A practical synthesis of optically active aromatic epoxides via asymmetric transfer hydrogenation of α-chlorinated ketones with chiral rhodium-diamine catalyst

Article abstract of DOI:10.1016/j.tet.2004.06.076

A practical method for the synthesis of optically active aromatic epoxides has been developed via the formation of optically active α-chlorinated alcohols and intramolecular etherification. Optically active alcohols with up to 99% ee can be obtained from

Full text of DOI:10.1016/j.tet.2004.06.076

Tetrahedron 60 (2004) 7411–7417
A practical synthesis of optically active aromatic epoxides via
asymmetric transfer hydrogenation of a-chlorinated ketones with
chiral rhodium–diamine catalyst
Takayuki Hamada,a Takayoshi Torii,a Kunisuke Izawaa and Takao Ikariyab
,
*
aAminoScience Laboratories, Ajinomoto Co., Inc., 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki 210-8681, Japan
bGraduate School of Science and Engineering, Tokyo Institute of Technology and Frontier Collaborative Research Center,
2-12-1 O-okayama, Meguro-ku, 152-8552 Tokyo, Japan
Received 22 April 2004; revised 15 June 2004; accepted 15 June 2004
Available online 8 July 2004
Abstract—A practical method for the synthesis of optically active aromatic epoxides has been developed via the formation of optically
active a-chlorinated alcohols and intramolecular etherification. Optically active alcohols with up to 99% ee can be obtained from the
asymmetric reduction of aromatic ketones with a substrate/catalyst ratio of 1000–5000 using a formic acid/triethylamine mixture containing
a well-defined chiral Rh complex, Cp*RhCl[(R,R)-Tsdpen]. The asymmetric reduction of a-chlorinated aromatic ketones with a chiral Rh
catalyst is characterized by a rapid and carbonyl group-selective transformation because of the coordinatively saturated nature of diamine-
based Cp*Rh(III) hydride complexes. The outcome of the reduction is significantly influenced by the structures of the ketonic substrates as
well as the hydrogen source such as formic acid or 2-propanol. Commercially available reagents and solvents can be used in this reaction
without special purification. This epoxide synthetic process in either a one- or two-pot procedure is practical and particularly useful for the
large-scale production of optically active styrene oxides from a-chlorinated ketones.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
convert these a-halogenated ketones to optically active
alcohols in a practical manner, except for some chiral Rh
hydrogenation catalysts that give the product in only
moderate ee.6
Optically active aromatic epoxides are now widely used as
important synthetic intermediates for the synthesis of a1-,
b2- and b3-adrenergic receptor agonists.1 This important
class of compounds is readily accessible by Jacobsen’s
asymmetric epoxidation with (salen)Mn(III) complex2a,b
and kinetic resolution of racemic epoxides with cobalt–
salen complexes,2c in addition to some microbial
approaches,3 as well as via conventional intramolecular
etherification of optically active chlorinated alcohols.
Although the oxidative transformation of alkenes is a
straightforward procedure, a sequential transformation of
a-chlorinated ketonic substrates through asymmetric
reduction and intramolecular etherification is attractive
because the starting carbonyl compounds are readily
available. For example, optically active epoxides are readily
accessible by means of asymmetric boron reduction4 or
microbial reduction of a-halogenated ketones,5 followed by
epoxidation of a-halogenated alcohols. However, none of
the currently available chiral catalyst systems can efficiently
Keywords: Asymmetric reduction; a-Chlorinated aromatic ketone;
Optically active epoxide.
We have recently developed a highly efficient asymmetric
transfer hydrogenation of aromatic ketones to the corre-
sponding optically active alcohols catalyzed by well-defined
*
Corresponding author. Tel.: þ813-573-42636; fax: þ813-573-42637;
e-mail address: tikariya@apc.titech.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.076

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T. Hamada et al. / Tetrahedron 60 (2004) 7411–7417
chiral complexes, Cp*RhCl[(R,R)-Tsdpen]7 (1a) and
RuCl[(R,R)-Tsdpen])(h6-arene) (1b),8 where Cp*¼
pentamethylcyclopentadienyl and TsDPEN¼(1R,2R)-N-p-
toluenesulfonyl-1,2-diphenylethylenediamine) (Fig. 1). In
particular, a-chlorinated carbonyl compounds, which can-
not be efficiently hydrogenated by conventional practical
hydrogenation catalysts, for example, Ru-BINAP catalysts,
were found to be readily transfer-hydrogenated with these
chiral complexes to the corresponding optically active
chlorinated alcohols with excellent ee’s.9 Thanks to the
characteristic bifunctional properties of these chiral cata-
lysts, functionalized aromatic ketones bearing neighboring
functional groups at the a-position of the carbonyl group
could be readily reduced to optically active alcohols with
extremely high ee’s. We describe here the details of the
asymmetric synthesis of optically active epoxides through
asymmetric transfer hydrogenation of a-chlorinated ketones
and intramolecular etherification of the reduction products,
optically active chlorinated alcohols. A mixture of formic
acid/triethylamine and 2-propanol can be used as practical
hydrogen sources, and the optimal hydrogen source was
dependent upon the structure of the carbonyl compound.
Table 1. Asymmetric transfer hydrogenation of a-chloroacetophenone, 2a,
catalyzed by chiral catalysts, 1, with a mixture of HCOOH/N(C2H5)3
a
Catalyst S/C Temp
(8C)
Solvent
Time Yield ee
(h)
(%)b (%)b
Configc
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
5000
5000
5000
5000
25
25
25
25
25
25
25
25
25
25
25
20
30
40
CH3COOC2H5
CH3COOC2H5
CH3COOC2H5
CH3CN
THF
Acetone
DMF
CH2Cl2
Toluene
—
1
24
4
1
1
1
1
1
1
1
2
5
2
99
36d
99
99
99
99
99
99
99
99
99
93
97
96
97
91
71
93
95
96
96
94
92
89
96
71
92
81
S
S
S
S
S
S
S
S
S
S
S
S
S
S
CH3COOC2H5
CH3COOC2H5
CH3COOC2H5
CH3COOC2H5
8
a
The reaction of 2a in a 0.8–1.0 M solution containing the (R,R)-metal
catalyst (1) was conducted with a mixture of HCOOH and N(C2H5)3 at
25 8C.
Unless otherwise noted, yields and ee values were determined by HPLC
analysis using a Daicel Chiralcel OB-H column.
Configuration was determined from the sign of rotation of the isolated
product.
b
c
d
Formyloxyacetophenone was formed as a main byproduct.
a-chloroacetophenones (2a). The reaction of 2a, even with
an S/C of 5000, under conditions otherwise identical to
those described in Table 1 proceeded rapidly to give the
optically active alcohol 3a almost quantitatively with 96%
ee and an initial turnover frequency (TOF) exceeding
2500 h21. The reaction rate and enantioselectivity were far
superior to those obtained with the catalyst generated in
situ.10a,b In contrast to the Rh system, a chiral Ru complex,
RuCl[(R,R)-Tsdpen]](p-cymene) (1b), which has a structure
that is isoelectronic with 1a and effects the asymmetric
transfer hydrogenation of simple acetophenones, exhibited
no remarkable activity for the reaction of 2a with the S/C of
1000, and gave a-formyloxyacetophenone as a main
product under the conditions described above. However, a
decrease in the volume of the azeotropic mixture to 1 equiv.
of the ketone 2a (2a:HCOOH¼1:1) in ethyl acetate
containing 0.1 mol% chiral Ru catalyst 1b caused an
increase in the yield of desired product 3a to 36 and 91%
ee (Table 1).10c,d Despite the structural similarity between
the Cp*Rh and (h6-arene)Ru complexes, the remarkable
difference in the reactivity toward a-chloroacetophenones
may be attributed to the electronic properties of the central
metals. An analogous Ir complex, Cp*IrCl[(R,R)-Tsdpen]
(1c),7 exhibited reasonably high reactivity but poor
enantioselectivity.
Figure 1. Chiral Rh, Ir, Ru catalysts for asymmetric transfer hydrogenation.
2. Results and discussion
2.1. Asymmetric transfer hydrogenation of a-chlori-
nated aromatic ketones with a formic acid/triethylamine
mixture
A well-defined chiral Rh complex (R,R)-1a was found to
effect the highly efficient asymmetric transfer hydrogen-
ation of a-chloroacetophenone (2a) with a 5:2 formic acid/
triethylamine azeotropic mixture (substrate/catalyst ratio (S/
C)¼1000, S/HCOOH¼1/1) in a 1.0 M ethyl acetate solution
at room temperature to give (S)-a-chlorinated alcohol (3a)
with 97% ee and in .99% yield after 1 h. Table 1 shows
some examples. The reaction proceeded equally well in
various solvents, including acetonitrile, DMF, THF,
toluene, CH2Cl2 and acetone, but not in methanol or
t-BuOH, in which a longer reaction time was required or a
lower ee was obtained. The reaction in a neat formic acid/
triethylamine mixture gave unsatisfactory results in terms of
enantioselectivity. A reaction temperature lower than 20 8C
led to a longer reaction time and gave the product with a
lower ee, and a temperature higher than 30 8C resulted in the
formation of a-formyloxyacetophenone generated from the
reaction of 2a with formic acid under these conditions.
A variety of ring-substituted a-chloroacetophenones
(2b–2l) can be transformed to the corresponding optically
active secondary alcohols with high enantiomeric purities
using a 5:2 formic acid/triethylamine azeotropic mixture as
a hydrogen donor and the Rh catalyst 1a, as shown in
Table 2. In general, a-chloroacetophenones are more
favorable substrates for transfer hydrogenation than the
parent acetophenone due to thermodynamic reasons.8d,11 In
fact, reduction of the simple acetophenone with 1a
(S/C¼1000) under the same conditions gave the corre-
sponding alcohol in only 6% yield with 91% ee after 24 h.8a
Noticeably, neither the rate nor the enantioselectivity are
The chiral Cp*Rh complex 1a is one of the most reactive
catalysts for the asymmetric transfer hydrogenation of

T. Hamada et al. / Tetrahedron 60 (2004) 7411–7417
7413
Table 2. Asymmetric transfer hydrogenation of a-chlorinated ketones, 2,
catalyzed by chiral Rh Catalyst, 1a, with a mixture of HCOOH/N(C2H5)3
catalyst 1a to the corresponding alcohols with excellent
ee’s. The reaction of furyl ketone (2p) or thienyl ketone (2q)
provided the reduction product with 99% ee or 98% ee,
respectively. Recently, it was reported that the reduction of
a-chlorinated pyridyl ketone (2r) successfully proceeded to
give the product with 96% ee.12
a
Substrate
R1
S/C Time (h) Yield (%)b ee (%)b Configc
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
H
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
99
81
93
90
90
90
94
93
92
80
80
93
98
93
95
95
95
95
97
88
95
92
95
95
94
95
96
96
97
98
59
58
68
99
98
91
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
o-Cl
m-Cl
p-Cl
o-CH3O
m-CH3O
p-CH3O
m-HO
m-CH3
m-CF3
p-MsNH
30,40-OCH2O 1000
—
—
—
—
—
—
Similarly, the reduction of acetophenones having func-
tional groups at the a-position in 1.0 M of ethyl acetate
containing chiral catalyst and a 5:2 formic acid/triethy-
lamine azeotropic mixture was examined.13 Table 3
summarizes representative results. When a-bromoaceto-
phenone (2s) was used instead of a-chloroacetophenone,
a side reaction gave a-formyloxyacetophenone. a-Hydro-
xyacetophenone (2t) gave a similar result as observed in a
reaction of a-chloroacetophenone with the S/C of 1000.
The reduction of a-methoxyacetophenone (2u) or a-
cyanoacetophenone (2v), was complete with an S/C of
500 under conditions described in Table 3. The reduction
of a-nitroacetophenone (2w) was complete with 0.1% of
Rh catalyst to give the corresponding reduction product
with 91% ee.13a a-Benzoylacetophenone was unsuitable
for this reduction.
1000
1000
200
1000
1000
500
a
The reaction of 2 in a 1.0 M CH3COOCH2CH3 solution containing the
(R,R)-Rh catalyst (1a) was conducted with a mixture of HCOOH and
N(C2H5)3 at 25 8C.
Unless otherwise noted, yields and ee values were determined by HPLC
analysis using a Daicel Chiralcel OB or OB-H column.
Configuration was determined from the sign of rotation of the isolated
product.
b
c
Table 3. Asymmetric transfer hydrogenation of a-substituted acetophe-
nones (2s–w: PhC(vO)CH2Y) catalyzed by chiral Rh catalyst, 1a, with a
HCOOH/N(C2H5)3 mixturea
seriously affected by the electronic properties of the ring
substituent. The enantiomeric excesses of the product
alcohols (3b–3l) were generally very high (up to 97% ee).
The electron-donating methoxy group on the phenyl group
(2e–2g) did not significantly affect either the reactivity or
enantioselectivity. An o-chloro group in acetophenone
slightly decreases the enantioselectivity, possibly due to
steric reasons.
Substrate
Y
S/C
Time (h) Yield (%)b ee (%)b Configc
2a
2s
2t
2u
2v
2w
2w
Cl
Br
OH
OCH3
CN
5000
1000
1000
500
500
500
2
1
2
2
2
2
4
99
65
93
92
95
93
90
96
10
97
94
98
95
91
S
S
S
S
R
S
S
NO2
NO2
1000
a
The reduction of a-chloroketones bearing a conjugated C–
C double (2m, 2n) or triple bond (2o) (Scheme 1), gave the
corresponding products with moderate ee values of 58–
68%. No reduction of the C–C double or triple bond was
observed in these reactions. a-Chlorinated ketones bearing
heterocyclic groups were readily reducible with the Rh
The reaction of 2 in a 1.0 M CH3COOCH2CH3 solution containing the
(R,R)-Rh catalyst (1a) was conducted with a mixture of HCOOH and
N(C2H5)3 at 25 8C.
Unless otherwise noted, yields and ee values were determined by HPLC
analysis using a Daicel Chiralcel OB or OB-H column.
Configuration was determined from the sign of rotation of the isolated
product.
b
c
Scheme 1.

7414
T. Hamada et al. / Tetrahedron 60 (2004) 7411–7417
2.2. Asymmetric transfer hydrogenation of a-
chlorinated aromatic ketones with 2-propanol
Table 5. Asymmetric transfer hydrogenation of a-chlorinatedketones, 2,
catalyzed by chiral Rh catalyst, 1a, with 2-propanola
Substrate
R1
Yield (%)b
ee (%)b
Configc
The outcome of the asymmetric transfer hydrogenation of
2a with chiral Rh catalyst was influenced by the hydrogen
source used. With 2-propanol, a strong base is required for
the formation of an active catalyst, chiral Rh amide
complex, which can react with 2-propanol to give another
catalyst intermediate, chiral Rh hydride amine complex.8c,f
During the reversible interconversion between the amide
and hydride amine complexes, the asymmetric reduction of
ketones with 2-propanol can be performed.
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
H
94
97
—
—
—
96
94
98
99
96
—
—
—
92
95
—
99
98
—
S
o-Cl
m-Cl
p-Cl
Trace
Trace
Trace
93
96
96
95
93
Trace
Trace
Trace
17
—
—
—
S
S
S
S
S
—
—
—
S
S
—
S
S
—
o-CH3O
m-CH3O
p-CH3O
m-HO
m-CH3
m-CF3
p-MsNH
30,40-OCH2O
—
The reaction of 2a with the S/C of 100 with 2-propanol in
the presence of a binary catalyst system, preformed Rh
catalyst 1a and t-C4H9OK, proceeded smoothly to give 3a in
94% yield and with 98% ee after 14 h. However, an increase
in the S/C ratio to 1000 caused a significant decrease in the
yield due to the inherent properties of the reversible reaction
with 2-propanol. Since a ternary catalyst system,
—
—
—
—
97
Trace
94
96
—
Trace
a
The reaction of 2 was conducted in a 0.1 M solution of ketone in
2-propanol at 25 8C. S/C¼100.
[Cp*RhCl2]2,
(R,R)-TsDPEN,
and
t-C4H9OK
b
c
(Rh:ligand:base¼1:2:5), gave almost the same results in
terms of reactivity and selectivity as the binary catalyst
system, the ternary catalyst system was used to optimize the
reaction conditions and to clarify the scope and limitations
of the reduction with 2-propanol. The results are sum-
marized in Table 4. The Rh catalyst strongly promoted
the asymmetric reduction of a-chloroacetophenones in
2-propanol, while it showed lower reactivity toward parent
acetophenone (2x) under the same conditions for thermo-
dynamic reasons.7,8a,10d,10f These results indicate that the
catalytic performance of the Rh catalyst is completely
different from that of the chiral Ru catalyst, which is an
excellent catalyst for the asymmetric transfer hydrogenation
of unsubstituted acetophenone.
Unless otherwise noted, yields and ee values were determined by HPLC
analysis using a Daicel Chiralcel OB or OB-H column.
Configuration was determined from the sign of rotation of the isolated
product.
under these reaction conditions. In contrast to the reduction
with formic acid discussed above, a-chloroacetophenones
bearing an aromatic ring substituents with electron-with-
drawing groups, such as chloro (2b–2d) or trifluoromethyl
(2j) groups, were scarcely reduced, possibly due to their
strong inhibitory effect. In fact, the reaction of 2e was
retarded by an addition of 5% of 2b, to give only 32%
conversion. Compound 2b with acidic protons might react
with Rh amide to lead to the irreversible formation of
catalytically inactive species.14
The structure of a-chlorinated acetophenones affected the
reactivity of asymmetric transfer hydrogenation in
2-propanol containing the chiral Rh catalyst. The results
are shown in Table 5. The acetophenones with electron-
donating alkyl (2i) and alkoxy (2e–g) groups on the
aromatic ring were reducible to give the corresponding
alcohols (3e–g, 3i) in high yield and excellent ee. There was
no substantial difference in reactivity between aromatic
ring-substituted ketones at the ortho (2e), meta (2f), and
para (2g) positions. Noticeably, compound 2h bearing
hydroxyl groups on the aromatic ring was also reduced
The reduction of 1-chloro-4-phenyl-2-butanone proceeded
smoothly to give the corresponding optically active alcohol
almost quantitatively with 19% ee.15 The reduction of
chlorinated conjugated ketones 2n bearing a strong
electron-donating ring substituent proceeded quantitatively
with good enantioselectivity. In this case, the use of
2-propanol as a hydrogen donor resulted in higher
enantioselectivity than formic acid. In the reduction of
aromatic heterocyclic chlorinated ketones, the electron-
donating furyl (2p) or thienyl ketone (2q) were smoothly
reducible to the corresponding optically active alcohols with
excellent ee, as observed in the reaction of aromatic ring-
substituted a-chloroacetophenone, but the electron-with-
drawing pyridine (2r) did not give a reduced product. These
results clearly show that asymmetric transfer hydrogenation
of a-chlorinated aromatic ketones are delicately influenced
by the structures of the ketonic substrates, and the
combination of the catalyst system and hydrogen source is
crucial for attaining high catalyst performance.
Table 4. Asymmetric transfer hydrogenation of a-chloroacetophenone, 2a,
or acetophenone, 2x, catalyzed by chiral Rh catalyst, 1a, with 2-propanola
Catalyst
Substrate
Y
Yield (%)b
ee (%)b
Configc
1a
1b
1c
1a
1b
1c
2a
2a
2a
2x
2x
2x
Cl
Cl
Cl
H
H
H
94
98
—
—
90
97
—
S
S
S
R
R
R
Trace
Trace
14
95
Trace
2.3. Epoxidation of a-chlorinated alcohols and one-pot
synthesis of optically active epoxides
a
The reaction of 2 was conducted in a 0.1 M solution of ketone in 2-
propanol at 25 8C. S/C¼100.
b
c
Unless otherwise noted, yields and ee values were determined by HPLC
analysis using a Daicel Chiralcel OB or OB-H column.
Configuration was determined from the sign of rotation of the isolated
product.
Optically active a-chlorinated alcohols 3 were readily
converted by conventional procedures to optically active
epoxides (4a, 4c, 4f) with excellent ee’s, as shown in

T. Hamada et al. / Tetrahedron 60 (2004) 7411–7417
7415
4. Experimental
4.1. General methods
The NMR spectra were recorded in CDCl3 with TMS (d
0.00) as an internal standard. Infrared (IR) spectra were
obtained by placing neat samples directly into the IR
instrument. Enantiomer excesses of samples were deter-
mined by HPLC. Elemental analyses were performed by
Tokyo Kasei Kogyo Co., Inc.
Scheme 2.
Scheme 2. For example, treatment of optically active
alcohol 3a with 4 M NaOH aq. in 2-propanol afforded (S)-
styrene oxides 4a (97% ee) in an 80% isolated yield without
loss of enantiomeric purity. In particular, m-chlorostyrene
oxide (S)-4c, which is obtained from the reduction product
(S)-3c (95% ee), is a key intermediate for the preparation of
several b3-adrenergic receptor agonist compounds.
4.2. Chemical procedure
4.2.1. Preparation of a-chlorinated alcohols (2a–2r). 2-
Propanol reduction system. A mixture of 1a (0.01 mmol)
and 2a (1.0 mmol) in 2-propanol (4.5 mL) was added to
0.1 M solution of t-C4H9OK (Rh:base:ketone¼1:1:100) in
2-propanol (0.5 mL), and the mixture was stirred for 14 h at
room temperature. HCl (0.5 M, 0.1 mL) was added, and the
mixture was concentrated in vacuo. The residue was
subjected to silica gel column chromatography to give 3a.
The ee value was determined by HPLC analysis. The
absolute configuration was determined by the sign of
rotation of the isolated product.
This reductive transformation of a-chloroacetophenones to
optically active epoxides was more appealing when a one-
pot synthetic procedure was used. As shown in Scheme 3,
sequential asymmetric reduction of 2a or 2c with a mixture
of formic acid and triethylamine in 2-propanol containing
catalyst 1a (S/C¼1000) for 2 h and treatment of the reaction
mixture with 2 M NaOH aqueous solution at 0 8C gave
optically active styrene oxide 4a or 4c, respectively, in an
isolated yield of 80–90% with 96–98% ee in a single
reactor.
Formic acid reduction system. A mixture of a-chloro-
acetophenone 2a (1.0 mmol) and catalyst 1a (1.0 mmol) in a
5:2 mixture of formic acid to triethylamine (0.2 mL) and
ethylacetate (1.0 mL) was stirred at 25 8C for 1 h. The
mixture was subjected to SiO2 column chromatography
(eluent: 20% C2H5OAc in hexane) to give a-chlorophenyl-
ethanol 3a. The ee value was determined by HPLC analysis.
Compounds 3a16, 3b17, 3c18, 3d17, 3g17, 3h17, 3i19, 3k16,
3l20, 3m21, 3o22 and 3r12 were identified by comparison to
the spectral data described in the literature.
4.2.2. Large-scale preparation. 2-Chloro-m-chloroaceto-
phenone 2c (4.73 g, 25.0 mmol) was added to a solution of
ethylacetate (31.3 mL) with catalyst 1a (3.4 mg, 5.0 mmol),
formic acid (1.03 mL, 26.3 mmol) and triethylamine
(3.76 mL, 26.3 mmol). The mixture was stirred at 25 8C
for 2 h and washed with 2 M HCl aq. and brine. The organic
layer was passed through a short SiO2 and MgSO4 column
and concentrated to give 3c (4.63 g, 97%). The 2-propanol
solution (12.5 mL) of 3c (4.60 g, 24.0 mmol) was treated
with 4 M NaOH aq. at 0 8C for 1 h. The mixture was
extracted with hexane. The organic layer was dried over
MgSO4 and concentrated to give m-chlorostyrene oxide 4c
(3.54 g, 96%).
Scheme 3.
3. Conclusions
We have described the successful reductive transformation
of a-chlorinated ketones to optically active epoxides via
asymmetric transfer hydrogenation and intramolecular
etherification. The asymmetric reduction of a-chlorinated
aromatic ketones with a chiral Rh catalyst is characterized
by a rapid and carbonyl group-selective transformation
because of the coordinatively saturated nature of diamine-
based Cp*Rh hydride complexes.7,8,13 The neighboring
chloro group at the a-position of the carbonyl group is
possibly free from the metal center, leading to excellent
reactivity and enantioselectivity. The outcome of the
reduction is significantly influenced by the structures of
the ketonic substrates as well as the hydrogen source. A
simple 1:1 mixture of 98% formic acid and triethylamine
can also be used instead of its azeotrope. Even commer-
cially available reagents and solvents could be used in this
reaction without special purification. This epoxide synthetic
process in either a one- or two-pot procedure is particularly
useful for the large-scale production of optically active
epoxides.
4.2.3. (S)-2-Chloro-1-(o-methoxyphenyl)ethanol (3e).
1
Oil; H NMR (400 MHz, CDCl3) d 3.60–3.90 (m, 2H),
3.85 (s, 3H), 5.05–515 (m, 1H), 6.85–7.45 (m, 4H), 13C
NMR (100 MHz, CDCl3) d 156.61, 129.60, 127.60, 121.50,
120.97, 110.83, 70.64, 55.72, 49.90; IR (neat, cm21), 3321,
20
Na
1692, 1603, 1534, 1235, 1158; [a] ¼þ51.2 (c 2.0, CHCl3);
MS(FAB), m/z 186 [M]þ. Anal. Calcd for C9H11ClO2: C,
57.92; H, 5.94. Found; C, 57.79; H, 5.94.
4.2.4. (S)-2-Chloro-1-(m-methoxyphenyl)ethanol (3f).
1
Oil; H NMR (400 MHz, CDCl3) d 3.58–3.73 (m, 2H),
3.99 (s, 3H), 4.82 (dd, 1H, J¼8.6, 3.6 Hz), 6.82–7.46 (m,
4H), 13C NMR (100 MHz, CDCl3) d 160.22, 142.10,

7416
T. Hamada et al. / Tetrahedron 60 (2004) 7411–7417
130.10, 118.77, 114.32, 112.03, 74.38, 55.67, 51.13; IR
(neat, cm21), 3329, 1603, 1586, 1258, 1150, 1040;
(eluent:hexane) to give styrene oxide 4a in 83% yield. The
ee value was determined by HPLC analysis.
[a] ¼þ41.5 (c 2.0, CHCl3); MS(FAB), m/z 186 [M]þ.
20
Na
Anal. Calcd for C9H11ClO2: C, 57.92; H, 5.94. Found; C,
57.91; H, 5.97.
Acknowledgements
4.2.5. (S)-2-Chloro-1-(m-trifluoromethoxyphenyl)etha-
1
nol (3j). Oil; H NMR (400 MHz, CDCl3) d 3.42–3.91
(m, 2H), 4.94 (dd, 1H, J¼8.4, 3.4 Hz), 7.46–7.66 (m, 4H),
13C NMR (100 MHz, CDCl3) d 141.33, 131.58, 131.26,
130.94, 129.86, 129.85, 129.52, 129.72, 129.67, 125.60,
125.56, 123.39, 123.35, 123.31, 123.27, 123.02, 73.78,
This work was partially supported by a Grant-in-aid from
the Ministry of Education, Science, Sports and Culture of
Japan (No. 14078209) and the 21st Century COE Program.
50.84 (observed complexity due to C–F splitting); IR
References and notes
20
(neat, cm21), 3334, 1328, 1164, 1119, 1071; [a] ¼þ42.8
Na
(c 1.0, CHCl3); MS(FAB), m/z 224 [M]þ. Anal. Calcd
for C9H8ClF3O: C, 48.13; H, 3.59. Found; C, 47.97; H,
3.48.
1. (a) Uehling, D. E.; Donaldson, K. H.; Deaton, D. N.; Hyman,
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2-ol (3n). Oil; H NMR (400 MHz, CDCl3), d 2.34 (brs,
1H), 3.55–3.61 (m, 1H), 3.68–3.73 (m, 1H), 4.46–4.54 (m,
1H), 5.96 (s, 2H), 6.00–6.06 (m, 1H), 6.63 (d, J¼15.9 Hz,
1H), 6.76 (d, J¼8.0 Hz, 1H), 6.83 (d, J¼8.0 Hz, 1H), 6.92
(s, 1H), 13C NMR (100 MHz, CDCl3) d 148.49, 148.08,
132.93, 130.90, 125.71, 121.96, 108.73, 106.19, 101.57,
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4.93–4.96 (m, 1H), 6.36–6.38 (m, 2H), 7.40–7.42 (m, 1H),
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