New synthetic routes towards various α-fluorinated aryl ketones and their enantioselective reductions using baker's yeast

Article abstract of DOI:10.1016/j.tet.2006.11.019

Highly electrophilic dichlorofluoromethyl aryl ketones were obtained by oxidation of dichlorofluoromethyl aryl alcohols. Subsequent dechlorination of these ketones using sodium formaldehyde sulfoxylate (Rongalite) and reductive dehalogenating system SnCl₂/Al led to various fluoromethyl aryl ketones and chlorofluoromethyl aryl ketones, respectively. Asymmetric reductions of these fluorinated ketones using the inexpensive baker's yeast produced the corresponding fluoromethyl aryl alcohols with different enantioselectivities.

Full text of DOI:10.1016/j.tet.2006.11.019

Tetrahedron 63 (2007) 970–976
New synthetic routes towards various a-fluorinated aryl ketones
and their enantioselective reductions using baker’s yeast
*
Balaka Barkakaty, Yutaka Takaguchi and Sadao Tsuboi
Department of Material and Energy Science, The Graduate School of Environmental Science, Okayama University,
Tsushima, Okayama 700-8530, Japan
Received 4 August 2006; revised 7 November 2006; accepted 8 November 2006
Available online 30 November 2006
Abstract—Highly electrophilic dichlorofluoromethyl aryl ketones were obtained by oxidation of dichlorofluoromethyl aryl alcohols. Sub-
sequent dechlorination of these ketones using sodium formaldehyde sulfoxylate (Rongalite) and reductive dehalogenating system SnCl2/
Al led to various fluoromethyl aryl ketones and chlorofluoromethyl aryl ketones, respectively. Asymmetric reductions of these fluorinated
ketones using the inexpensive baker’s yeast produced the corresponding fluoromethyl aryl alcohols with different enantioselectivities.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
group of fluorinated ketones has been suggested as being re-
sponsible for the inhibition of a variety of enzymes.4 For ex-
ample, some trifluoromethyl ketones were found to act as
inhibitors of male responses to the pheromone of the proces-
sionary moth Thaumetopea pityiocampa.5 The trifluoro-
methyl ketones are highly electrophilic compounds, which
form stable hydrates or hemiketals in aqueous solutions
with a serine residue of the enzyme.6 The tetrahedral adducts
formed in such reactions are similar to the transition state
of the water addition to the carbonyl group of a peptide
substrate.
The success stories in achieving novel biological activities
on introduction of a fluorine atom into different organic
compounds have been so profound and fruitful that there
has been a constant surge in research activities leading to
the innovation of newer methods and synthetic techniques
to incorporate a fluorine atom at different sites of various or-
ganic molecules.1 More specifically, synthetic strategies or
novel methodologies to attach the highly electronegative,
low polarizable and hard fluorine atom near a carbonyl cen-
tre draw special attention due to the potentiality of such com-
pounds to be used as important building blocks for other
desired fluorinated targets. For example, since the synthesis
of a number of biologically active compounds such as ami-
nothiazoles, triazole, etc. relies on the nucleophilic displace-
ments of a-halo carbonyl compounds, the presence of an
adjacent fluoro atom in similar a-halo carbonyl synthons
would pave the way for the synthesis of a gamut of novel
fluoro containing biologically active compounds.2 Further-
more, various condensation reactions are also possible due to
the presence of highly acidic a-hydrogen atoms in a-fluoro-
carbonyl moieties, which makes the synthesis of a-fluoro-
carbonyl compounds a significant step towards numerous
novel fluoro entities and thereby novel biological activities.3
However, there has already been a considerable effort on
the introduction of a fluoro atom at the a-site of a carbonyl
group by using various eletrophilic fluorinating agents.7
Moreover, the synthetic utilization of environmentally haz-
ardous chemicals such as trichlorofluoromethane (CFC-11)
for the design of new fluoro compounds is emerging as a
potential and useful fluorine fixation technique.8 Recently,
we have reported the reductive addition of CFCl3 (CFC-11)
to aromatic aldehydes using activated Al under ultrasonic
irradiation.9 This method leads to the formation of di-
chlorofluoromethyl aryl alcohols in reasonable to excellent
yields. It indeed underscores one more important contribu-
tion towards safe and useful utilization of environmentally
demanding compounds like CFC-11. Moreover, bioreduc-
tions of prochiral compounds to generate new chiral deriva-
tives have always been the topic of immense scientific
explorations. Among the various methods known so far, bio-
reduction by baker’s yeast (Saccharomyces cerevisiae) is
one of the most extensively studied and reported because
of its easy availability, low cost, high efficiency in many
cases and easy work-up procedure. We have already
The presence of a fluorine atom adjacent to a carbonyl group
increases the electrophilicity of the carbonyl carbon consid-
erably, thereby facilitating nucleophilic addition. Nucleo-
philic addition of an enzyme active site to the carbonyl
* Corresponding author. Tel./fax: +81 86 251 8898; e-mail: stsuboi6@cc.
okayama-u.ac.jp
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.11.019

B. Barkakaty et al. / Tetrahedron 63 (2007) 970–976
971
contributed a number of reports encompassing a wide range
of useful substrates that permits asymmetric induction by the
use of baker’s yeast.10 Herein, we wish to report novel strat-
egies towards various a-fluorinated aryl ketones by selective
dehalogenation of dichlorofluoromethyl aryl ketones and
a comparative study of asymmetric baker’s yeast reductions
of the different kinds of a-fluorinated aryl ketones obtained
from dichlorofluoromethyl aryl alcohols.
dechlorination of the dichlorofluoromethyl aryl ketones. Af-
ter optimizing the conditions (Table 1), it was found that
2.0 equiv of Rongalite in reflux ethanol gave the correspond-
ing fluoromethyl phenyl ketone (4a) from dichlorofluoro-
methyl phenyl ketone (3a) in moderate yields in less than
1 h.
O
R
Rongalite
2. Results and discussion
O
R
reflux EtOH
Cl2FC
4
3
The starting compounds i.e., the dichlorofluoromethyl aryl
alcohols were easily obtained by the reductive addition of
CFCl3 to aromatic aldehydes using SnCl2 and activated Al
in DMF under ultrasonic irradiation (Scheme 1) as reported
in our previous work.9
F
58-65%
3a: R = C6H5
3b: R = 4-MeOC6H4
3c: R = 4-BrC6H4
4a: R = C6H5
4b: R = 4-MeOC6H4
4c: R = 4-BrC6H4
Scheme 3.
OH
CFCl3
R
H
O
CFCl2
R
Al, SnCl2,
DMF
The mechanism of the dechlorination reactions by this
reagent was supposed to be similar to that reported by Ait-
Mohand et al.15a However, this particular system was appli-
cable in the selective formation of fluoromethyl products
only. As seen in Table 1, the reaction of dichlorofluoro-
methyl phenyl ketone 3a with various amounts of Rongalite
gave mixtures of fluoromethyl phenyl ketone 4a with chloro-
fluoromethyl phenyl derivative 5a or with acetophenone 6a
except entry 3 showing selective formation of 4a with
2.0 equiv of Rongalite in reflux ethanol. The chlorofluoro-
methyl aryl ketones 4 were however obtained using the
reductive dehalogenating system of SnCl2/Al in DMF at
60 ꢀC. Such a method was previously employed by Torii
and co-workers for the mono-dechlorination of trichloro-
methyl carbinols employing PbBr2/Al system in DMF.17
We employed SnCl2 for the required conversions instead
of PbBr2 because of lower toxicity of Sn compounds com-
pared to that of Pb congeners (Scheme 4).
H
2
1
Ultrasound
(70-87%)
2a: R = C6H5
2b: R = 4-MeOC6H4
2c: R = 4-BrC6H4
1a: R = C6H5
1b: R = 4-MeOC6H4
1c: R = 4-BrC6H4
Scheme 1.
The dichlorofluoromethyl aryl alcohols were then oxidized
to the corresponding highly electrophilic dichlorofluoro-
methyl aryl ketones using 5 mol % of pyridinium chloro-
chromate (PCC) and 1.15 equiv of co-oxidant, H5IO6, in
acetonitrile, as reported by Hunsen (Scheme 2).11
5 mol% PCC,
OH
R
H5IO6
O
CFCl2
R
Cl2FC
3
CH3CN
H
2
58-62%
Next, we investigated the asymmetric reductions of the var-
ious kinds of a-fluorinated aryl ketones, obtained from the
precursor compounds, dichlorofluoromethyl aryl alcohols,
with baker’s yeast. Baker’s yeast produces many enzymes
including many oxidoreductases18,19 having diverse
3a: R = C6H5
3b: R = 4-MeOC6H4
3c: R = 4-BrC6H4
2a: R = C6H5
2b: R = 4-MeOC6H4
2c: R = 4-BrC6H4
Scheme 2.
A number of methods were then investigated for the selec-
tive dechlorination reactions. For example, reduction with
systems like Zn/AcOH, LAH, DIBAL-H, 10% Pd/C gave
a mixture of products with very low selectivities. Reactions
employing HI equivalents generated from NaI and H2SO4
and even by using Ph3PHI13 also failed to give the required
conversions.
Table 1. Reduction of dichlorofluoromethyl phenyl ketonea with Rongalite
(NaO2SCH2OH)
O
12
O
O
Cl
Ph
Ph
CFCl2
Ph
+
5a
4a
F
3a
F
O
+
Ph
However, on using sodium formaldehyde sulfoxylate (Ron-
galite) in ethanol, selective dechlorination was observed
leading to the formation of fluoromethyl aryl ketones
(Scheme 3). Reductive dechlorination reactions of various
halogenated ketones using Rongalite have been known,14
but surprisingly, the synthetic utility of this reagent is not
fully explored and have been limited only to a few examples
to form R–CF2H or RCOCF2H moieties15 and mostly in
free-radical addition or cyclization reactions with perfluoro-
alkyl halides as starting materials.16 In this paper, we inves-
tigated the utility of this reducing agent for the selective
6a
Entry
Rongalite (equiv)
Time (min)
Product/%b
1
2
3
4
5
4.0
2.4
2.0
1.0
2.0
30
20
30
30
4a/10, 6a/30
4a/50, 6a/10
4a/60
4a/40, 5a/20
4a/45, 5a/20
180
a
Carried out with dichlorofluoromethyl phenyl ketone 3a (1.0 equiv) in
absolute EtOH under reflux conditions except entry 5 at rt.
Isolated yields based on amount of 3a consumed.
b

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B. Barkakaty et al. / Tetrahedron 63 (2007) 970–976
O
O
the corresponding asymmetric alcohols 7, 8 and 9, respec-
tively, with different enantioselectivities and with no de-
halogenated products. It was seen that in case of the
dichlorofluoromethyl aryl ketones, the chemical yields
(35–38%) as well as the optical yields (47–55%) of the chiral
products did not depend on the nature of the substituents on
the aromatic rings. But, the low optical yields (47–55%) in
case of 3a, 3b and 3c to give 7a, 7b and 7c, respectively,
and a slight improvement to 62% (with respect to the re-
duced carbonyl centre) in case of 5a forming the correspond-
ing diastereomeric chiral alcohol 8a and a sharp increase to
92% and 94% in case of 4a and 4c forming 9a and 9c, res-
pectively, reflected the dependence of such enzymatic selec-
tive reductions on steric factors of the substituents flanking
the carbonyl centre. However, in the case of 2-fluoro-1-(4-
methoxyphenyl) ethanone (4b), even being activated by
the a-fluoro atom, no reaction occurred. In fact, this result
is consistent with some other reported reductions of baker’s
yeast, which suggested that in systems such as 1-(4-methoxy-
phenyl)-1-ethanone20 or 1-(1,3-benzodioxol-5-yl)-1-etha-
none,21 the carbonyl carbon is deactivated by the presence
of electron donating substituents to undergo a nucleophilic at-
tack by the hydride atom mediated by S. cerevisiae. In case of
the dichlorofluoromethyl aryl ketone having the methoxy
substituent (3b), the carbonyl group was however effectively
reduced by the baker’s yeast to give 7b as a result of addi-
tional activation provided by the two chloro and one fluoro
atoms attached to the carbonyl moiety.
Cl
Al, SnCl2
R
CFCl2
R
DMF, 60 °C
5
3
F
52-56%
5a: R = C6H5
3a: R = C6H5
3b: R = 4-MeOC6H4
3c: R = 4-BrC6H4
5b: R = 4-MeOC6H4
5c: R = 4-BrC6H4
Scheme 4.
activities. Therefore, the interaction of such whole-cells with
the a-fluoro ketones having different steric demands with
respect to the number of chlorine atoms in the a-position
and also to the difference in nature of the substituents in
the aromatic ring prompted us to carry out such kind of
investigations (Scheme 5, Table 2).
O
HO
H
X
Y
X
Y
Baker's Yeast
R
R
F
F
3a: R = C6H5
X = Cl, Y = Cl
3b: R = 4-MeOC6H4
X = Cl, Y = Cl
3c: R = 4-BrC6H4
X = Cl, Y = Cl
7a: R = C6H5
X = Cl, Y = Cl
7b: R = 4-MeOC6H4
X = Cl, Y = Cl
7c: R = 4-BrC6H4
X = Cl, Y = Cl
8a: R = C6H5
X = Cl, Y = H
However, it is often found that the stereoselectivity and re-
gioselectivity associated with the reduction of an artificial
substrate by a whole yeast is not always satisfactory22 and
could be improved further by various methods such as the
use of isolated enzymes23 instead of whole-cells, use of or-
ganic media,24 addition of other compounds,25 use of differ-
ent carbon sources for the regeneration of the co-enzyme,26
etc. But all these methods are not feasible in terms of prac-
tical utility to obtain high enantioselectivities and high
chemical yields of the required compounds in terms of
energy, time and expenses. Therefore, as obtained by our
reported method, enantiomeric excesses (92% and 94%)
for compounds 4a and 4c using baker’s yeast with moderate
chemical yields of 44% and 46%, respectively, offers a much
easier, practically viable and an economical approach to
obtain the required compounds.
5a: R = C6H5
X = Cl, Y = H
4a: R = C6H5
9a: R = C6H5
X = H, Y = H
4b: R = 4-MeOC6H4
X = H, Y = H
4c: R = 4-BrC6H4
X = H, Y = H
X = H, Y = H
9c: R = 4-BrC6H4
X = H, Y = H
Scheme 5.
The baker’s yeast reductions of the various kinds of di-
chlorofluoromethyl aryl ketones (3), chlorofluoromethyl aryl
ketones (5) and the fluoromethyl aryl ketones (4) produced
The absolute configuration of the stereogenic centre of each
homochiral aryl dichlorofluoromethyl aryl alcohol was de-
duced as R by comparing the sign of their specific rotations
with that obtained for previously reported homochiral aryl
trichloromethyl aryl alcohols27 and that of trifluoromethyl
aryl alcohols.28 The configurations of other chiral halo-
hydrins were also confirmed by comparison of the sign of
the specific rotations with similar29 and other authentic
samples.30 The enantiomeric excess of each of the chiral
Table 2. Baker’s yeast reductions of various fluoromethyl aryl ketones
Substrate
R
X
Y
Time Product/yield (%)a ee%b,c
(days)
3a
3b
3c
5a
4a
4b
4c
C6H5 Cl Cl
4-MeOC6H4 Cl Cl
3
3
7a/35
7b/38
7c/36
8a/38
9a/44
No reaction
9c/46
55
47
50
62d
92
4-BrC6H4
C6H5
C6H5
Cl Cl 3.5
Cl
H
H
H
H
H
H
H
3
2
5
2
4-MeOC6H4
4-BrC6H4
1
94
halohydrin was determined by H NMR analysis of the
a
corresponding MTPA ester by the chiral derivatization
method using the Mosher’s ester.31 Furthermore, since no
dehalogenated product was detected in the reaction products
of the baker’s yeast reductions, the results indicated that the
reduction occurred via a hydride transfer mechanism and
not an electron transfer as was demonstrated previously by
Moran et al. in the case of a-haloacetophenones.30
Isolated yields based on starting materials consumed.
Enantiomeric excess based on 1H NMR analysis of the corresponding
MTPA ester.
b
c
Stereochemistry of each of the chiral product was found to be (R).
Diastereomeric mixture with respect to the halogenated chiral centre
while the stereospecificity of the reduced carbonyl centre was deduced
as (1R). Separation of the diastereomeric mixture of 8a was not possible
even by HPLC technique.
d

B. Barkakaty et al. / Tetrahedron 63 (2007) 970–976
973
3. Conclusions
of 86 mg (5 mol %) PCC in 5 ml acetonitrile (in two por-
tions), reaction mixture was stirred at 0 ꢀC for 10 min and
then at room temperature for 3.5 h. The reaction mixture
was then diluted with 100 ml ethyl acetate and washed with
1:1 brine/water, saturated aqueous Na2SO3 solution and
brine. Then the organic extract was dried over anhydrous
MgSO4 and concentrated to give the crude product. The
crude product was purified by silica gel flash column chroma-
tography (hexane/EtOAc, 4:1) to yield 60% of 3a (0.67 g,
3.25 mmol; based on starting material 2a consumed).
In conclusion, we have shown here the synthetic utilization
of our previously synthesized dichlorofluoromethyl aryl
alcohols towards various a-fluorinated aryl ketones by
employing very simple, facile and selective methodologies.
These building blocks are expected to act as valuable starting
materials for the synthesis of numerous novel fluorinated
biologically active compounds. Asymmetric reductions of
the various kinds of a-fluorinated aryl ketones with the inex-
pensive baker’s yeast produced various chiral fluoro hydrins
with different enantioselectivities depending on the steric
size of the substituents on the a-carbon atom i.e., the number
of chloro atoms attached to it. Although the presence of an
electron donating group on the aromatic ring did not alter
the reactivity in case of dichlorofluoromethyl aryl ketone
but in case of fluoromethyl aryl ketone, the presence of an
electron donating group such as –MeO totally deactivated
the carbonyl moiety to such nucleophilic hydride addition
mediated by the baker’s yeast.
4.4.1. 2,2-Dichloro-2-fluoro-1-phenylethanone (3a). Yield
60% (3.5 h); IR (neat): 3077, 2985, 1721, 1593, 1445, 1248,
1
1116, 1042, 944, 865, 807, 684 cmꢁ1; H NMR (CDCl3):
d 8.17 (m, 2H), 7.66 (m, 1H), 7.52 (m, 2H); 19F NMR
(CDCl3) d 138.36. Anal. Calcd for C8H5Cl2FO: C, 46.41;
H, 2.43. Found: C, 46.76; H, 2.39.
4.4.2. 2,2-Dichloro-2-fluoro-1-(4-methoxyphenyl) etha-
none (3b). Yield 62% (2.5 h); IR (neat): 3074, 2946, 2844,
1704, 1593, 1564, 1462, 1260, 1186, 1116, 1030, 984,
1
869, 664 cmꢁ1; H NMR (CDCl3) d 8.17 (d, J¼9.3 Hz,
4. Experimental
4.1. General
2H), 6.98 (d, J¼7.5 Hz, 2H), 3.93 (s, 3H); 19F NMR
(CDCl3) d 138.78. Anal. Calcd for C9H7Cl2FO: C, 45.60;
H, 2.98. Found: C, 45.45; H, 2.92.
1H and 19F (external C6F6) NMR spectra were recorded
on JEOL JNM-AL300 spectrometer. FTIR spectra were
recorded on a Thermo Nicolet Avatar 360T2 infrared spec-
trophotometer. Elemental analyses were performed on a
Perkin–Elmer 2400 series II CHNS/O analyzer. For thin
layer chromatography, aluminium sheets (Merck silica gel
coated 60 F254) were used and the plates were visualized
with UV light and phosphomolybdic acid (5% in EtOH).
Merck silica gel 60 N (spherical, neutral) (40–50 mm) was
used for the flash chromatography.
4.4.3. 2,2-Dichloro-2-fluoro-1-(4-bromophenyl) ethanone
(3c). Yield 58% (3.5 h); IR (neat): 3088, 2977, 1713, 1598,
1449, 1249, 1120, 1095, 1074, 1036, 991, 863, 690 cmꢁ1; 1H
F
NMR (CDCl3) d 138.25. Anal. Calcd for C8H4BrCl2FO:
C, 33.61; H, 1.41. Found: C, 33.27; H, 1.19.
NMR (CDCl3) d 8.04 (d, J¼8.1 Hz, 2H), 7.67 (m, 2H); 19
4.5. Preparation of fluoromethyl aryl ketones 4a–c.
General procedure
Into a three-necked flask equipped with a reflux condenser
and a nitrogen inlet were added under nitrogen, dichloro-
fluoromethyl phenyl ketone 3a (51.5 mg, 0.25 mmol) in
5 ml of absolute EtOH. Then after 5 min of stirring, Ronga-
lite (59 mg, 0.50 mmol) was added and the solution was
heated at reflux until complete consumption of starting
material (30 min, TLC). The solution was then filtered and
evaporated to dryness. The crude product was filtered
through a short pad of silica gel eluting with hexane/EtOAc
(4:1) to give 60% (21 mg, 0.15 mmol) of 4a.
4.2. Materials
Trichlorofluoromethane and absolute ethanol were obtained
˚
from commercial source and stored over 4-A molecular
sieves. Unless otherwise noted, materials were obtained
from commercial suppliers and used without further purifi-
cation. Acetonitrile, DMF and methanol were dried and
purified by standard procedures before use.
4.3. Preparation of dichlorofluoromethyl aryl alcohols
2a–c. General procedure
4.5.1. 2-Fluoro-1-phenylethanone (4a). Yield 60%
(30 min). The compound was identified by comparison of
its spectral data with authentic sample as given in Ref. 7b.
All compounds were synthesized according to the procedure
described in Ref. 9.
4.5.2. 2-Fluoro-1-(4-methoxyphenyl) ethanone (4b). Yield
65% (45 min); IR (neat): 2951, 2852, 1684, 1597, 1470,
4.3.1. Products 2a–c. Products 2a–c were identified by
comparison of their spectral data with authentic samples as
given in Ref. 9.
1429, 1256, 1169, 1095, 964, 836 cmꢁ1
;
1H NMR
(CDCl3): d 7.90 (d, J¼8.4 Hz, 2H), 6.97 (d, J¼9.0 Hz,
2H), 5.48 (d, J¼47.1 Hz, 2H), 3.90 (s, 3H); 19F NMR
(CDCl3) d 29.56. Anal. Calcd for C9H9FO2: C, 64.28; H,
5.39. Found: C, 63.95; H, 5.28.
4.4. Preparation of dichlorofluoromethyl aryl ketones
3a–c. General procedure
To 20 ml of acetonitrile was added 2.1 g (9.2 mmol) of
H5IO6 and stirred vigorously at room temperature for
15 min. Dichlorofluoromethyl phenyl alcohol 2a (1.64 g,
8.0 mmol) was then added (in ice-bath) followed by addition
4.5.3. 2-Fluoro-1-(4-bromophenyl) ethanone (4c). Yield
58% (40 min); IR (neat): 3075, 3040, 2941, 1699, 1587,
1411, 1242, 1075, 986, 819 cmꢁ1 1H NMR (CDCl3):
;
d 7.77 (m, 2H), 7.65 (m, 2H), 5.48 (d, J¼47.1 Hz, 2H);

974
B. Barkakaty et al. / Tetrahedron 63 (2007) 970–976
19F NMR (CDCl3) d 29.28. Anal. Calcd for C8H6BrFO: C,
44.27; H, 2.79. Found: C, 43.98; H, 2.43.
4.7.2. (R)-2,2-Dichloro-2-fluoro-1-(4-methoxyphenyl)
ethanol (7b). Spectral data as for racemic compound in
Ref. 9: [a]2D2 ꢁ12.52 (c 1, CHCl3).
4.6. Preparation of chlorofluoromethyl aryl ketones
5a–c. General procedure
4.7.3. (R)-2,2-Dichloro-2-fluoro-1-(4-bromophenyl) etha-
nol (7c). Spectral data as for racemic compound in Ref. 9:
[a]2D5 ꢁ1.82 (c 1, CHCl3).
A two-necked flask was charged with SnCl2 (24 mg,
0.25 mmol) and Al powder (6.8 mg, 0.25 mmol) in DMF
(1 ml) and allowed to stir at room temperature for 3 min.
Then the starting material dichlorofluoromethyl phenyl
ketone 3a (51.5 mg, 0.25 mmol) in 1 ml of DMF was added
and the reaction mixture was heated at 60 ꢀC until comple-
tion of reaction (1.5 h, TLC). The reaction was quenched
with two drops of aqueous 5% hydrochloric acid and the
mixture was extracted with EtOAc. The combined extracts
were washed with aqueous NaHCO3 and brine, dried over
anhydrous MgSO4 and concentrated. The crude product
was purified by flash column chromatography (hexane/
EtOAc, 4:1) to give 55% (24 mg, 0.14 mmol) of 5a.
4.7.4. (1R)-2-Chloro-2-fluoro-1-phenylethanol (8a). [a]D23
ꢁ22.93 (c 0.5, CHCl3); IR (neat): 3445, 3067, 1478, 1365,
950 cmꢁ1 1H NMR (CDCl3) d 7.39 (m, 5H), 6.15 (d,
;
J¼48 Hz, 1H), 4.93 (m, 1H), 2.63 (s, 1H); 19F NMR
(CDCl3) d 70.92. Anal. Calcd for C8H8ClFO: C, 55.03; H,
4.62. Found: C, 54.89; H, 4.78.
4.7.5. (R)-2-Fluoro-1-phenylethanol (9a). The product was
identified by comparison of its spectral data with the authen-
tic samples as given in Ref. 30. [a]2D5 ꢁ49.9 (c 1.2, CHCl3)
(lit. ꢁ50.6).30
4.6.1. 2-Chloro-2-fluoro-1-phenylethanone (5a). Yield
55% (1.5 h); IR (neat): 2970, 1698, 1587, 1430, 1178, 985,
4.7.6. (R)-2-Fluoro-1-(4-bromophenyl) ethanol (9c). [a]D25
ꢁ25.94 (c 0.9, CHCl3); IR (neat): 3403, 2930, 1708, 1589,
1
1
656 cmꢁ1; H NMR (CDCl3) d 8.08 (d, J¼8.1 Hz, 2H),
1490, 1301, 898 cmꢁ1; H NMR (CDCl3) d 7.51 (m, 2H),
7.67 (m, 1H), 7.51 (m, 2H), 6.83 (d, J¼50.7 Hz, 1H); 19F
NMR (CDCl3) d 53.07. Anal. Calcd for C8H6ClFO: C,
55.67; H, 3.50. Found: C, 55.64; H, 3.19.
7.28 (m, 2H), 4.99 (m, 1H), 4.43 (m, 2H), 3.21 (s, 1H);
19F NMR (CDCl3) d 67.33. Anal. Calcd for C8H8BrFO: C,
43.86; H, 3.68. Found: C, 43.84; H, 3.76.
4.6.2. 2-Chloro-2-fluoro-1-(4-methoxyphenyl) ethanone
(5b). Yield 52% (1.5 h); IR (neat): 2939, 1688, 1601,
4.8. Determination of enantiomeric purity of a-fluoro
aryl alcohols 7a–c, 8a, 9c (derivatization method)
1
1569, 1425, 1182, 980, 853, 630 cmꢁ1; H NMR (CDCl3):
d 8.07 (d, J¼8.4 Hz, 2H), 6.99 (d, J¼9.0 Hz, 2H), 6.78 (d,
J¼50.7 Hz, 1H), 3.90 (s, 3H); 19F NMR (CDCl3) d 54.55.
Anal. Calcd for C9H8ClFO2: C, 53.35; H, 3.98. Found: C,
53.46; H, 3.67.
Chiral derivatization of each a-fluoro aryl alcohol was
carried out by the chiral derivatization method using the
Mosher’s ester31 on a 70 mmol scale. The resulting MTPA
ester was analyzed by 1H NMR spectroscopy.
4.6.3. 2-Chloro-2-fluoro-1-(4-bromophenyl) ethanone
(5c). Yield 56% (1 h); IR (neat): 2967, 1703, 1591, 1436,
4.8.1. MTPA ester of 7a. 1H NMR (CDCl3) d 7.33 (m, 13H),
6.38 (d, J¼10.2 Hz, 0.29H), 6.31 (d, J¼9.6 Hz, 1H), 3.56 (d,
J¼1.2 Hz, 0.87H), 3.43 (d, J¼1.2 Hz, 3H).
1
1187, 989, 660 cmꢁ1; H NMR (CDCl3) d 7.95 (m, 2H),
7.67 (m, 2H), 6.76 (d, J¼50.7 Hz, 1H); 19F NMR (CDCl3)
d 53.93. Anal. Calcd for C8H5BrClFO: C, 38.21; H, 2.00.
Found: C, 38.27; H, 1.89.
1
4.8.2. MTPA ester of 7b. H NMR (CDCl3) d 7.36 (m,
9.52H), 6.90 (m, 0.72H), 6.83 (m, 2H), 6.40 (d, J¼
10.2 Hz, 0.38H), 6.33 (d, J¼9.9 Hz, 1H), 3.84 (s, 1H),
3.82 (s, 3H), 3.62 (d, J¼1.5 Hz, 3H), 3.56 (d, J¼1.5 Hz, 1H).
4.8.3. MTPA ester of 7c. 1H NMR (CDCl3) d 7.55 (m, 4H),
7.40 (m, 9H), 6.33 (d, J¼9.6 Hz, 0.33H), 6.24 (d, J¼10.2 Hz,
1H), 3.63 (d, J¼1.2 Hz, 3H), 3.49 (d, J¼1.2 Hz, 0.33H).
4.7. General procedure for the synthesis of 7a–c, 8a,
9a, 9c
To a stirring mixture of KH2PO4 (40 mg), NH4H2PO4
(40 mg), MgSO4 (20 mg), CaCO3 (12 mg), glucose (1.0 g)
and water (24 ml) was added baker’s yeast (1.0 g) at
38 ꢀC. After stirring for 30 min, dichlorofluoromethyl
phenyl ketone 3a (62 mg, 0.30 mmol) was added and the
reaction mixture was stirred at 38 ꢀC. Baker’s yeast (1.0 g)
and glucose (1.0 g) were added after every 24 h. After three
days of stirring, the reaction mixture was treated with Celite
for 1 h and filtrated. The filtrate was then extracted six
times with EtOAc and washed with brine. The combined or-
ganic extracts were dried over anhydrous MgSO4 and evapo-
rated. The residual crude products were purified by flash
column chromatography to give 35% (22 mg, 0.11 mmol)
of 7a.
1
4.8.4. MTPA ester of 8a. H NMR (CDCl3) d 7.39 (m,
12.4H), 6.37 (m, 0.6H), 6.142 (m, 1.24H), 3.62 (s, 3H),
3.48 (s, 0.7H).
1
4.8.5. MTPA ester of 9c. H NMR (CDCl3) d 7.45 (m,
9.3H), 6.22 (m, 1H), 6.08 (m, 0.03H), 4.65 (m, 2H), 4.51
(m, 0.06H), 3.61 (s, 3H), 3.48 (s, 0.09H).
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Spectral data as for racemic compound in Ref. 9: [a]D20
ꢁ2.44 (c 1.5, CHCl3).

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