetate (3c)
(R)-1-(2,4,5-trifluorophenyl)ethyl acetate (3d)
(R)-1-(2-(trifluoromethyl)phenyl)ethyl acetate (3e)
Nd
ꢃ
½
½
½
½
a 2D6
a 2D5
a 3D2
a 2D6
ꢃ
+3.9 (c 0.023, CHCl3)
+178.1 (c 0.015, CHCl3)
+78.41 (c 0.011, CHCl3)
+1202 (c 0.94, CHCl3)
–
–
–
–
ꢃ
ꢃ
ꢃ
Nd
½
a 2D5
ꢃ
+48.5 (CHCl3) [25]
Nd: not determined.
larger fluorinated aryl group and the other is the smaller alkyl
group. This composition determined the stereochemical outcome
of the product in the lipase-catalyzed transesterification reactions,
and the enantioselectivity follows Kazlauskas’ rule [27].
In summary, a detailed studies conducted by Soloshonok et al.
has shown that the stereochemical outcome of reactions using
various fluorinated compounds is strongly influenced by fluoro
group. The stereochemical course of the reactions may not only be
rationalized by means of steric factors, but also involves the
electronic influences fluorine atom, and the nature of the catalyst
[28–34].
mixtures of hexane/ethyl acetate (9:1 and 8:2) and monitored by
TLC, using Sorbent aluminum-backed pre-coated silica gel 60 F254
thin layers.
3.2. Synthesis of (ꢀ)-organofluoro alcohols 2a–e
Racemic secondary alcohols 2a–e were prepared by reduc-
ing ketones 1a–e with sodium borohydride in methanol. The
ketones (1a, 7.1 mmol; 1b, 3.2 mmol; 1c, 3.2 mmol; 1d,
3.8 mmol; 1e, 6.7 mmol), NaBH4 (1.1 equivalents of the
quantity of ketone) and methanol (10 mL) were mixed in a
25 mL flask equipped with a magnetic stirrer. The mixtures
were stirred for 45 min in on ice bath (Scheme 1). The reactions
were then quenched by adding water (1 mL), the methanol was
removed by evaporation under vacuum and the residue
extracted with ethyl acetate (3ꢂ 20 mL). The combined organic
phases were dried over anhydrous sodium sulfate (Na2SO4) and
then filtered. The organic solvent was evaporated under
reduced pressure and the residue was purified by silica gel
column chromatography, using hexane and ethyl acetate as
eluents to produce racemic alcohols 2a–e in excellent yields
(2a, 93%; 2b, 78%; 2c, 82%; 2d, 97%; 2e, 86%).
3. Experimental
3.1. General methods
The 2,2,2-trifluoroacetophenone 1a, 3-bromo-2,2,2-trifluoroa-
cetophenone 1b, 4-bromo-2,2,2-trifluoacetophenone 1c, 2,4,5-
trifluoroacetophenone 1d and 2-(trifluoromethyl)acetophenone
1e were purchased from Sigma–Aldrich. Sodium borohydride and
methanol were purchased from Synth and Tedia (Brazil),
respectively. Enzymatic kinetic resolution (KR) under conventional
conditions (orbital shaking) was carried out in a Tecnal TE-421
orbital shaker. Enzyme reaction products were analyzed with a
Shimadzu GC 2010 gas chromatograph equipped with an AOC 20i
auto injector and a flame ionization detector (FID). The tempera-
ture programs used for the GC–FID analyses of rac-alcohols 2a–e
and rac-acetates 3a–e are detailed in Table 4. The injector and
detector were maintained at 200 8C, the split ratio of the injector
was 1:20 and the carrier gas was N2 at 60 kPa. The enantiomeric
excess (ee) of alcohols 2a–e and acetates 3a–e were determined by
GC–FID analysis (Tables 1–3). The ee of unreacted alcohol 2a was
determined after its derivatization with Ac2O/py by chiral column.
All the compounds were separated out by column chromatography
(CC) over silica gel (230–400 mesh). The column was eluted with
3.3. Synthesis of (ꢀ)-organofluoro acetates 3a–e
Alcohols (2a, 2.19 mmol; 2b, 0.13 mmol; 2c, 0.13 mmol; 2d,
0.22 mmol; 2e, 0.0005 mmol), pyridine (1.0 mL, 12.41 mmol) and
acetic anhydride (Ac2O) (1.0 mL, 10.49 mmol) were mixed in a
25 mL flask equipped with a magnetic stirrer. The mixture was
stirred for 24 h at room temperature (Scheme 1). The reactions
were stopped by the addition of 10% HCl (2 mL) and the acetate
produced was extracted with ethyl acetate (3ꢂ 20 mL). The
combined organic phases were dried over Na2SO4 and then
filtered. The organic solvent was evaporated under reduced
pressure and the residue purified by silica gel column chroma-
Scheme 1. Syntheses of racemic alcohols 2a–e and respective acetates 3a–e.