Oxidative kinetic resolution of racemic alcohols catalyzed by chiral ferrocenyloxazolinylphosphine - Ruthenium complexes

Article abstract of DOI:10.1021/jo0345087

Oxidative kinetic resolution of racemic secondary alcohols by using acetone as a hydrogen acceptor in the presence of a catalytic amount of [RuCl₂(PPh₃)(ferrocenyloxazolinylphosphine)] (2) proceeds effectively to recover the corresponding alcohols in high yields with an excellent enantioselectivity. When 1-indanol is employed as a racemic alcohol, the oxidation proceeds quite smoothly even in the presence of 0.0025 mol % of the catalyst 2 to give an optically active 1-indanol in good yield with high enantioselectivity (up to 94% ee), where turnover frequency (TOF) exceeds 80 000 h^-1. From a practical viewpoint, the kinetic resolution is investigated in a large scale, optically pure (S)-1-indanol (75 g, 56% yield, > 99% ee) being obtained from racemic 1-indanol (134 g) by employing this kinetic resolution method twice.

Full text of DOI:10.1021/jo0345087

Oxid a tive Kin etic Resolu tion of Ra cem ic Alcoh ols Ca ta lyzed by
Ch ir a l F er r ocen yloxa zolin ylp h osp h in e-Ru th en iu m Com p lexes
Yoshiaki Nishibayashi, Akiyoshi Yamauchi, Gen Onodera, and Sakae Uemura*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University,
Yoshida, Sakyo-ku, Kyoto 606-8501, J apan
uemura@scl.kyoto-u.ac.jp
Received April 21, 2003
Oxidative kinetic resolution of racemic secondary alcohols by using acetone as a hydrogen acceptor
in the presence of a catalytic amount of [RuCl2(PPh3)(ferrocenyloxazolinylphosphine)] (2) proceeds
effectively to recover the corresponding alcohols in high yields with an excellent enantioselectivity.
When 1-indanol is employed as a racemic alcohol, the oxidation proceeds quite smoothly even in
the presence of 0.0025 mol % of the catalyst 2 to give an optically active 1-indanol in good yield
with high enantioselectivity (up to 94% ee), where turnover frequency (TOF) exceeds 80 000 h-1
.
From a practical viewpoint, the kinetic resolution is investigated in a large scale, optically pure
(S)-1-indanol (75 g, 56% yield, >99% ee) being obtained from racemic 1-indanol (134 g) by employing
this kinetic resolution method twice.
CHART 1
In tr od u ction
The oxidation of alcohols is one of the most common
and well-studied reactions in organic chemistry.1 Highly
efficient and selective oxidative methods of alcohols to
the corresponding ketones, aldehydes, and carboxylic
acids have been developed.2 We have also found the se-
lective palladium-catalyzed oxidation of alcohols with
molecular oxygen as an oxidant.3 Application of these
oxidation methods to kinetic resolution of racemic alco-
hols might give optically active alcohols together with
carbonyl compounds. However, there are only a few suc-
cessful examples of catalytic enantioselective methods for
this purpose,4 in sharp contrast to so-far well-known ex-
cellent catalytic enantioselective methods for epoxida-
tion,5 dihydroxylation,6 and aziridination,7 all involving
oxidation processes.
to FOXAP) by us in 1995,8,9 we have developed many
enantioselective reactions catalyzed by various transition
(4) (a) Hashiguchi, S.; Fujii, A.; Haack, K.-J .; Matsumura, K.;
Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 288. (b)
Masutani, K.; Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron Lett. 2000,
41, 5119. (c) J ensen, D. R.; Pugsley, J . S.; Sigman, M. S. J . Am. Chem.
Soc. 2001, 123, 7475. (d) Ferreira, E. M.; Stoltz, B. M. J . Am. Chem.
Soc. 2001, 123, 7725. (e) Sun, W.; Wang, H.; Xia, W. C.; Li, J .; Zhao,
P. Angew. Chem., Int. Ed. 2003, 42, 1042. (f) Rychnovsky, S. D.;
McLernon, T. L.; Rajapakse, H. J . Org. Chem. 1996, 61, 1194.
(5) For examples, see: (a) Katsuki, T.; Sharpless, K. B. J . Am. Chem.
Soc. 1980, 102, 5974. (b) Hanson, R. M.; Sharpless, K. B. J . Org. Chem.
1986, 51, 1922. (c) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(6) For examples, see: (a) Hentges, S. G.; Sharpless, K. B. J . Am.
Chem. Soc. 1980, 102, 4263. (b) J acobsen, E. N.; Marko´, I.; Mungall,
W. S.; Schro¨der, G.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110,
1968.
Since the first preparation of optically active ferrocen-
yloxazolinylphosphines (Chart 1; 1; we abbreviate these
* Corresponding author.
(1) For examples, see: (a) Sheldon, R. A.; Kochi, J . K. Metal-
Catalyzed Oxidations of Organic Compounds; Academic Press: New
York, 1984. (b) Hudlicky, M. Oxidations in Organic Chemistry; ACS
Monograph Series 186; American Chemical Society: Washington, DC,
1990.
(2) Selected examples, see: (a) Marko´, I. E.; Giles, P. R.; Tsukazaki,
M.; Brown, S. M.; Urch, C. J . Science 1996, 274, 2044. (b) Sato, K.;
Aoki, M.; Takagi, J . Noyori, R. J . Am. Chem. Soc. 1997, 119, 12386.
(c) Marko´, I. E.; Giles, P. R.; Tsukazaki, M.; Chelle-Regnaut, I.; Urch,
C. J .; Brown, S. M. J . Am. Chem. Soc. 1997, 119, 12661. (d) Hanyu,
A.; Takezawa, E.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 1998, 39,
5557. (e) Brink, G.-J .; Arends, I. W. C. E.; Sheldon, R. A. Science 2000,
287, 1636. (f) Dijksman, A.; Marino-Gonza´lez, A.; Payeras, A. M.;
Arends, I. W. C. E.; Sheldon, R. A. J . Am. Chem. Soc. 2001, 123, 6826.
(g) Son, Y.-C.; Makwana, V. D.; Howell, A. R.; Suib, S. L. Angew. Chem.,
Int. Ed. 2001, 40, 4280. (h) Mori, K.; Yamaguchi, K.; Hara, T.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. J . Am. Chem. Soc. 2002, 124,
11572. (i) Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2002,
41, 4538.
(3) (a) Nishimura, T,; Onoue, T.; Ohe, K.; Uemura, S. J . Org. Chem.
1999, 64, 6750. (b) Nishimura, T.; Maeda, Y.; Kakiuchi, N.; Uemura,
S. J . Chem. Soc., Perkin Trans. 1 2000, 4301. (c) Kakiuchi, N.;
Nishimura, T.; Inoue, M.; Uemura, S. Bull. Chem. Soc. J pn. 2001, 74,
165. (d) Kakiuchi, N.; Maeda, Y.; Nishimura, T.; Uemura, S. J . Org.
Chem. 2001, 66, 6620.
(7) For examples, see: (a) Evans, D. A.; Woerpel, K. A.; Hinman,
M. M.; Faul, M. M. J . Am. Chem. Soc. 1991, 113, 726. (b) Li, Z.; Conser,
K. R.; J acobsen, E. N. J . Am. Chem. Soc. 1993, 115, 5326. (c) Nishioka,
H. Katsuki, T. Tetrahedron Lett. 1996, 37, 9245.
(8) (a) Nishibayashi, Y.; Uemura, S. Synlett 1995, 79. (b) Nishiba-
yashi, Y.; Segawa, K.; Arikawa, Y.; Ohe, K.; Hidai, M.; Uemura, S. J .
Organomet. Chem. 1997, 545-546, 381 and references therein. (c)
Borman, S. Chem. Eng. News 1996, J uly 22, 38. (d) A ferrocenylox-
azolinylphosphine (1a ) is commercially available from Wako Pure
Chemical Industries (J apan) as ip-FOXAP (ferrocenyloxazolinylphos-
phine).
(9) The first preparation of optically active ferrocenyloxazolinylphos-
phines was independently reported by our group8a and Richards et al.9a
(a) Richards, C. J .; Damalidis, T.; Hibbs, D. E.; Hurshouse, M. B.
Synlett 1995, 74. (b) Richards, C. J .; Mulvaney, A. W. Tetrahedron:
Asymmetry 1996, 7, 1419. Independently, Sammakia et al. reported
the diastereoselective lithiation of oxazolinylferrocenes.9c-e (c) Sam-
makia, T.; Latham, H. A.; Schaad, D. R. J . Org. Chem. 1995, 60, 10.
(d) Sammakia, T.; Latham, H. A. J . Org. Chem. 1995, 60, 6002. (e)
Sammakia, T.; Latham, H. A. J . Org. Chem. 1996, 61, 1629.
10.1021/jo0345087 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/28/2003
J . Org. Chem. 2003, 68, 5875-5880
5875

Nishibayashi et al.
SCHEME 1
metal complexes having FOXAP as chiral ligands. Rh-
and Ir-catalyzed asymmetric hydrosilylation of prochiral
ketones has been found to afford the corresponding chiral
alcohols after acid hydrolysis.10 It is noteworthy that
the chiral alcohols of the opposite configuration were
produced from the same ketones by changing Rh to Ir.10
The chiral FOXAP has been found to be effective ligands
for the Ir-catalyzed asymmetric hydrosilylation of prochiral
imines to give secondary amines with high enantioselec-
tivities.11 In addition, we have prepared the ruthenium
complexes having FOXAP and investigated the asym-
metric Ru-catalyzed hydrosilylation of prochiral ketones,
imines, and ketoximes to give the corresponding chiral
secondary alcohols, secondary amines, and primary
amines with high enantioselectivities, respectively.12,13
Optically active FOXAP has been found to work ef-
fectively as chiral ligands in Ni-catalyzed cross-coupling
reactions of allylic compounds with arylboronic acids and
Grignard reagents, which are known to behave as hard
nucleophiles, to give the expected coupling products in
good yields with a high enantioselectivity.14,15 More
recently, we disclosed the kinetic resolution of racemic
alcohols via Pd-catalyzed enantioselective acylation using
CO and organobismuth compound, although the enanti-
oselectivities of the produced esters were moderate.16
In our continuing study, we have found the enantiose-
lective redox reaction of ketones and alcohols catalyzed
by [RuCl2(PPh3)(FOXAP)] (Chart 1; 2).17,18 In the presence
of a catalytic amount of 2, transfer hydrogenation of
prochiral ketones proceeded effectively to give the cor-
responding chiral alcohols with an extremely high enan-
tioselectivity (up to 99.9% ee), while asymmetric oxida-
tion of racemic secondary alcohols occurred to lead to the
kinetic resolution of the alcohols with similar high
enantioselectivity.17a It is noted that the chiral alcohols
of the opposite configuration were obtained by using this
redox reaction in the presence of 2a . For example, (R)-
1-phenylethanol (3a ) was produced in the transfer hy-
oxidation system, acetone worked as an oxidant of
alcohols in the presence of 2. This preliminary result
prompted us to investigate this oxidative kinetic resolu-
tion in more detail, because acetone is considered to be
one of the most appreciable oxidant from economical and
environmental viewpoints. In this paper, we will describe
the detailed results of the 2-catalyzed oxidative kinetic
resolution of racemic secondary alcohols in acetone.
Resu lts a n d Discu ssion
Treatment of racemic 1-phenylethanol (3a ) (1 mmol)
in the presence of a catalytic amount of 2a (0.25 mol %)
i
and PrONa (1.00 mol %) in anhydrous acetone (10 mL)
at 50 °C for 30 min afforded a mixture of 1-phenylethanol
(53% yield with 93% ee) and acetophenone (47% yield)
(Scheme 1; Table 1, run 1). The absolute configuration
of the recovered 1-phenylethanol is S, and the turnover
frequency (TOF) was 400 h-1. In the absence of iPrONa,
no reaction occurred at all. The reaction proceeded even
at room temperature, but the efficiency of the kinetic
resolution was lower than that of the reaction at 50 °C.
The ratio of substrate and catalyst (S/C) could be
increased up to 1200, and thus, the reaction using 3a (3
mmol) at 50 °C for 30 min gave chiral 3a (53% yield with
97% ee) and acetophenone (47% yield) (Table 1, run 4).
The TOF in this reaction was 1200 h-1. However, when
S/C ratio was increased to 1600, only moderate enantio-
selectivity of the recovered 3a was obtained (Table 1, run
5), indicating that the S/C is one of the important factors
to achieve the high efficiency of the kinetic resolution.
In the oxidation of 3a at 50 °C for 150 min under the
same reaction conditions using 2b as a catalyst, the
unreacted alcohol was obtained in 48% yield with 95%
ee (S) together with acetophenone in 52% yield (Table 1,
run 2). The oxidation using 2b proceeded more slowly
than that using 2a .
Asymmetric oxidation of a variety of secondary alcohols
proceeded with high enantioselectivity. Typical results
are also shown in Table 1. Reactions of racemic benzylic
alcohols such as 1-phenyl-1-propanol (3b ), 1-phenyl-1-
butanol (3c), 1-phenyl-1-pentanol (3d ), 1-phenyl-1-hex-
anol (3e), and 1-phenyl-1-heptanol (3f) were investigated
at 50 °C for 30 min (Table 1, runs 6-11). In all cases,
the corresponding unreacted alcohols were recovered in
high yields with an excellent enantioselectivity. Interest-
ingly, the reaction of 2-methyl-1-phenyl-1-propanol (3g)
did not proceed at all (Table 1, run 12). On the other
hand, the reaction of cyclopropylphenylmethanol (3h )
proceeded smoothly, but moderate enantioselectivity of
the recovered alcohol was observed (Table 1, run 13).
Next, reactions of phenylethanol derivatives were
investigated under the same conditions as above (S/C )
1000). Typical results are shown in Table 2. Introduction
of a p-halogeno or p-methyl substituent to the aromatic
ring of phenylethanol slightly decreased the reactivity
and selectivity (Table 2, runs 1-4). In contrast, introduc-
tion of a p-methoxy substituent to the aromatic ring of
i
drogenation of acetophenone with PrOH. On the other
hand, (S)-1-phenylethanol (3a ) was recovered in kinetic
resolution of racemic 3a with acetone. In the latter
(10) (a) Nishibayashi, Y.; Segawa, K.; Ohe, K.; Uemura, S. Organo-
metallics 1995, 14, 5486. (b) Nishibayashi, Y.; Segawa, K.; Takada,
H.; Ohe, K.; Uemura, S. Chem. Commun. 1996, 847.
(11) Takei, I.; Nishibayashi, Y.; Arikawa, Y.; Uemura, S.; Hidai, M.
Organometallics 1999, 18, 2271.
(12) Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai, M. Organome-
tallics 1998, 17, 3420.
(13) Takei, I.; Nishibayashi, Y.; Ishii, Y.; Mizobe, Y.; Uemura, S.;
Hidai, M. Chem. Commun. 2001, 2360.
(14) Chung, K.-G.; Miyake, Y.; Uemura, S. J . Chem. Soc., Perkin
Trans. 1 2000, 15.
(15) Chung, K.-G.; Miyake, Y.; Uemura, S. J . Chem. Soc., Perkin
Trans. 1 2000, 2725.
(16) (a) Miyake, Y.; Iwata, T.; Chung, K.-G.; Nishibayashi, Y.;
Uemura, S. Chem. Commun. 2001, 2584. (b) Iwata, T.; Miyake, Y.;
Nishibayashi, Y.; Uemura, S. J . Chem. Soc., Perkin Trans. 1 2002,
1548.
(17) (a) Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai, M. Organo-
metallics 1999, 18, 2291. (b) Arikawa, Y.; Ueoka, M.; Matoba, K.;
Nishibayashi, Y.; Hidai, M.; Uemura, S. J . Organomet. Chem. 1999,
572, 163.
(18) Sammakia et al. previously reported the asymmetric transfer
hydrogenation of alkyl aryl ketones using the catalyst prepared in situ
from RuCl2(PPh3)3 and an oxazolinylferrocenylphosphine at 80 °C for
1 h. The NMR study of the reaction of RuCl2(PPh3)3 and [2-(4′-
phenyloxazolin-2′-yl)ferrocenyl]diphenylphosphine showed that the
produced catalyst consisted of two diastereomers in an approximately
5:1 ratio. For example, acetophenone was reduced by using this catalyst
with up to 94% ee: Sammakia, T.; Stangeland, E. L. J . Org. Chem.
1997, 62, 6104-6105.
5876 J . Org. Chem., Vol. 68, No. 15, 2003

Oxidative Kinetic Resolution of Racemic Alcohols
TABLE 1. Kin etic Resolu tion of Ra cem ic sec-Alcoh ols
TABLE 2. Kin etic Resolu tion of Ra cem ic P h en yleth a n ol
Der iva tives Ca ta lyzed by 2a a
Ca ta lyzed by 2a
a
All reactions of racemic alcohol (3; 2.50 mmol) were carried
i
out in the presence of 2a (0.0025 mmol) and PrONa (0.010 mmol)
b
in acetone (10 mL) at 50 °C (S/C ) 1000). Determined by GLC.
c Determined by GLC with chiral capillary column. The ratio was
d
estimated based on the final conversion and enantiomeric purity
of the recovered alcohol. e Isolated yield. f Determined by HPLC
g
h
with chiral capillary column. At room temperature. S/C ) 200.
CHART 2
smoothly and the corresponding unreacted 1-indanol
derivatives were recovered in good yields with high
enantioselectivity (Table 3, runs 8 and 9). However,
oxidative kinetic resolution of other cyclic alcohols such
as 1,2,3,4-tetrahydro-1-naphthol (3s) and 6,7,8,9-tetrahy-
dro-5H-benzocyclohepten-5-ol (3t) did not proceed so
selectively under the same reaction conditions (Chart 2).
Recently, Noyori and co-workers developed clean and
effective oxidation method of a variety of alcohols with
hydrogen peroxide in the presence of tungsten catalyst.2b
The TON value, defined as mols of product per mol of
catalyst, approached 179 000 (1-phenylethanol). More
recently, Kaneda and co-workers reported a highly ef-
ficient palladium-catalyzed aerobic oxidation of alcohols,
where TON value approached 236 000 (1-phenylethanol).2h
Both oxidation processes are quite efficient and syntheti-
cally useful methods to obtain the corresponding carbonyl
compounds. On the other hand, the highly efficient
oxidative kinetic resolution of racemic alcohols is strictly
limited to the Noyori’s system. In this system, the
enantioselective ruthenium-catalyzed kinetic resolution
of racemic or meso alcohols has been achieved, where S/C
a
All reactions of racemic alcohol 3 were carried out in the
i
presence of 2a (0.0025 mmol) and PrONa (0.010 mmol) in acetone
(10 mL) at 50 °C. b Determined by GLC. c Determined by GLC with
d
chiral capillary column. The ratio was estimated based on the
final conversion and enantiomeric purity of the recovered alcohol.
e Complex 2b was used in place of 2a . f Determined by HPLC
chiral capillary column.
phenylethanol greatly increased the reactivity without
affecting a high enantioselectivity (Table 2, run 5). In this
case, the reaction was complete within 5 min. The
oxidative kinetic resolution of 1-(1-naphthyl)-1-ethanol
(3o) did not proceed smoothly in contrast to that of 1-(2-
naphthyl)-1-ethanol (3n ) (Table 2, runs 6 and 7).
Interestingly, oxidative kinetic resolution of 1-indanol
proceeded quite rapidly. Typical results are shown in
Table 3. In sharp contrast to the reaction of phenylethan-
ol derivatives, 1-indanol (3p ) was oxidized to 1-indanone
even at 0 °C within 10 min (Table 3, run 1). The absolute
configuration of the recovered 1-indanol is S. The result
of this high-speed oxidation prompted us to investigate
the reactivity of 1-indanol in detail. When the S/C is
40 000 at 50 °C for 15 min, 3p was recovered in 42% yield
with 94% ee (S) (Table 3, run 6). The TOF of this reaction
exceeded 80 000 h-1. Even at S/C ) 80,000, 3p was
oxidized in the presence of 2a at 50 °C for 40 min, and
3p was recovered in 51% yield with 84% ee (Table 3, run
7). Reactions of indanol derivatives such as 6-methoxy-
1-indanol (3q) and 6-methyl-1-indanol (3r ) proceeded
is up to 500 and TOF is up to 100 h-1 4a
It is noteworthy
.
that our method presented here is the so-far known most
efficient oxidative kinetic resolution of racemic alcohols,
where S/C is up to 80 000.
To obtain the information on the reaction mechanism,
we examined the reactivities of (S)- and (R)-3p in this
oxidation process. At first, we compared the initial rates
of oxidation and racemization of (S)- and (R)-3p . Time
J . Org. Chem, Vol. 68, No. 15, 2003 5877

Nishibayashi et al.
TABLE 3. Kin etic Resolu tion of Ra cem ic 1-In d a n ol (3p ) Ca ta lyzed by 2a a
unreacted 1-indanol
1-indanol
(mmol)
2a
(mmol)
iPrONa
(mmol)
acetone
(mL)
T
(°C)
time
(min)
recoveryb
(%)
eec
(%)/(S)
d
run
S/C
200
1000
5000
10 000
20 000
40 000
80 000
10 000
10 000
kf/ks
1
2
3
4
5
6
1
5
25
25
50
100
200
25
0.005
0.005
0.005
0.0025
0.0025
0.0025
0.0025
0.0025
0.0025
0.02
0.02
0.02
0.01
0.01
0.01
0.01
0.01
0.01
10
50
50
25
25
25
25
25
25
0
rt
rt
30
50
50
50
30
30
10
40
155
30
7
15
40
12
12
45
45
50
33
39
42
51
30
34
97
97
98
99
94
94
84
94
99
36
36
>200
14
13
18
28
7
15
7
8e
9f
25
a
All reactions of racemic 1-indanol (3p ) were carried out in the presence of 2a and iPrONa in acetone. b Determined by GLC. c Determined
d
by GLC with chiral capillary column. The ratio was estimated based on the final conversion and enantiomeric purity of the recovered
alcohol. e 6-Methoxy-1-indanol (3q) was used in place of 3p . f 6-Methyl-1-indanol (3r ) was used in place of 3p .
F IGURE 2. Time profile of the racemization of (R)- and (S)-
1-indanol (3p ) (0.50 mmol) in the presence of 2a (0.5 mol %)
and PrONa (2.0 mol %) in acetone (25 mL) at 0 °C.
F IGURE 1. Time profile of the oxidation of (R)- and (S)-1-
indanol (3p ) (0.50 mmol) in the presence of 2a (0.5 mol %)
and PrONa (2.0 mol %) in acetone (25 mL) at 0 °C.
i
i
profile of the oxidation of indanols in the presence of 2a
and PrONa is shown in Figure 1. The result indicated
i
Next, the role of PrONa to the oxidation was investi-
i
gated. Ba¨ckvall and co-workers recently reported that the
role of base in RuCl2(PPh3)3-catalyzed hydrogen transfer
is to generate a highly reactive catalyst RuH2(PPh3)3 from
the dichloride via two consecutive alkoxide displacement-
â-elimination sequences.20 A similar displacement of
chloride to hydride should occur in our asymmetric oxi-
dation (Scheme 2). In addition, the use of an excess
amount of iPrONa increased the rate of the oxidation as
shown in Figure 3. The oxidation in the presence of a
that the oxidation of (R)-3p is ca. 15 times faster than
that of (S)-3p . The difference of the reaction rate was
consistent with the selectivity factor (kf/ks) shown in
Table 3, which was estimated from the recovered yield
and enantiomeric excess of the recovered 1-indanol.19
Time profile of the racemization of optically active 3p in
i
the presence of 2a and PrONa is shown in Figure 2. No
racemization of (S)-3p occurred, while (R)-3p slowly
racemized. These results indicate that dynamic kinetic
resolution of racemic 3p is possible by using this oxida-
tion system. Namely, optically active (S)-3p might be
obtained in >50% yield from racemic 3p .
i
large excess amount of PrONa (8 equiv to the catalyst)
proceeds ca. 4 times faster than that in the presence of
a slight excess amount of iPrONa (4 equiv to the catalyst),
and yet the use of an excess amount of iPrONa does not
influence the enantioselectivity of the recovered alcohol.
This result indicates that an excess amount of PrONa
such as 4 equiv to the catalyst is essential to achieve the
highly efficient oxidation of alcohols.
(19) The efficiency of the kinetic resolution is characterized by kf/
ks, the selectivity factor ) (rate of fast-reacting enantiomer)/(rate of
slow-reacting enantiomer); For a review, see: Noyori, R.; Tokunaga,
M.; Kitamura, M. Bull. Chem. Soc. J pn. 1995, 68, 36 and references
therein. When the recovered yields of alcohols are estimated to be a
few % high, the selectivity factors are also estimated to be quite high.
Thus, the simple calculation for run 3 in Table 3 affords the kf/ks value
of 458. To avoid misunderstanding, such extremely high value was
expressed as >200.
i
(20) Aranyos, A.; Csjernyik, G.; Szabo´, K. J .; Ba¨ckvall, J .-E. Chem.
Commun. 1999, 351.
5878 J . Org. Chem., Vol. 68, No. 15, 2003

Oxidative Kinetic Resolution of Racemic Alcohols
reactive alkoxides, which are prepared from the depro-
i
tonation of alcohols with PrONa, makes this replacement
step more facile. Finally, the â-hydride elimination from
C leads to the formation of the starting Ru-dihydride
complex A and a ketone. Thus, unreacted (S)-alcohol is
recovered with a high enantioselectivity. Substantial
isotope effect (kH/kD ) 4) was observed when the oxidation
of racemic 1-indanol and that of 1-indan-1-d1-ol was
i
carried out in the presence of 2 and PrONa at 0 °C. This
result clearly indicates that the C-H bond breaking at
the benzylic position of the alcohol (â-hydride elimination
step) is involved in the rate-determining step.
To account for the high efficiency of the oxidation of
(R)-1-indanol 3p , we propose a transition-state model
shown in Scheme 4. Thus, the formation of 1-indanone,
which has a rigidly conjugated system in the same plane
derived from carbon-oxygen double bond in carbonyl
moiety and carbon-carbon double bond in the benzene
ring, is considered to be a driving force to promote a facile
â-hydride elimination in the Ru-hydride-1-indanoxide
complex (D). This is in sharp contrast to that in the Ru-
hydride-1-phenylethoxide complex (E) to form acetophen-
one, which does not have such a rigidly conjugated
system as in the case of 1-indanone. On the other hand,
the kinetic resolution of other cyclic alcohols such as
1,2,3,4-tetrahydro-1-naphthol (3s) and 6,7,8,9-tetrahydro-
5H-benzocyclohepten-5-ol (3t) did not proceed so selec-
tively as shown in Chart 2. In these cases, the steric
repulsion between cyclic moieties on 3s and 3t and phenyl
group on the ligand in the Ru-hydride complexes (F and
G) might prevent the formation of a favorable transition
state which gives a high selectivity.
F IGURE 3. Time profile of the oxidation of 1-indanol (3p )
(0.50 mmol) in the presence of 2a (0.5 mol %) and PrONa in
acetone (25 mL) at 0 °C.
i
SCHEME 2
SCHEME 3
Finally, oxidative kinetic resolution of racemic 1-in-
danol (3p ) was investigated in a large scale from a
practical viewpoint (Scheme 5). When a mixture of 3p
i
(134 g, 1.00 mol), 2a (22.8 mg, 0.025 mmol), and PrONa
(8.2 mg, 0.10 mmol) in acetone (250 mL) was heated at
50 °C for 15 min, optically active (S)-1-indanol 3p (52 g,
0.39 mol) was obtained with >99% ee after recrystalli-
zation (Scheme 5). Quantitative reduction of the recov-
ered ketone provides an opportunity for the preparation
of optically active alcohol in >50% overall yield from a
racemic alcohol by employing sequentially this oxidative
kinetic resolution method. Actually, the second oxidative
kinetic resolution of the recovered 3p gave the optically
active (S)-1-indanol (23 g, 0.17 mol). Thus, the optically
active (S)-3p (75 g, 0.56 mol) was obtained in 56% overall
yield with >99% ee. The oxidative kinetic resolution of
racemic alcohols described in this paper provides a
practically useful method for optically active alcohols
with high enantioselectivity.
Con clu sion
The plausible reaction pathway of the oxidative kinetic
resolution is shown in Scheme 3. At first, two chlorides
in the complex 2 are removed in two consecutive alkoxide
displacement-â-elimination sequences to form the active
Ru-dihydride complex (A). The complex A reacts with
acetone to give the Ru-hydride-2-propoxide complex (B).
The replacement of the propoxide on B with the more
reactive (R)-alcohol affords the Ru-hydride-alkoxide
complex (C) together with 2-propanol. In the presence of
We have found that oxidative kinetic resolution of
racemic secondary alcohols using acetone as a hydroge-
nacceptor in the presence of a catalytic amount of [RuCl2-
(PPh3)(FOXAP)] (2) proceeded quite effectively to recover
the corresponding alcohols in high yields with an excel-
lent enantioselectivity. A variety of alcohols such as
1-phenylethanol derivatives are available for this oxida-
tive kinetic resolution. Especially, oxidative kinetic reso-
lution of 1-indanol proceeded quite rapidly. The TOF of
i
an excess amount of PrONa, the formation of more
J . Org. Chem, Vol. 68, No. 15, 2003 5879

Nishibayashi et al.
SCHEME 4
SCHEME 5
this oxidation exceeded 80 000 h-1 and TON value
approached 40 000. The method presented in this paper
provides a practically useful method for the preparation
of optically active alcohols with a high enantioselectiv-
ity.
15685006) from the Ministry of Education, Culture,
Sports, Science, and Technology of J apan.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for oxidative kinetic resolution of racemic alcohols.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research (Nos. 13305062 and
J O0345087
5880 J . Org. Chem., Vol. 68, No. 15, 2003