Practical synthesis of optically active styrene oxides via reductive transformation of 2-chloroacetophenones with chiral rhodium catalysts

Article abstract of DOI:10.1021/ol020213o

(equation presented) A practical method for the synthesis of optically active styrene oxides has been developed via formation of optically active 2-chloro-1-phenylethanols generated by reductive transformation of ring-substituted 2-chloroacetophenones. Th

Full text of DOI:10.1021/ol020213o

ORGANIC
LETTERS
2
002
Vol. 4, No. 24
373-4376
Practical Synthesis of Optically Active
Styrene Oxides via Reductive
Transformation of
4
2-Chloroacetophenones with Chiral
Rhodium Catalysts
†
†
,†
‡
Takayuki Hamada, Takayoshi Torii, Kunisuke Izawa,* Ryoji Noyori, and
Takao Ikariya*
,§
AminoScience Laboratories, Ajinomoto Co., Inc., 1-1, Suzuki-cho, Kawasaki-ku,
Kawasaki, 210-8681 Japan, Department of Chemistry and Research Center for
Materials Science, Nagoya UniVersity, Chikusa, Nagoya, 464-8602 Japan, and
Graduate School of Science and Engineering, Tokyo Institute of Technology and
CREST, Japan Science and Technology Cooperation (JST), 2-12-1 O-okayama,
Meguro-ku, Tokyo, 152-8552 Japan
tikariya@o.cc.titech.ac.jp
Received October 17, 2002
ABSTRACT
A practical method for the synthesis of optically active styrene oxides has been developed via formation of optically active 2-chloro-1-
phenylethanols generated by reductive transformation of ring-substituted 2-chloroacetophenones. The optically active alcohols with up to
98% ee are obtainable from the asymmetric reduction of acetophenones with an S/C ) 1000−5000 with a formic acid triethylamine mixture
containing a well-defined chiral Rh complex, Cp*RhCl[(R,R)-Tsdpen].
Optically active styrene oxides are useful building blocks
pounds of this important class, Jacobsen’s asymmetric
epoxidation of styrenes with (salen)Mn(III) complex2 and
kinetic resolution of racemic epoxides with cobalt-salen
complexes have been well-established as practical synthetic
procedures in addition to some microbial approaches.3
Besides these transformations, chiral styrene oxides are also
a,b
for the synthesis of various pharmaceuticals such as R1-,
1
â2-, and â3-adrenergic receptor agonists. To access com-
2c
*
Corresponding author.
Ajinomoto Co., Inc.
Nagoya University.
Tokyo Institute of Technology and CREST.
†
‡
§
(
1) (a) Uehling, D. E.; Donaldson, K. H.; Deaton, D. N.; Hyman, C. E.;
259-267. (d) AJ9677: Kato, S.; Harada, H.; Fujii, A.; Kotai, O. JP
11255743, 1999. (e) Ro40-2148: Alig, L.; Mueller, M. EP 386603, 1991.
(2) (a) Palucki, M.; Pospisil, P. J.; Zhang, W.; Jacobsen, E. N. J. Am.
Chem. Soc. 1994, 116, 9333-9334. (b) Palucki, M.; McCormick, G. J.;
Jacobsen, E. N. Tetrahedron Lett. 1995, 36, 5457-5460 (c) Brandes, B.
D.; Jacobsen; E. N. Tetrahedron: Asymmetry 1997, 8, 3927-3933.
(3) (a) Matsuyama, A.; Kobayashi, Y. EP 0611826A2, 1994. (b) Tanaka,
K.; Yasuda, M. Tetrahedron: Asymmetry 1998, 9, 3275-3282.
Sugg, E. E.; Barrett, D. G.; Hughes, R. G.; Reitter, B.; Adkison, K. K.;
Lancaster, M. E.; Lee, F.; Hart, H.; Paulik, M. A.; Sherman, B. W.; True,
T.; Cowman, C. J. Med. Chem. 2002, 45, 567-583. (b) CL316243: Bloom,
J. D.; Dutia, M. D.; Johnson, B. D.; Wissner, A.; Burns, M. G.; Largis, E.
E.; Dolan, J. A.; Claus, T. H. J. Med. Chem. 1992, 35, 3081-3084. (c)
SR58611A: Cecchi, R.; Croci, T.; Boijegrain, R.; Boveri, S.; Baroni, M.;
Boccardi, G.; Guimbard, J. P.; Guzzi, U. Eur. J. Med. Chem. 1994, 29,
1
0.1021/ol020213o CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/07/2002

Table 1. Asymmetric Transfer Hydrogenation of 2-Chloroacetophenone, 2a, Catalyzed by Chiral Catalysts 1a-c with a HCOOH/
N(C
Mixture or 2-Propanola
2
5 3
H )
catalyst
S/C
HCOOH/N(C2H5)3
solvent
time, h
yield, %b
ee, %b
configc
1
1
1
1
1
1
1
a
a
a
a
a
b
c
1000
5000
1000
100
1000
1000
1000
5:2
5:2
5:2
2-propanol
2-propanol
1:1
CH3CO2C2H5
CH3CO2C2H5
1
2
1
14
16
24
4
99
99
99
94
trace
36
99
97
96
89
98
S
S
S
S
2-propanol
2-propanol
CH3CO2C2H5
CH3CO2C2H5
91
71
S
S
5:2
a
Reaction of 2a in a 1.0 M solution containing the (R,R)-Rh catalyst (1a) was conducted with a mixture of HCOOH and N(C2H5)3 at 25 °C. b 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. 2-Formyloxyacetophenone was formed as the main byproduct.
readily accessible with conventional procedures from chiral
-aryl-2-haloethanols, which are prepared with asymmetric
2a with S/C ) 100 with 2-propanol as a hydrogen source in
the presence of chiral Rh complex 1a proceeded to give 3a
in 94% yield and with 98% ee after 14 h, 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. The reaction in a neat formic acid/triethylamine
mixture gave unsatisfactory results in terms of enantio-
selectivity. These results indicate that formic acid with
triethylamine is the best choice of hydrogen source in a
practical sense.
1
4
5
boron reduction or microbial reduction of 2-haloaceto-
phenones. However, none of the currently available chiral
catalyst systems can efficiently convert these 2-haloaceto-
phenones to chiral alcohols in a practical manner except for
some chiral Rh hydrogenation catalysts that give the product
6
in only moderate ees. We now describe a practical method
for the synthesis of optically active styrene oxides via
optically active 2-halo-1-phenylethanols. These optically
active alcohols are obtainable from the asymmetric reduction
of acetophenones with a formic acid triethylamine mixture
containing an isolable chiral Rh complex, Cp*RhCl[(R,R)-
Tsdpen] (1a), where Cp* ) pentamethylcyclopentadienyl and
TsDPEN ) (1R,2R)-N-p-toluenesulfonyl-1,2-diphenylethyl-
Scheme 1
7
enediamine), as a catalyst and can be converted to optically
active epoxides with excellent yields and ees in either a one-
or two-pot procedure.
A well-defined chiral Rh complex (R,R)-1a has proven to
effect highly efficient asymmetric transfer hydrogenation of
2
-chloroacetophenone (2a) with a 5:2 formic acid/triethyl-
amine azeotropic mixture (substrate/catalyst ratio (S/C) )
000, S/HCOOH ) 1/1) in a 0.8 M ethyl acetate solution at
1
room temperature to give (R)-2-chlorophenylethanol (3a)
8
with 97% ee and in >99% yield after 1 h (Scheme 1). Table
1
lists some examples. The reaction proceeded equally well
in various solvents, including acetonitrile, DMF, THF,
8
2 2
toluene, CH Cl , and acetone, but not in methanol or
t-BuOH in which a longer reaction time was required or a
lower ee was obtained. Although asymmetric reduction of
(
4) (a) For a review, see: Wallabaum, S.; Martens, J. Tetrahedron:
A preformed Cp*Rh complex, 1a, is one of the most
reactive catalysts for the asymmetric transfer hydrogenation
of 2-chloroacetophenones. The reaction of 2a even with an
S/C ) 5000 under conditions otherwise identical to those
described in Table 1 proceeded rapidly to give almost
quantitatively chiral alcohol 3a with 96% ee and an initial
Asymmetry 1992, 3, 1475-1504. (b) Hett, R.; Senanayake, C. H.; Wald, S.
A. Tetrahedron Lett. 1998, 39, 1705-1708. (c) Yaozhong, J.; Yong, Q.;
Aiqiao, M.; Zhitang, M. Tetrahedron: Asymmetry 1994, 5, 1211-1214.
(5) (a) Sawa, I.; Konishi, Y.; Maemoto, S.; Hasegawa, J. WO 9201804
A1, 1992. (b) Yasohara, Y.; Sawa, I.; Ueda, M.; Hasegawa, J.; Shimizu,
A.; Kataoka, M.; Wada M.; Kawabata, J. JP 11215995, 1999.
(
6) Devocelle, M.; Mortreux, A.; Agbossou, F.; Dormoy, J.-P. Tetrahe-
dron Lett. 1999, 40, 4551-4554.
7) Murata, K.; Ikariya, T.; Noyori, R. J. Org. Chem. 1999, 64, 2186-
187.
8) A mixture of 2-chloroacetophenone 2a (1 mmol) and catalyst 1a
0.001 mmol) in a 5:2 mixture of formic acid to triethylamine (0.2 mL)
-1
-1
(
turnover frequency (TOF) exceeding 2500 h (0.7 s ). The
reaction rate and enantioselectivity were far superior to those
2
(
9
obtained from the catalyst generated in situ. In contrast to
(
and ethyl acetate (1.0 mL) was stirred at 25 °C for 1 h. The mixture was
passed though a SiO2 column chromatography (eluent: 20% CH3CO2C2H5
in hexane) to give almost quantitatively 2-chlorophenylethanol 3a. The ee
value was determined by HPLC analysis. See Supporting Information.
the Rh system, a chiral Ru complex, RuCl[(R,R)-Tsdpen)]-
1
0
(p-cymene) (1b), which has a structure isoelectronic with
1a and effects asymmetric transfer hydrogenation of simple
4374
Org. Lett., Vol. 4, No. 24, 2002

more favorable substrates for transfer hydrogenation than the
1
2
parent acetophenone due to thermodynamic reasons. In fact,
the reduction of the simple acetophenone with 1a (S/C )
1000) under the same conditions gave 1-phenylethanol in
Table 2. Asymmetric Transfer Hydrogenation of the
Ring-Substituted 2-Chloroacetophenones, RC COCH
2b-m) Catalyzed by Chiral Rh Complex 1a with a HCOOH/
N(C
Mixturea
H
6 4
2
Cl,
(
10a
2
H )
5 3
only 6% with 91% ee after 24 h. Noticeably, the rate and
enantioselectivity are not seriously affected by the electronic
properties of the ring substituent (Table 2). The enantiomeric
excesses of the product alcohols were generally very high
product alcohol
R
yield, %b
ee, %
configc
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
H
99
81
93
90
90
90
94
93
80
80
92
93
97
88
95
92
95
95
94
95
96
97
96
98
S
S
S
S
S
S
S
S
S
S
S
S
o-Cl
m-Cl
p-Cl
(up to 97% ee). The electron-donating methoxy group on
the phenyl group (2e-g) exerted no significant effect on
either reactivity or enantioselectivity. An o-chloro group in
acetophenone slightly decreases the enantioselectivity pos-
sibly due to steric reasons.
o-CH3O
m-CH3O
p-CH3O
m-OH
m-CF3
p-MsNH
m-CH3
2-Chloro-1-phenylethanol and the ring-substituted 2-chloro-
1
-phenylethanols (3a, 3c, 3f) were readily convertible with
j
k
l
conventional procedures to optically active styrene oxides
(4a, 4c, 4f, respectively) with excellent ees as shown in
Scheme 2. Treatment of (R)-3a (96% ee) with 4 M aqueous
3′,4′-OCH2O
a
Reaction of 2a in a 1.0 M solution containing the (R,R)-Rh catalyst
(
1a) was conducted with a mixture of HCOOH and N(C2H5)3 at 25 °C.
Isolated yields. The ee values were determined by HPLC analysis using
b
c
a Daicel Chiralcel OB or OB-H column. Configuration was determined
from the sign of rotation of the isolated product. 2-Formyloxyacetophenone
was formed as the main byproduct.
Scheme 2
acetophenones, exhibited no remarkable activity for the
reaction of 2a with S/C ) 1000, giving 2-formyloxyaceto-
phenone 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:HCOOH ) 1:1) in
ethyl acetate containing 0.1 mol % chiral Ru catalyst caused
an increase in the desired product 3a to 36% yield and 91%
NaOH in 2-propanol afforded (R)-styrene oxide 4a (97% ee)
in an 80% isolated yield without loss of enantiomeric purity.
In particular, m-chlorostyrene oxide (R)-4b, which is obtained
from the reduction product (R)-3b (92% yield and 95% ee),
is a key intermediate for the preparation of several â-3-
adrenergic receptor agonist compounds. This reductive
transformation of 2-chloroacetophenones to the optically
active epoxides is more appealing when the one-pot synthetic
procedure was applied. As shown in Scheme 3, sequential
1
1
ee (Table 1). Despite the structural similarity between the
6
Cp*Rh(III) and the (η -arene)Ru(II) complexes, the remark-
able difference in the reactivity toward 2-chloroaceto-
phenones may be attributed to the electronic properties of
the central metals. An analogous Ir complex, Cp*IrCl[(R,R)-
7
Tsdpen] (1c), exhibited reasonably high reactivity but poor
enantioselectivity.
A variety of ring-substituted 2-chloroacetophenones (2b-
l) can be transformed with 1a to the corresponding optically
active secondary alcohols with high enantiomeric purities
as shown in Table 2. In general, 2-chloroacetophenones are
Scheme 3
(
9) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045-
2
061. Cross, D. J.; Kenny, J. A.; Houson, I.; Campbell, L.; Walsgrove, T.;
Wills, M. Tetrahedron: Asymmetry 2001, 12, 1801-1806. The reduction
of 2a with a binary Rh catalyst from 0.25 mol % [Cp*RhCl2]2 and 0.5 mol
%
(R,R)-TsDPEN gave an 85% yield and 75% ee.
10) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R.
(
J. Am. Chem. Soc. 1995, 117, 7562-7563. (b) Fujii, A.; Hashiguchi, S.;
Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521-
2
522. (c) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 285-288. (d) Hashiguchi, S.; Fujii,
A.; Haack, K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 288-290. (e) Matsumura, K.; Hashiguchi, S.;
Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738-8739. (f) Noyori,
R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97-102.
asymmetric reduction of 2a or 2b with a mixture of formic
acid and triethylamine in 2-propanol containing catalyst 1a
(
11) (a) Bayston, D. J.; Travers, C. B.; Polywka, M. E. C. Tetrahedron:
(S/C ) 1000) for 2 h and the treatment of its reaction mixture
Asymmetry 1998, 9, 2015-2018. The asymmetric transfer hydrogenation
of 2-chloroacetophenone catalyzed by polymer supported Ru-(S,S)-
TsDPEN with formic acid as a hydrogen source in DMF proceeded to give
with 2 M NaOH aqueous solution at 0 °C gave optically
1
-aryl-2-chloro ethanol in 95% ee and with a S/C of 100. (b) Kenny, J. A.;
Palmer, M. J.; Smith, A. R. C.; Walsgrove, T.; Wills, M. Synlett 1999, 10,
615-1617.
(12) Adkins, H.; Elofson, R. M.; Rossow, A. G.; Robinson, C. C. J.
Am. Chem. Soc. 1949, 71, 3622-3829.
1
Org. Lett., Vol. 4, No. 24, 2002
4375

active styrene oxide 4a or 4b, respectively, in 80-90%
isolated yield with 96-98% ee in a single reactor.
saturated nature of the diamine-based Cp*Rh(III) hydride
1
3
7,10,14
complexes.
The neighboring chloro group at the R
This asymmetric reduction of 2-chloroacetophenone with
a chiral Rh catalyst is characterized by a rapid and carbonyl
group-selective transformation because of the coordinatively
position of the carbonyl group is possibly free from the metal
center, leading to excellent reactivity and enantioselectivity.
This epoxide synthetic process in either a one- or two-pot
procedure is particularly useful for the large-scale production
(13) One-Pot Procedure for Synthesis of 4a. A mixture of 2-chloro-
13
of optically active styrene oxides.
acetophenone 2a (5 mmol) and catalyst 1a (0.005 mmol) in a 5:2 mixture
of formic acid to triethylamine (1.0 mL) and 2-propanol (6.0 mL) was stirred
at 25 °C for 2 h. The reaction mixture was then treated with 2 M NaOH
aqueous solution (10.0 mL) at 0 °C for 1 h. After the usual workup
procedure, (R)-styrene oxide 4a with 96.8% ee was obtained in 83% yield.
The ee value was determined by HPLC analysis. In a large-scale experiment.
the reaction of 4.73 g of 2a with 1a (S/C ) 5000) gave the corresponding
optically active styrene oxide with 94% ee in a 93% total isolated yield
Acknowledgment. This work was financially supported
by a grant-in-aid from the Ministry of Education, Science,
Sports and Culture of Japan (Nos. 12305057, 14078209).
Supporting Information Available: Experimental pro-
cedure and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
3.54 g). Even commercially available reagents and solvents without special
purification could be used in this reaction.
14) (a) Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.;
(
Ikariya, T. Org. Lett. 1999, 1, 1119-1121. (b) Okano, K.; Murata, K.;
Ikariya, T. Tetrahedron Lett. 2000, 41, 9277-9280. (c) Koike, T.; Murata,
K.; Ikariya, T. Org. Lett. 2000, 2, 3833-3836. (d) Watanabe, M.; Murata,
K.; Ikariya, T., J. Org. Chem. 2002, 67, 1712-1715.
OL020213O
4376
Org. Lett., Vol. 4, No. 24, 2002