(η6-arene)RuII/chiral SN ligand: A novel bifunctional catalyst system for asymmetric transfer hydrogenation of aromatic ketones

Article abstract of DOI:10.1055/s-0029-1217349

A binary catalyst system of [RuCl₂(η⁶-arene)] ₂ and a protic aminothiol (SN) ligand has been found to promote hydrogen transfer between alcohols and carbonyl compounds. The chiral catalyst system with the pipecolinol-derived chiral SN ligand displays excellent stereoselectivity in the asymmetric transfer hydrogenation of aromatic ketones using HCO₂H-Et₃N. Novel unsymmetrical bis(thiolate)- bridged binuclear complex, which is relevant to the generation of catalytically active species, has been synthesized and structurally characterized. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217349

CLUSTER
1621
(h6-Arene)RuII/Chiral SN Ligand: A Novel Bifunctional Catalyst System for
Asymmetric Transfer Hydrogenation of Aromatic Ketones
6
II
(
h
-Arene)Ru /Chiral
a
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, O-okayama 2-12-1-E4-1,
Meguro, Tokyo 152-8552, Japan
Fax +81(3)57342637; E-mail: tikariya@apc.titech.ac.jp
Received 27 January 2009
compounds, as observed in the well-established (h6-ar-
Abstract: A binary catalyst system of [RuCl2(h6-arene)]2 and a pro-
ene)Ru complexes having monosulfonylated 1,2-diamine
tic aminothiol (SN) ligand has been found to promote hydrogen
(NN) or 2-amino alcohol (ON) ligands.1c,d
transfer between alcohols and carbonyl compounds. The chiral cat-
alyst system with the pipecolinol-derived chiral SN ligand displays
excellent stereoselectivity in the asymmetric transfer hydrogenation
of aromatic ketones using HCO2H–Et3N. Novel unsymmetrical
cally active SN ligands shows an excellent catalyst perfor-
bis(thiolate)-bridged binuclear complex, which is relevant to the
generation of catalytically active species, has been synthesized and
In fact, we have found that a binary system of
[RuCl2(hmb)]2 (hmb = h6-hexamethylbenzene)6 and opti-
mance in terms of stereoselectivity in the asymmetric
transfer hydrogenation (ATH) of aromatic ketones using
HCO2H–Et3N. Herein we report the development of a
novel bifunctional catalyst system of (h6-arene)Ru and the
chiral SN ligand.
structurally characterized.
Key words: [RuCl2(h6-arene)]2, protic aminothiol ligand, asym-
metric transfer hydrogenation, aromatic ketone, bifunctionality
A variety of chiral 2-aminoethanethiols were convenient-
ly prepared from 2-oxazolidinones by the base-induced
decarboxylative C–S bond formation7a,b using benzyl
mercaptan and the subsequent reductive cleavage of the
benzyl group using Na/NH3.7c The products were isolated
as their hydrochloric salts in moderate to good yields as
summarized in Scheme 2. Primary SN ligands bearing
phenyl [(S)-2b], isopropyl [(S)-2c], and benzyl substituent
[(S)-2d] at the 2-position as well as cyclic secondary SN
ligands with pyrrolidine [(S)-2e] or piperidine ring [(S)-
2f] were readily obtainable with this synthetic sequence.
Unfortunately, however, the similar C–S bond formation
between benzyl mercaptan and 2-oxazolidinones having
substituents at the 5-position were not successful.7a,b
Recently we have developed Ru-based bifunctional mo-
lecular catalysts, {Cp*RuII[L(CH2)2NH2]} (L = tertiary
amine or phosphine, Cp* = h5-C5Me5) for a number of se-
lective organic transformations.1–3 Their excellent catalyst
performance can be attributed to the bifunctional property
based on the Ru/NH acid–base synergy. Notably, the re-
placement of the second-row ancillary ligand with the
third-row one in L has caused a dramatic change in their
catalyst performance. This finding has turned our atten-
tion to the catalytic activity of (h6-arene)Ru complexes
bearing a protic aminothiol (SN) ligands4 as a new family
of Ru(amine)(h6-arene) catalysts with a half-sandwich
structure. Our preliminary screen on the acceleration
effect of chelating NH2 ligands for the Ru-catalyzed
racemization3a,5 of optically active 2-phenylethanol (R)-1
shown in Scheme 1 revealed that 2-aminoethanethiol (2a)
exhibited the most significant effect to decrease the ee
value of (R)-1. These results strongly indicated that the
catalyst system including an (h6-arene)Ru complex and 2-
aminothiol ligands may display reasonable activity for
transfer hydrogenation between alcohols and carbonyl
The resulting chiral SN ligands accelerated racemization
of nonracemic 1 in toluene containing [RuCl2(hmb)]2 and
KOt-Bu {1/Ru/SN ligand·HCl/KOt-Bu = 100:1:1:3, [1] =
0.625 M, 30 °C}, but a considerable difference in the rate
of the reaction of both enantiomers (R)-1 and (S)-1 was
observed. For example, the chiral catalyst system with
(S)-2b racemized (S)-1 (>99% ee) very rapidly to afford
rac-1 within 3 h, while the ee value of (R)-1 (>99% ee) re-
chelating NH2 ligands:
OH
OH
[RuCl2(hmb)]2
ligand, KOt-Bu
TsHN
NH2
HO
NH2
14%
NH2
HO
NH2
E
76% ee
E = CO, 58%
E = SO2, 86%
toluene, 30 °C
24 h
PhS
NH2
HS
HS
NMe2
(R)-1 (>99% ee)
rac-1
2a
7%
1/Ru/ligand/KOt-Bu = 100:1:1:2
[(R)-1] = 0.63 M in toluene
91%
>99%
Scheme 1 Acceleration effect of several chelating NH2 ligands in the racemization of (R)-1
SYNLETT 2009, No. 10, pp 1621–1626
x
x
.x
x
.2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217349; Art ID: Y00309ST
© Georg Thieme Verlag Stuttgart · New York

1622
M. Ito et al.
CLUSTER
R1
R1
BnSH
R2N
H
SBn
R2N
O
KOt-Bu, t-BuOH
HCl⋅H2N
(S)-2b⋅HCl, 69%
SH HCl⋅H2N
SH HCl⋅H2N
SH
O
(S)-2c⋅HCl, 13%
(S)-2d⋅HCl, 80%
R1
1) Na/NH3
2) HCl
R2N
H2Cl
(S)-2b–f⋅HCl
SH
N
SH
N
SH
H2Cl
H2Cl
(S)-2e⋅HCl, 43%
(S)-2f⋅HCl, 64%
Scheme 2 Preparation of chiral SN ligands
mained 15% ee in the presence of the same catalyst sys- These results turned our attention to employ HCO2H–
tem even after the prolonged reaction time (72 h), as Et3N as a hydrogen source.10a Fortunately, in contrast to
shown in Figure 1.8
the instability of the related (h6-arene)Ru/chiral ON cata-
lyst systems toward the formic acid reaction medium,10b,c
the binary catalyst system including [RuCl2(hmb)]2 and
(S)-2b·HCl reduced efficiently 3 in a 3:5 mixture of
HCO2H–Et3N [3/Ru/(S)-2b·HCl = 100:1:1, 3/HCO2H/
Et3N = 2:3:5, 30 °C, 24 h) to yield (S)-1 in 81% yield with
76% ee. It should be noted that the ee value of the product
remained constant throughout the reaction. Not only (S)-
2b but other chiral SN ligands (S)-2c–f also promoted
ATH of 3 under identical conditions to give (S)-1 in ap-
preciable ees [(S)-2c: 82% yield, 77% ee, (S)-2d: 47%
yield, 23% ee, (S)-2e: 60% yield, 88% ee, (S)-2f: 84%
yield, 90% ee]. The binary system of [RuCl2(hmb)]2 and
(S)-2f also displayed excellent catalyst performance in the
ATH of a wide variety of prochiral ketones, giving the
corresponding secondary alcohols with high ee. Table 1
lists the representative results. While the enantioselectivi-
ty for the reaction of phenyl alkyl ketones gradually de-
creased as the chain length of the alkyl group became
longer [Me (3): 90% ee, Et (4): 76% ee, n-Pr (5): 75% ee],
2-furyl (6) or 2-thienyl (7) methyl ketones were reduced
to the corresponding secondary alcohols in a highly enan-
tioselective manner (entries 1–5). The new reaction sys-
tem reduced efficiently aromatic cyclic ketones including
indanone (8), a-tetralone (9), chroman-4-one (10 and 11),
and thiochroman-4-one derivatives (12–14), to the chiral
alcohols in excellent ee (entries 6–12). The significance of
the thiol moiety in the ligand structure was further con-
firmed by the control experiment using (S)-pipecolinol as
a chiral ligand, which gave inferior results under other-
wise identical conditions.11 Additionally, the HMB ligand
in the present catalyst system is the best arene ligand of
choice, which seems to play an important role. The h6-p-
cymene and h6-benzene ligand resulted in unsatisfactory
catalytic activity and stereoselectivity.12
Notably, the same catalyst promoted intermolecular enan-
tioselective transfer hydrogenation of acetophenone (3) in
2-propanol {3/Ru/SN ligand·HCl/KOt-Bu = 500:1:1:3, [3] =
1.0 M, 30 °C} to produce (S)-1 preferentially. However,
as shown in Figure 2, the deterioration of the product ee
became prominent immediately after the reaction started,
possibly due to the higher transfer hydrogenation ability
of (h6-arene)Ru with SN ligands with compared to those
with NN9a,b or ON ligands.9c
Figure 1 Time course of ee values of (S)-1 and (R)-1 in toluene con-
taining a ternary catalytic system of [RuCl2(hmb)]2, (S)-2b·HCl, and
KOt-Bu
To further gain insight into the catalytically active spe-
cies, we next focused our efforts on the isolation of half-
sandwich-type (h6-arene)Ru complex bearing an SN
ligand. Fortunately, we obtained a series of novel unsym-
metrical binuclear complexes from the reaction of
[RuCl2(hmb)]2, an SN ligand·HCl, and KOt-Bu.13a For ex-
ample, the reaction of a 1:2:3 mixture of [RuCl2(hmb)]2,
(S)-2e·HCl, and KOt-Bu in CH2Cl2 at room temperature
for 12 h gave a dark-yellow powder, from which unsym-
Figure 2 Time course of conversion and ee in the transfer hydro-
genation of 3 using 2-propanol containing a ternary catalytic system
of [RuCl2(hmb)]2, (S)-2b·HCl, and KOt-Bu
Synlett 2009, No. 10, 1621–1626 © Thieme Stuttgart · New York

CLUSTER
(h6-Arene)RuII/Chiral SN Ligand
1623
Table 1 ATH of Aromatic Ketones with HCO2H–Et3N in the Presence of a Catalyst System of [RuCl2(hmb)]2 and (S)-2f·HCl
O
OH
R1
[RuCl2(hmb)]2
(S)-2f⋅HCl
R1
R2
R2
HCO2H—Et3N
30 °C, 24 h
N
H2Cl
SH
ketone/HCO2H/Et3N = 2:3:5
ketone/Ru/(S)-2f = 100:1:1
(S)-2f⋅HCl
O
O
O
O
R
R
Ar
X
9: X = CH2, R = H
3: R = Me
4: R = Et
5: R = n-Pr
6: Ar = 2-furyl
7: Ar = 2-thienyl
8
10: X = O, R = H
11: X = O, R = Me
12: X = S, R = H
13: X = S, R = Me
14: X = S, R = Cl
Entry
Ketones
Yield (%)
84
ee (%)
90
Config.
1
2
3
4
S
77
76
S
3
5
52
75
S
4
6
>99
98
94
S
5
7
94
S
6
8
>99
>99
>99
>99
>99
>99
>99
97
S
7
9
99
S
8
10
11
12
13
14
97
S
9
98
S
10
11
12
95
S
97
n.d.
n.d.
89
metrical bis(thiolato)-bridged binuclear complex, Interestingly, (S,S)-15e alone exhibited almost identical
{[Ru(hmb)][(S)-SCH2CHRNHR-k2-S,N][(S)-SCH2CHRNH2R- catalyst performance in the ATH of 3 with HCO2H–Et3N
k1- S][RuCl(hmb)]}Cl2 [(S,S)-15e: R = -(CH2)3-] was iso- as the binary catalytic system of [RuCl2(hmb)]2 and (S)-
lated in moderate yield (63%) after recrystallization from 2e·HCl to furnish (S)-1 with 88% ee. Although the possi-
methanol and diethyl ether. The molecular structure of
(S,S)-15e was unequivocally determined by X-ray diffrac-
tion study13b as shown in Figure 3.
It should be noted that two nonequivalent HMB ligands
adopt cis orientation with respect to the Ru2S2 plane and
that the relatively short distance between the Ru1-ligated
N1 and the Ru2-ligated Cl1 [3.210(3) Å] indicates the
presence of a hydrogen bonding. In good agreement with
this solid-state structure, the CD2Cl2 solution of (S,S)-15e
showed two singlets at d = 2.02 and 2.11 ppm for methyl
groups of HMB in 1H NMR, and it also showed two sets
of peaks at d = 15.3, 15.6 ppm for ring carbons and d =
95.3, 96.0 ppm for methyl groups of HMB in 13C{1H}
NMR spectra. The strong propensity of thiolato ligand to
bridge two Ru as well as the hydrogen bonding between
protic NH and Cl should considerably contribute to the ro-
bust structural feature of (S,S)-15e.
Figure 3 Molecular structure of (S,S)-15e; the anionic part and all
hydrogens except that on N1 are omitted for clarity
Synlett 2009, No. 10, 1621–1626 © Thieme Stuttgart · New York

1624
M. Ito et al.
CLUSTER
R1
Cl2
R2N
Ru
H
Cl
S
S
HCO2H—Et3N
Ru
Ru
– CO2, Et3N⋅HCl
S
H
NHR2
R1
R2N
H2
R1
(S,S)-15
a possible catalytically
active species, (S)-16
Scheme 3 Possible pathway for the generation of catalytically active species in the ATH
ble mononuclear complex was not isolable,13a we believe
that the treatment of the unsymmetrical binuclear com-
plex with HCO2H–Et3N effectively reduce their chloro
ligand to generate double amounts of catalytically active
mononuclear Ru hydride complex14 bearing chelating SN
ligand [(S)-16], as illustrated in Scheme 3. The Ru/NH bi-
functionality of (S)-16 should lead to the excellent catalyst
performance in the ATH of aromatic ketones.
degassed 2-PrOH and Et2O [100/100 mL (v/v)], and the insoluble
materials were removed by filtration through a pad of Celite. Con-
centration of the filtrate gave (S)-2f·HCl as a colorless solid16e,g,h
(308 mg, 79% yield), which was further purified by recrystallization
from MeOH (7 mL) and Et2O (30 mL). 1H NMR (300 MHz, CDCl3,
300K): d = 1.45–2.13 (m, 7 H), 2.84–2.94 (m, 2 H), 3.05–3.20 (m,
2 H), 3.55 (d, J = 13 Hz, 1 H), 9.35 (br s, 1 H), 9.64 (br s, 1 H).
13C{1H} NMR (75 MHz, CD3OD, 300 K): d = 23.3, 23.7, 28.0, 29.2,
46.5, 60.4. [a]D +127.7 (c 0.15, MeOH).
In summary, we have developed a novel catalyst system
of [RuCl2(hmb)]2 and a chiral SN ligand for the ATH of
aromatic ketones with HCO2H–NEt3. The pipecolinol-
derived SN ligand (S)-2f displayed an excellent catalyst
performance in terms of stereoselectivity. Our results
clearly indicate a potential use of (h6-arene)Ru complexes
bearing an SN ligand as a new platform in the molecular
design of bifunctional catalysts. Further studies to eluci-
date the unique property of our new catalysts originating
form their Ru–S bond are in progress.
Spectral Data for (S)-2b–e·HCl
(S)-2b·HCl: 73% yield based on (S)-2-benzylthio-1-phenylethyl-
amine; 15a 1H NMR (300 MHz, CDCl3, 300 K): d = 1.56 (t, J = 8.6
Hz, 1 H), 3.06–3.16 (m, 2 H), 4.35–4.37 (m, 1 H), 7.32–7.61 (m, 5
H), 8.89 (br s, 3 H). 13C{1H} NMR (75 MHz, CD3OD, 300 K): d =
27.8, 57.5, 127.0, 129.1, 129.3, 135.8. [a]D +17.7 (c 0.13,
MeOH).16a
(S)-2c·HCl: 50% yield based on (S)-2-benzylthio-1-isopropylethyl-
amine;15b 1H NMR (300 MHz, CD3OD, 300 K): d = 1.05 (d, J = 7.0
Hz, 3 H), 1.06 (d, J = 6.7 Hz, 3 H), 2.14–2.16 (m, 1 H), 2.97 (dd,
J = 14.7, 8.9 Hz, 1 H), 3.19 (dd, J = 14.7, 4.0 Hz, 1 H), 3.39–3.44
(m, 1 H), 7.36 (br s, 3 H). 13C{1H} NMR (75 MHz, CD3OD, 300 K):
d = 16.9, 17.0, 29.8, 36.7, 55.8. [a]D +60.7 (c 0.13, MeOH).16b–16d
General Procedure for the Preparation of (S)-2b–f·HCl
(S)-2d·HCl: 98% yield based on (S)-1-benzylthiomethyl-2-phenyl-
ethylamine;15c 1H NMR (300 MHz, CDCl3, 300 K): d = 1.98–2.04
(m, 1 H), 2.77–2.82 (m, 1 H), 2.87–2.95 (m, 1 H), 3.07 (dd, J = 13.8,
9.5 Hz, 1 H), 3.30 (dd, J = 13.8, 5.4 Hz, 1 H), 3.65 (dd, J = 9.5, 5.4
Hz, 1 H), 7.26–7.37 (m, 5 H), 8.65 (br s, 3 H). 13C{1H} NMR (75
MHz, CD3OD, 300 K): d = 25.4, 37.0, 54.3, 127.3, 128.8, 129.1,
135.3. [a]D +23.9 (c 0.17, MeOH).16a,b
A mixture of (S)-8-oxa-1-azabicyclo[4.3.0]nonan-9-one3d (2.17 g,
15.4 mmol), benzyl mercaptan (3.60 mL, 30.5 mmol), and KOt-Bu
(1.73 g, 15.4 mmol) in t-BuOH (50 mL) was refluxed for 40 h. The
solvent was removed under reduced pressure, and the residue was
acidified by adding 1 N HCl aq, washed with Et2O, and then made
basic by the addition of aq NaOH. The crude product was extracted
with Et2O from the aqueous layer, dried over MgSO4, and filtered
through a pad of Celite. The filtrate was concentrated in vacuo to
give (S)-2-(benzylthiomethyl)piperidine as colorless liquid (2.75 g,
(S)-2e·HCl: 53% yield based on (S)-2-(benzylthiomethyl)pyrroli-
dine;15d 1H NMR (300 MHz, CDCl3, 300 K): d = 1.82–1.90 (m, 1
H), 2.00–2.24 (m, 3 H), 2.36–2.40 (m, 1 H), 2.94–3.05 (m, 2 H),
3.38–3.42 (m, 2 H), 3.77–3.81 (m, 1 H), 9.49 (br s, 1 H), 10.10 (br
s, 1 H). 13C{1H} NMR (75 MHz, CD3OD, 300 K): d = 23.5, 25.1,
29.2, 45.3, 63.0. [a]D +38.4 (c 0.41, MeOH).16e,f
1
12.4 mmol, 81% yield). H NMR (300 MHz, CDCl3, 300 K): d =
1.05–1.39 (m, 3 H), 1.50–1.63 (m, 2 H), 1.72–1.76 (m, 1 H), 1.98
(br s, 1 H), 2.27–2.35 (m, 1 H), 2.43–2.56 (m, 3 H), 3.01–3.05 (m,
1 H), 3.67 (s, 2 H), 7.20–7.29 (m, 5 H). 13C{1H} NMR (75 MHz,
CDCl3, 300 K): d = 24.3, 26.2, 32.7, 36.6, 38.8, 47.1, 55.2, 127.1,
128.6, 128.9, 138.5.
ATH Using HCO2H–Et3N; ATH of 4 as a Typical Procedure
A mixture of formic acid (13.2 mmol), Et3N (22.0 mmol), and 4
(8.80 mmol) was degassed by three freeze-pump-thaw cycles and
then added to a mixture of [RuCl2(hmb)]2 (0.044 mmol), (S)-2f·HCl
(0.088 mmol) under Ar. The mixture was stirred at 30 °C for 24 h,
and the resulting mixture was passed through a silica plug eluting
with EtOAc. The filtrate was concentrated under reduced pressure,
To a solution of this compound (515 mg, 2.34 mmol) in anhyd Et2O
(50 mL) placed in a round-bottomed flask equipped with dry ice
condenser was introduced gaseous ammonia at –78 °C until the
whole volume became 80 mL. Then sodium metal in small pieces
was added until a permanent blue color remained, and the resulting
mixture was stirred at the same temperature for 2 h. Then the excess
sodium was decomposed by adding solid NH4Cl and NH3 was al-
lowed to evaporate by argon purging at r.t. The residue was diluted
with anhyd Et2O (200 mL), slowly acidified by adding 1 N HCl in
Et2O (10 mL, 10 mmol), and stirred for 2 h at r.t. The resulting pre-
cipitates were collected by filtration, washed with degassed Et2O,
and dissolved in degassed 2-PrOH (3 × 100 mL). Insoluble materi-
als were removed by filtration through a pad of Celite, and the fil-
trate was concentrated. The residue was redissolved in a mixture of
1
and the aliquot of the residue was subjected to H NMR analysis
whose integration of well-resolved signals of 4 and the correspond-
ing alcohol determines the conversion. Purification of the residue
by column chromatography (Kanto Silica Gel 60 N, spherical, neu-
tral) eluting with n-hexane–EtOAc (v/v = 3:1) provided the product
alcohol (931.2 mg, 77% yield). The ee of the alcohol was analyzed
by HPLC analysis using Daicel Chiralcel OD–H column (df = 4.6
mm i.d. × 250 mm; eluent, n-hexane–2-PrOH = 99:1; temp, 30 °C;
Synlett 2009, No. 10, 1621–1626 © Thieme Stuttgart · New York

CLUSTER
(h6-Arene)RuII/Chiral SN Ligand
1625
flow rate, 0.5 mL/min; detection (UV), l = 254 nm light); tR = 47.0
min (R-isomer) and 52.6 min (S-isomer).
(2) (a) Ito, M.; Hirakawa, M.; Murata, K.; Ikariya, T.
Organometallics 2001, 20, 379. (b) Ito, M.; Hirakawa, M.;
Osaku, A.; Ikariya, T. Organometallics 2003, 22, 4190.
(c) Ito, M.; Sakaguchi, A.; Kobayashi, C.; Ikariya, T. J. Am.
Chem. Soc. 2007, 129, 290. (d) Ito, M.; Koo, L.-W.;
Himizu, A.; Kobayashi, C.; Sakaguchi, A.; Ikariya, T.
Angew. Chem. Int. Ed. 2009, 48, 1324.
HPLC Conditions for the Alcohols Derived from 3–14
Compound 3: Chiralcel OD column; df = 4.6 mm i.d. × 250 mm;
eluent, n-hexane–2-PrOH = 95:5; temp, 30 °C, flow rate, 0.5 mL/
min; detection (UV), l = 254 nm light; tR = 16.2 min (R-isomer)
and 18.1 min (S-isomer).
(3) (a) Ito, M.; Osaku, A.; Kitahara, S.; Hirakawa, M.; Ikariya,
T. Tetrahedron Lett. 2003, 44, 7521. (b) Ito, M.; Kitahara,
S.; Ikariya, T. J. Am. Chem. Soc. 2005, 127, 6172. (c) Ito,
M.; Osaku, A.; Shiibashi, A.; Ikariya, T. Org. Lett. 2007, 9,
1821. (d) Ito, M.; Osaku, A.; Kobayashi, C.; Shiibashi, A.;
Ikariya, T. Organometallics 2009, 28, 390.
(4) (a) Capper, G.; Davies, D. L.; Fawcett, J.; Russell, D. R. Acta
Crystallogr., Sect. C: Cryst. Struct. Commun. 1995, 51, 578.
(b) Wang, F.; Chen, H.; Parkinson, J. A.; Murdoch, P. S.;
Sadler, P. J. Inorg. Chem. 2002, 41, 4509. (c) A part of this
work was presented in 2007 on the 54th symposium on
organometallic chemistry at Hiroshima, Japan (A206) as
well as in 2008 on the 102nd CATSJ Meeting at Nagoya,
Japan (3K03).
Compound 5: Chiralcel OB column; df = 4.6 mm i.d. × 250 mm;
eluent, n-hexane–2-PrOH = 99:1; temp, 30 °C, flow rate, 0.5 mL/
min; detection (UV), l = 254 nm light; tR = 21.7 min (S-isomer) and
26.3 min (R-isomer).
Compound 6: Chiralpak AS-H column; df = 4.6 mm i.d. × 250 mm;
eluent, n-hexane–2-PrOH = 99:1; temp, 30 °C, flow rate, 0.5 mL/
min; detection (UV), l = 254 nm light; tR = 39.1 min [R-(+)-iso-
mer] and 41.2 min [S-(–)-isomer].
Compound 7: Chiralcel OD-H column; df = 4.6 mm i.d. × 250 mm;
eluent, n-hexane–2-PrOH = 999:1; temp, 30 °C, flow rate, 0.5 mL/
min; detection (UV), l = 254 nm light; tR = 46.9 min [R-(+)-iso-
mer] 54.5 min for [S-(–)-isomer].
(5) Dijksman, A.; Elzinga, J. M.; Li, Y.-X.; Arends, I. W. C. E.;
Sheldon, R. A. Tetrahedron: Asymmetry 2002, 13, 879.
(6) (a) Bennett, M. A.; Matheson, T. W.; Robertson, G. B.;
Smith, A. K.; Tucker, P. A. Inorg. Chem. 1980, 19, 1014.
(b) Bennett, M. A.; Huang, T.-N.; Matheson, T. W.; Smith,
A. K. Inorg. Synth. 1982, 21, 74.
(7) (a) Ishibashi, H.; Uegaki, M.; Sakai, M. Synlett 1997, 915.
(b) Ishibashi, H.; Uegaki, M.; Sakai, M.; Takeda, Y.
Tetrahedron 2001, 57, 2115. (c) Carroll, F. I.; White, J. D.;
Wall, M. E. J. Org. Chem. 1963, 28, 1236.
(8) The rate difference between enantiomeric 1 became more
significant with the catalyst system with (S)-2e. Thus, it
reduced the ee value of (S)-1 (>99% ee) to 13% within 6 h
but that of (R)-1 (>99% ee) did not change significantly
(94%) under identical conditions.
(9) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562. (b) Haack,
K. J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 285. (c) Takehara,
J.; Hashiguchi, S.; Fujii, A.; Inoue, S.-I.; Ikariya, T.; Noyori,
R. Chem. Commun. 1996, 233.
Compound 8: Chiralcel OD-H column; df = 4.6 mm i.d. × 250 mm;
eluent, n-hexane–2-PrOH = 98:2; temp, 30 °C, flow rate, 0.5 mL/
min; detection (UV), l = 254 nm-light; tR = 30.6 min (S-isomer)
and 34.7 min for (R-isomer).
Compound 9: Chiralpak AD-H column; df = 4.6 mm i.d. × 250 mm;
eluent, n-hexane–2-PrOH = 98:2; temp, 30 °C, flow rate, 0.5 mL/
min; detection (UV), l = 254 nm light; tR = 30.7 min (S-isomer) and
33.8 min (R-isomer).
Compound 10: Chiralcel OD-H column; df = 4.6 mm i.d. × 250
mm; eluent, n-hexane–2-PrOH = 99:1; temp, 30 °C, flow rate, 0.5
mL/min; detection (UV), l = 254 nm light; tR = 51.0 min (S-iso-
mer) and 63.8 min (R-isomer).
Compound 11: Chiralcel OD-H column; df = 4.6 mm i.d. × 250
mm; eluent, n-hexane–2-PrOH = 98:2; temp, 30 °C, flow rate, 0.5
mL/min; detection (UV), l = 254 nm light; tR = 28.0 min [S-(–)-iso-
mer] and 34.7 min [R-(+)-isomer].
Compound 12: Chiralcel OB column; df = 4.6 mm i.d. × 250 mm;
eluent, n-hexane–2-PrOH = 98:2; temp, 30 °C, flow rate, 0.5 mL/
min; detection (UV), l = 254 nm light; tR = 36.2 min (R-isomer)
and 56.5 min (S-isomer).
(10) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521. (b) Palmer,
M.; Walsgrove, T.; Wills, M. J. Org. Chem. 1997, 62, 5226.
(c) Alonso, D. A.; Nordin, S. J. M.; Roth, P.; Tarnai, T.;
Andersson, P. G.; Thommen, M.; Pittelkow, U. J. Org.
Chem. 2000, 65, 3116.
Compound 13: Chiralpak AS-H column; df = 4.6 mm i.d. × 250
mm; eluent, n-hexane–2-PrOH = 98:2; temp, 30 °C, flow rate, 0.5
mL/min; detection (UV), l = 254 nm light; tR = 24.4 min (major
isomer) and 36.3 min (minor isomer).
Compound 14: Chiralpak AS-H column; df = 4.6 mm i.d. × 250
mm; eluent, n-hexane–2-PrOH = 98:2; temp, 30 °C, flow rate, 0.5
mL/min; detection (UV), l = 254 nm light; tR = 32.7 min (major
isomer) and 40.1 min (minor isomer).
(11) In contrast with the outcome in entry 1 of Table 1, (S)-1 with
moderate ee (61%) was obtained from 3 in lower yield
(38%) with the binary catalyst system of [RuCl2 (hmb)]2 and
(S)-pipecolinol with under otherwise identical conditions.
(12) The catalyst system of [RuCl2 (h6-p-cymene)]2 and (S)-
2f·HCl promoted the ATH of 3 to give (S)-1 with 12% ee in
31% yield and that with [RuCl2 (h6-benzene)]2 and (S)-
2f·HCl hardly promoted the ATH of 3 to give rac-1 in 4%
yield under otherwise identical conditions.
Acknowledgment
This research was financially supported by the MEXT (Nos.
16750073 and 18065007) and partially supported by G-COE pro-
gram and the Asahi Glass Foundation (M.I.).
(13) (a) Details will be reported separately.
(b) Preparation of (S,S)-15e
A mixture of [RuCl2 (hmb)]2 (314.5 mg, 0.470 mmol), (S)-
2e·HCl (143.1 mg, 0.931 mmol), and KOt-Bu (157.1 mg,
1.40 mmol) in CH2Cl2 (6 mL) was stirred at r.t. for 12 h.
Removal of the solvent under reduced pressure gave a dark
yellow powder, which was washed with THF and then
extracted with CH2Cl2. The extract was concentrated in
vacuo to give a red solid, which was purified by recrys-
tallization from MeOH and Et2O to give pure (S,S)-15e as
References and Notes
(1) (a) Ito, M.; Ikariya, T. J. Synth. Org. Chem. Jpn. 2008, 66,
1042. (b) Ito, M.; Ikariya, T. Chem. Commun. 2007, 5134.
(c) Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40,
1300. (d) Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol.
Chem. 2006, 4, 393.
Synlett 2009, No. 10, 1621–1626 © Thieme Stuttgart · New York

1626
M. Ito et al.
CLUSTER
red crystals (258.0 mg, 63%). 1H NMR (300 MHz, CD2Cl2,
300 K): d = 1.81–1.90 (m, 5 H), 1.98–2.10 (m, 4 H), 2.02 (s,
18 H), 2.11 (s, 18 H), 2.02–2.32 (m, 5 H), 2.69–2.72 (m, 2
H), 2.88–2.90 (m, 1 H), 3.25–3.27 (m, 1 H), 3.81–3.83 (m, 1
H), 6.07 (br s, 1 H), 9.61 (br s, 1 H), 10.32 (br s, 1 H).
13C{1H} NMR (75 MHz, CO2Cl2, 300 K): d = 15.3, 15.6,
24.0, 26.6, 27.2, 27.6, 30.8, 45.1, 50.1, 52.8, 58.5, 75.0, 95.3,
96.0. Anal. Calcd for C34H57Cl3N2Ru2S2⋅5/2H2O: C, 44.8; H,
6.86; N, 3.07. Found: C, 44.74; H, 6.94; N, 3.20. CCDC-
717904 contains the supplementary crystallographic data
for (S,S)-15e. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
2.24 (dd, J = 13.6, 3.7 Hz, 1 H), 2.56–2.61 (m, 2 H), 3.69 (s,
2 H), 7.18–7.30 (m, 5 H). (c) Yield 82%, based on (S)-4-
benzyl-2-oxazolidinone. 1H NMR (300 MHz, CDCl3, 300
K): d = 1.27 (br s, 2 H), 2.34 (dd, J = 13.2, 8.3 Hz, 1 H),
2.56–2.62 (m, 2 H), 2.73 (dd, J = 13.2, 5.6 Hz, 1 H), 3.04–
3.12 (m, 1 H), 3.69 (s, 2 H), 7.16–7.30 (m, 10 H). (d) Yield
81%, based on N,O-carbonyl-L-prolinol.3d 1H NMR (300
MHz, CDCl3, 300 K): d = 1.31–1.43 (m, 1 H), 1.67–1.93 (m,
4 H), 2.49–2.53 (m, 2 H), 2.82–2.88 (m, 1 H), 2.92–3.00 (m,
1 H), 3.13–3.22 (m, 1 H), 3.74 (s, 2 H), 7.21–7.31 (m, 5 H).
(16) (a) Bruk, Y. A.; Derzhavets, A. A.; Pavlova, L. V.;
Rachinskii, F. Y.; Slavachevskaya, N. M. J. Gen. Chem.
USSR 1970, 40, 2300. (b) Meinzer, A.; Breckel, A.; Thaher,
B. A.; Manicone, N.; Otto, H.-H. Helv. Chim. Acta 2004,
87, 90. (c) Myllymäki, V. T.; Lindvall, M. K.; Koskinen,
A. M. P. Tetrahedron 2001, 57, 4629. (d) Handrick, G. R.;
Atkinson, E. R.; Granchelli, F. E.; Bruni, R. J. J. Med. Chem.
1965, 8, 762. (e) Schwenkkraus, P.; Otto, H.-H. Arch.
Pharm. 1990, 323, 93. (f) Chi, D. Y.; O’Neil, J. P.;
(14) Koike, T.; Ikariya, T. Adv. Synth. Catal. 2004, 346, 37.
(15) (a) Yield 95%, based on (S)-4-phenyl-2-oxazolidinone. 1H
NMR (300 MHz, CDCl3, 300 K): d = 1.21 (br s, 2 H), 2.53
(dd, J = 13.3, 9.0 Hz, 1 H), 2.68 (dd, J = 13.3, 4.2 Hz, 1 H),
3.61 (s, 2 H), 3.94 (dd, J = 9.0, 4.2 Hz, 1 H), 7.18–7.27
(m, 10 H). (b) Yield 25%, based on (S)-4-isopropyl-2-
oxazolidinone. 1H NMR (300 MHz, CDCl3, 300 K):
Anderson, C. J.; Welch, M. J.; Katzenellenbogen, J. A.
J. Med. Chem. 1994, 37, 928. (g) Franzen, V. Chem. Ber.
1957, 90, 2036. (h) Searles, S. Jr.; Roelofs, G. E.; Tamres,
M.; McDonald, R. N. J. Org. Chem. 1965, 30, 3443.
d = 0.83–0.86 (m, 6 H), 1.28 (br s, 2 H), 1.54–1.65 (m, 1 H),
Synlett 2009, No. 10, 1621–1626 © Thieme Stuttgart · New York

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