Ruthenium-catalyzed oxidative kinetic resolution of unactivated and activated secondary alcohols with air as the hydrogen acceptor at room temperature

Article abstract of DOI:10.1002/anie.201310426

Enantiopure alcohols are versatile building blocks for asymmetric synthesis and the kinetic resolution (KR) of racemic alcohols is a reliable method for preparing them. Although many KR methods have been developed, oxidative kinetic resolution (OKR), in which dioxygen is used as the hydrogen acceptor, is the most atom-efficient. Dioxygen is ubiquitous in air, which is abundant and safe to handle. Therefore, OKR with air has been intensively investigated and the OKR of benzylic alcohols was recently achieved by using an Ir catalyst without any adjuvant. However, the OKR of unactivated alcohols remains a challenge. An [(aqua)Ru(salen)] catalyzed OKR with air as the hydrogen acceptor was developed, in which the aqua ligand is exchanged with alcohol and the Ru complex undergoes single electron transfer to dioxygen and subsequent alcohol oxidation. This OKR can be applied without any adjuvant to activated and unactivated alcohols with good to high enantioselectivity. The unique influence of substrate inhibition on the enantioselectivity of the OKR is also described. Alcohol resolution: An (aqua)ruthenium salen complex catalyzes the efficient oxidative kinetic resolution of both activated and unactivated secondary alcohols with air as the hydrogen acceptor at room temperature. The reaction is compatible with various functional groups, including halogen, ether, silyl ether, and ester groups. The reaction rate is lower at higher substrate concentrations as a result of substrate inhibition.

Full text of DOI:10.1002/anie.201310426

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Communications
DOI: 10.1002/anie.201310426
Kinetic Resolution
Ruthenium-Catalyzed Oxidative Kinetic Resolution of Unactivated
and Activated Secondary Alcohols with Air as the Hydrogen Acceptor
at Room Temperature**
Hirotaka Mizoguchi, Tatsuya Uchida, and Tsutomu Katsuki*
Abstract: Enantiopure alcohols are versatile building blocks
for asymmetric synthesis and the kinetic resolution (KR) of
racemic alcohols is a reliable method for preparing them.
Although many KR methods have been developed, oxidative
kinetic resolution (OKR), in which dioxygen is used as the
hydrogen acceptor, is the most atom-efficient. Dioxygen is
ubiquitous in air, which is abundant and safe to handle.
Therefore, OKR with air has been intensively investigated and
the OKR of benzylic alcohols was recently achieved by using
an Ir catalyst without any adjuvant. However, the OKR of
unactivated alcohols remains a challenge. An [(aqua)Ru-
(salen)] catalyzed OKR with air as the hydrogen acceptor was
developed, in which the aqua ligand is exchanged with alcohol
and the Ru complex undergoes single electron transfer to
dioxygen and subsequent alcohol oxidation. This OKR can be
applied without any adjuvant to activated and unactivated
alcohols with good to high enantioselectivity. The unique
influence of substrate inhibition on the enantioselectivity of the
OKR is also described.
room temperature.[5b,c] However, the OKR of unactivated
secondary alcohols by using air without any adjuvant at room
temperature remains a challenge in asymmetric oxidation.
In 2000, we achieved the first OKR of secondary alcohols
with air at room temperature under visible-light irradiation in
the presence of [(ON)Ru(salen)] complex 1.[4] Both activated
and unactivated alcohols can be oxidized with good enantio-
mer differentiation (Scheme 1).[4a] Based on kinetics and
kinetic isotope effect (KIE) studies, we proposed a mechanism
T
he oxidative kinetic resolution (OKR) of racemic alcohols
is a useful method for preparing highly enantioenriched
alcohols.[1] Alcohol oxidation is a dehydrogenation reaction
and requires a hydrogen acceptor. Of the various possible
acceptors, dioxygen, which is ubiquitous in air, is the most
atom-efficient. OKR that uses dioxygen as an acceptor has
thus been extensively investigated[2,3] and not surprisingly, KR
with air has also been achieved.[1a,4,5] However, except for one
example, these reactions require the addition of base,[5a]
heating,[5d] or photoirradiation.[4] Ikariya and coworkers
have reported the highly enantioselective iridium-catalyzed
OKR of secondary benzylic alcohols when using solely air at
Scheme 1. The [(ON)Ru(salen)]-catalyzed aerobic OKR of secondary
alcohols under irradiation and its proposed mechanism. The salen
ligand is simplified for clarity.
for this oxidation[4c] in which irradiation promotes both NO-
dissociation and single electron transfer (SET). We thus
inferred that this alcohol oxidation would proceed without
irradiation if the oxidation potential of intermediate A was
reduced through the coordination of a donating ligand.
Indeed, an achiral [Ru(salen)] complex bearing a PPh3
ligand catalyzed alcohol oxidation in air without irradiation,[6]
but its chiral derivative could not be synthesized.
[*] H. Mizoguchi
Department of Chemistry, Graduate School of Science
Kyushu University, Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan)
Dr. T. Uchida
Faculty of Arts and Science, and International Institute for Carbon-
Neutral Energy Research (WPI-I2CNER), Kyushu University
Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan)
To our surprise, however, it was found that pre-irradiation
in air followed by vacuum-drying rendered 1 catalytically
active for alcohol oxidation even in the dark (Scheme 2).[7]
This result suggested that NO dissociation is reversible, that
the oxidation of free NO in the reaction mixture is slow, and
that irradiation is not necessarily required for SET. Therefore,
we expected that alcohol-bound intermediate A (Scheme 2)
or a corresponding water-bound complex would catalyze the
OKR of secondary alcohols with air without irradiation.
Herein, we describe an efficient OKR of unactivated and
activated secondary alcohols with air as the hydrogen
acceptor at room temperature.
Prof. T. Katsuki
WPI-I2CNER, and Institute for Advanced Study, Kyushu University
Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan)
E-mail: katsuscc@chem.kyushu-univ.jp
[**] Financial support from Nissan Chemical Industries, Ltd., and World
Premier International Research Center Initiative (WPI) and JSPS
KAKENHI Grant Nos. 23245009 from MEXT (Japan) is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310426.
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the selectivity (Table 1, entry 6). The oxidation with 2 mol%
3 in the dark showed the same level of selectivity (krel = 25 at
conv. 52.5%).
Under the optimized conditions, we examined the oxida-
tion of other alcohols (Table 2). Although the reactions of p-,
m-, or o-substituted 1-pheneylethanols proceeded with good
to high krel values, o-substituents generally produced better
enantioselectivity than p- or m- substituents, and electron-
Scheme 2. Aerobic oxidation of 1-phenylethanol by using pre irradiated
1 as the catalyst in the dark.
We prepared the [(aqua)Ru-salen] complexes 2, 3 and 4-8
(Figure S1 in the Supporting Information).[8,9] We first
examined the oxidation of 1-phenylethanol when using 2 as
the catalyst in dichloromethane under air at 258C without
irradiation (Table 1, entry 1). As anticipated, the reaction
proceeded with a good krel value (krel = 12), which was almost
equal to that obtained with complex 1 (krel = 11) under
irradiation,[4a] but the reaction proceeded rather slowly.
Alcohol oxidation produces hydrogen peroxide that may
competitively coordinate to the Ru ion and slow the desired
oxidation. Under irradiation, this adverse effect may be
mitigated.[10]
Table 2: Aerobic oxidative kinetic resolution of racemic alcohols.[a]
[c]
Entry Substrate
Time Conv. ee
[h]
krel(obs.)
[%][b] [%][b]
1
2
3
4
5
6
7
8
R=Cl
R=Br
9
9
23
12
9
54.6
57.6
54.3
54.2
59.6
59.6
51.6
51.2
55.4
53.9
56.9
58.1
65.5
56.9
56.2
63.5
57.7
91.9[d] 24
95.4[d] 21
R=COOMe
R=CF3
R=MeO
R=Me
R=Cl
82.5[d] 16
92.1[d] 26
83.6[d]
9
7
9
88.5[d] 11
92.4[d] 46
93.5[d] 60
93.1[d] 23
94.8[d] 35
94.0[d] 20
95.5[d] 20
98.3[d] 14
90.3[d] 16
94.7[d] 24
95.3[d] 12
89.2[f] 14
R=Br
12
24
24
9
11
9
9
R=MeO
R=Me
R=Cl
R=Br
R=MeO
R=Me
Table 1: Optimization of the reaction conditions.[a]
10
11
12
13
14
15
16[e]
17[e]
11
Entry Cat. MS X [ꢀ][b] Time [h] Conv. [%][c] ee [%][c,d] krel(obs.)
[e]
R=1-naphthyl 15
R=(E)-
1
2
3
2
2
3
3
3
3
–
55
15
13
10
7
54.3
67.9
54.7
53.6
54.3
55.6
80.3
94.2
89.9
89.3
91.1
94.3
12
8
21
23
24
25
19
28
MS 5 ꢀ
MS 5 ꢀ
MS 5 ꢀ
MS 5 ꢀ
MS 5 ꢀ
=
PhCH CH
=
R=(E)-EtCH
4[f]
5[g]
6[g,h]
CMe
18[g,h]
19[g,h]
20[g]
21[g,h]
22[g]
23[g]
24
R=PhCH2CH2 25
R=cyclohexyl 24
R=cyclopentyl
R=n-Hexyl
R=n-Butyl
61.4
58.2
52.1
60.9
65.8
51.2
18.0
66.3
94.3[d] 13
98.3[d] 26
86.3[d] 24
91.5[d] 12
97.7[d] 12
81.5[d] 20
9
9
11
11
[a] Reaction conditions: CH2Cl2 (0.3 mL), 1-phenylethanol (0.3 mmol,
1m), Ru complex (9 mmol, 3 mol%), bicyclohexyl (one drop, internal
standard), 258C, air, unless otherwise noted. [b] 30 mg of MS was added.
[c] Conversion and ee were determined by GC analysis (see the
Supporting Information). [d] Configuration of the remaining isomer is R
(see the Supporting Information). [e] Calculated by using Kagan’s
equation (Ref. [12a]). [f] Run in CHCl3 (0.3 mL). [g] Run in CHCl3
(1.0 mL). [h] Run with 2 mol% of 3.
R=TBSOCH2 15
21
28
5.0
2
25[i]
95.2[j] 10
[a] Reaction conditions: CHCl3 (1 mL), alcohol (0.3 mmol), 3 (6 mmol,
2 mol%), MS 5 ꢀ (30 mg), bicyclohexyl (1 drop, internal standard), 258C,
air, unless otherwise noted. [b] Conversion and ee were determined by GC
analysis (see the Supporting Information). [c] Calculated by using Kagan’s
equation (Ref. [12a]). [d] The configuration of each slow-reacting isomer is
R (see the Supporting Information). [e] Run with 3 mol% of 3 in EtOAc.
[f] The absolute configuration is unknown. [g] Run in ClCH2CH2Cl. [h] Run
with 1 mol% of 3. [i] Run with 3 mol% of 8 in EtOAc. [j] The configuration
of the slow-reacting isomer is S (see the Supporting Information).
To enhance the reaction rate, we examined the reaction in
the presence of molecular sieves (MS). The addition of MS
3 ꢀ or 4 ꢀ enhanced the reaction rate but significantly
reduced the krel values (Table S1 in the Supporting Informa-
tion, entries 2 and 3). The addition of MS 5 ꢀ further
enhanced the reaction rate without much deterioration of
enantioselectivity (krel = 8, Table 1, entry 2).[11] The oxidation
in the presence of MS 5 ꢀ proceeded in the dark at an almost
equal rate with the same krel value (8 at conv. 67.9%).
Complexes 3–7 were examined as catalysts in the presence of
MS 5 ꢀ without irradiation (Table S1, entries 5–9). Complex
3, which has a methyl group at position C2“, produced the
best krel value of 21 (Table 1, entry 3).
The rate and krel values were improved, albeit slightly,
when the reaction was carried out in chloroform (Table 1,
entry 4). Fortunately, we found that the reaction at a lower
substrate concentration (0.3m) proceeded more rapidly with
an almost equal krel value (24; Table 1, entry 5). The catalyst
loading could also be reduced to 2 mol% without reducing
withdrawing substituents produced better results than elec-
tron-donating substituents (Table 2, entries 1–14). The max-
imum krel value of 60 was observed for the oxidation of 1-(o-
bromophenyl)ethanol (Table 2, entry 8). The oxidation of 1-
(1-naphthyl)ethanol gave a krel value of 24 (Table 2, entry 15).
The oxidation of allylic alcohols, (E)-4-phenylbut-3-en-2-ol
and (E)-3-methylhex-3-en-2-ol, proceeded with good krel
values and the best solvent for this reaction was found to be
ethyl acetate (Table 2, entries 16 and 17). To our delight, this
method was also successfully applied to the oxidation of
secondary aliphatic alcohols (Table 2, entries 18–23),
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although 1,2-dichloroethane was the solvent of choice for
these reactions. The oxidations of 1-cyclohexylethanol and 1-
cyclopentylethanol gave high krel values of 26 and 24, and
good krel values of 12 were obtained even in the oxidations of
2-octanol and 2-hexanol. However, the cyclic alcohol 1-
indanol was oxidized with only a modest krel value (Table 2,
entry 24). Fortunately, however, the efficiency of the KR was
increased to krel = 10 by using complex 8, a diastereomer of 2,
as the catalyst in ethyl acetate (Table 2, entry 25).
We further investigated the dependence of the rate on
substrate concentration that was observed during the opti-
mization of the reaction conditions (Table 1, entries 4 and 5).
The rate of a catalytic reaction depends not only on catalytic
activity but also on the reaction pattern. In many metal-
catalyzed reactions, the catalyst and substrate (or reagent) are
in equilibrium with a catalyst–substrate (or catalyst–reagent)
complex, which reacts with the reagent (or substrate) to give
the product [Eq. (1) and Eq. (S1) in the Supporting Informa-
tion]. This type of reaction shows a first order dependence on
substrate concentration and Kaganꢁs equation[12] can be
applied; however, the observed krel is not k2f/k2s but rather
k2fKf/k2sKs.[13] This equation seems to agree with the reaction
mechanism described in Scheme 1, as long as substrate
concentration is constant.
Figure 1. Initial rates of 1-phenylethanol oxidation when using 3
(6 mmol) in the presence of MS 5 ꢀ (30 mg) in CHCl3 under air at
*
different substrate concentrations. a) Racemic 1-phenylethanol;
~
&
[S]0 =0.10m; [S]0 =0.15m; [S]0 =0.2m, ꢁ [S]0 =0.3m. (b) (S)- and
~
&
(R)-1-Phenylethanols; (S)-isomer, blue [S]0 =0.15m; blue
~
&
[S]0 =0.3m. (R)-isomer, red [S]0 =0.15m; red [S]0 =0.3m.
and observed that the oxidation rate increased at lower
concentrations, (Figure 1a, competitive experiment). The
obtained result is consistent with the above speculation
[Eq. (2)]: the reaction rates of the fast and slow isomers are
vf = k2f[Af][O2] and vs = k2s[As][O2] and the pre-equilibrium
constants Kf and Ks are Kf = [Af]/[Sf][cat] and Ks = [As]/
[Ss][cat], respectively, wherein [cat] and [O2] are the same in
the reactions of the fast and slow isomers. Accordingly, vf/vs =
k2f[Af]/k2s[As] = k2fKf[Sf]/k2sKs[Ss].[15] The observed relative
rate constant [krel(obs.) = kf (obs.)/ks (obs.)] is k2fKf/k2sKs.
Indeed, krel(obs.) was constant during the reaction (Figure S2
in the Supporting Information). However, the reaction rate
(vf + vs) becomes slower as the substrate concentration
increases because of a decrease in the concentrations of Af
and As owing to substrate inhibition.[15]
If the catalyst has two empty coordination sites, the
substrate–catalyst complex is coordinatively unsaturated, and
if the product formation step is slow, active species A can be
pre-equilibrated with catalytically inactive species (B and C),
to which dioxygen cannot coordinate, and the reaction suffers
substrate inhibition [Eq. (2)].[14] Since the SET step is the
rate-determining step (Scheme 1),[4c] we speculated that this
type of substrate inhibition would be responsible for the
dependence of the rate on substrate concentration. The extent
of substrate inhibition should increase with substrate concen-
tration.
To further confirm the participation of pre-equilibriation
in this oxidation, we then measured the reaction rate and the
relative reaction rate in a noncompetitive experiment [Eq. (3)
and Figure 1b). In the noncompetitive experiment, pre-
equilibration between A and C should not be possible and
the influence of substrate inhibition on the reaction rate
should be smaller than in the competitive experiment. This
was consistent with the experimental result (Figure 1). More-
over, [cat] and [O2] are not the same in the reactions of the
fast and slow isomers. The reaction rate for the fast isomer is
vf = k2f[Af][O2(f)]. Since the total catalyst concentration [cat]0
is equal to the concentration of free catalyst [cat(f)] plus the
concentrations of the substrate-bound complexes (Af and Bf):
[cat]0 = [cat(f)] + [Af] + [Bf]. Accordingly, [Af] = [cat]0/{1+1/
We therefore measured the rate of the oxidation of
racemic 1-phenylethanol at several different concentrations
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Kf[Sf] + Kff[Sf]} (for the fast isomer) and [As] = [cat]0/{1+1/
Ks[Ss] + Kss[Ss]} (for the slow isomer). Thus, vf/vs = k2f{1+1/
[1] For a review of the oxidative kinetic resolution of racemic
alcohols: a) M. Wills, Angew. Chem. 2008, 120, 4334 – 4337;
Angew. Chem. Int. Ed. 2008, 47, 4264 – 4267; b) M. J. Schultz,
M. S. Sigman, Tetrahedron 2006, 62, 8227 – 8241; c) J. M. Keith,
J. F. Larrow, E. N. Jacobsen, Adv. Synth. Catal. 2001, 343, 5 – 26;
d) T. Katsuki, V. S. Martin, Org. React. 1996, 48, 1 – 299; e) For
the review of acylative kinetic resolution, see: C. E. Mꢂller, P. R.
Schreiner, Angew. Chem. 2011, 123, 6136 – 6167; Angew. Chem.
Int. Ed. 2011, 50, 6012 – 6042.
[Ss]Ks + [Ss]Kss}[O2(f)]/k2s{1+1/[Sf]Kf + [Sf]Kff}[O2(s)].[15]
The
terms {1 + 1/Kf(or s) + [S]Kff(or ss)} show the substrate inhibition
by the fast and slow isomers, respectively. This equation
indicates that the relative reaction rate (k2f/k2s) and the
relative substrate inhibition observed for the slow- and fast-
isomer reactions might cancel out. Indeed, the relative
reaction rates determined by the oxidation of (S)- and (R)-
1-phenylethanols was as small as 1.04–1.18, although the
relative reaction rate observed in the oxidation of the
racemate was 23.
The above discussion is premised on the fact that SET is
the rate-determining step for the oxidation with 1 under
irradiation. We thus investigated the kinetics and KIE for the
alcohol oxidation when using 3 without irradiation, to
ascertain whether the oxidation with 3 follows the same
reaction pathway as that with 1 under irradiation (Scheme 1).
The KIE values for the oxidation of benzyl alcohol when
using 3 as the catalyst were determined to be 6.27 and 1.18 by
using an intermolecular competitive experiment and an
intermolecular noncompetitive experiment, respectively
(Table S2).[16] These KIE values indicate that this oxidation
process includes a hydrogen-atom transfer (HAT) step[17] but
the HAT step is not the rate-determining step.[4c] On the other
hand, the kinetics study showed that the oxidation is first
order with respect to catalyst and oxygen.[18] These results
indicate that the reactions with 1 and 3 follow an identical
reaction pathway and that SET is the rate-determining
step.[4c,19]
In summary, we have developed a highly efficient
oxidative kinetic resolution of activated and unactivated
secondary alcohols that makes use of an [(aqua)Ru(salen)]
complex (3) as the catalyst and air as the hydrogen acceptor at
room temperature. Increased substrate concentration was
found to negatively affect the oxidation rate, a result ascribed
to substrate inhibition based on the measurement of the
relative reaction rates in competitive and noncompetitive
experiments. To our knowledge, this is the first report that
addresses the influence of substrate inhibition on the relative
reaction rate of kinetic resolution.
[2] Selected reports of oxidative KR of secondary alcohols by using
molecular oxygen: a) D. R. Jensen, J. S. Pugsley, M. S. Sigman, J.
Am. Chem. Soc. 2001, 123, 7475 – 7476; b) E. M. Ferreira, B. M.
Stoltz, J. Am. Chem. Soc. 2001, 123, 7725 – 7726; c) D. E. J. E.
Robinson, S. D. Bull, Tetrahedron: Asymmetry 2003, 14, 1407 –
1446; d) S. K. Mandal, D. R. Jensen, J. S. Pugsley, M. S. Sigman,
J. Org. Chem. 2003, 68, 4600 – 4603; e) A. T. Radosevich, C.
Musich, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 1090 – 1091;
f) M. J. Schultz, M. S. Sigman, Tetrahedron Lett. 2006, 62, 8227 –
8241; g) S.-S. Weng, M.-W. Shen, J.-Q. Kao, Y. S. Munot, C.-T.
Chen, Proc. Natl. Acad. Sci. USA 2006, 103, 3522 – 3527; h) V. D.
Pawar, S. Bettigeri, S.-S. Weng, J.-Q. Kao, C.-T. Chen, J. Am.
Chem. Soc. 2006, 128, 6308 – 6309; i) C.-T. Chen, S. Bettigeri, S.-
S. Weng, V. D. Pawar, Y.-H. Lin, C.-Y. Liu, W.-Z. Lee, J. Org.
Chem. 2007, 72, 8175 – 8185; j) R. A. Shiels, K. Venkatasub-
baiah, C. W. Jones, Adv. Synth. Catal. 2008, 350, 2823 – 2834;
k) D. C. Ebner, J. T. Bagdanoff, E. M. Ferreira, R. M. MaFad-
den, D. D. Caspi, R. M. Trend, B. M. Stoltz, Chem. Eur. J. 2009,
15, 12978 – 12992; l) S.-J. Liu, L.-J. Liu, M. Shi, Appl. Organomet.
Chem. 2009, 23, 183 – 190, and references therein; m) S. K.
Alamsetti, P. Muthupandi, G. Sekar, Chem. Eur. J. 2009, 15,
5424 – 5427; n) T. Yamada, S. Higano, T. Yano, Y. Yamashita,
Chem. Lett. 2009, 38, 40 – 41; o) S. K. Alamsetti, S. Mannam, P.
Muthupandi, G. Sekar, Chem. Eur. J. 2009, 15, 1086 – 1090;
p) S. K. Alamsetti, G. Sekar, Chem. Commun. 2010, 46, 7235 –
7237.
[3] The kinetic resolution of sec-phenylethanol (krel = 1.67) by using
dioxygen as the hydrogen acceptor has been achieved by using
a Co salen complex as the catalyst: M. E. Beckett, R. Homer,
Inorg. Chim. Acta 1986, 122, L5 – L7.
[4] a) K. Masutani, T. Uchida, R. Irie, T. Katsuki, Tetrahedron Lett.
2000, 41, 5119 – 5123; b) H. Shimizu, K. Nakata, T. Katsuki,
Chem. Lett. 2002, 31, 1080 – 1081; c) H. Shimizu, S. Onitsuka, H.
Egami, T. Katsuki, J. Am. Chem. Soc. 2005, 127, 5396 – 5413;
d) H. Egami, S. Onitsuka, T. Katsuki, Tetrahedron Lett. 2005, 46,
6049 – 6052; e) H. Tanaka, H. Nishikawa, T. Uchida, T. Katsuki,
J. Am. Chem. Soc. 2010, 132, 12034 – 12041.
[5] a) J. T. Bagdanoff, B. M. Stoltz, Angew. Chem. 2004, 116, 357 –
361; Angew. Chem. Int. Ed. 2004, 43, 353 – 357; b) S. Arita, T.
Koike, Y. Kayaki, T. Ikariya, Angew. Chem. 2008, 120, 2481 –
2483; Angew. Chem. Int. Ed. 2008, 47, 2447 – 2449; c) T. Ikariya,
S. Kuwata, y. Kayaki, Pure Appl. Chem. 2010, 82, 1471 – 1483;
d) T. Kunisu, T. Oguma, T. Katsuki, J. Am. Chem. Soc. 2011, 133,
12937 – 12939.
[6] H. Mizoguchi, T. Uchida, K. Ishida, T. Katsuki, Tetrahedron Lett.
2009, 50, 3432 – 3435.
[7] S. Koya, Y. Nishioka, H. Mizoguchi, T. Uchida, T. Katsuki,
Angew. Chem. 2012, 124, 8368 – 8371; Angew. Chem. Int. Ed.
2012, 51, 8243 – 8246.
Experimental Section
General procedure for the OKR of secondary alcohols: Racemic
secondary alcohol (0.3 mmol), CHCl3 (1.0 mL), one drop of bicyclo-
hexyl as an internal standard for GC analysis, and MS 5 ꢀ (30 mg)
were placed in a test tube at 258C under air. After stirring for 30 min,
3 (5.1 mg, 6 mmol) was added to the mixture and aliquots (20 mL each)
of this suspension were removed immediately after the addition, as
the time-point zero sample, and then at appropriate intervals of time.
Each aliquot (20 mL) was diluted with MeOH (0.6 mL) and submitted
to GC analysis with a chiral column to determine the conversion and
ee values.
[8] For the preparation of [(aqua)Ru(Cl)(salen)] complexes, see the
Supporting Information.
[9] Based on this discovery, we have reported that (Ra,S)-8 and its
tetrachloro derivative catalyze aerobic epoxidation (Ref. [7]).
Their catalytic activity was impaired by the addition of
molecular sieves.
[10] For the acceleration of ligand exchange by irradiation: a) J.
Bossert, C. Daniel, Coord. Chem. Rev. 2008, 252, 2493 – 2503;
Received: December 2, 2013
Published online: February 12, 2014
Keywords: aerobic oxidation · asymmetric catalysis · dioxygen ·
.
kinetic resolution · ruthenium
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b) H. T. Chifotides, D. A. Lutterman, K. R. Dunbar, C. Turro,
Inorg. Chem. 2011, 50, 12099 – 12107.
[11] MS not only serve as drying agents but also have acid-base
effects on catalysis and these effects differ between MS: N.
Fontes, J. Partridge, P. J. Halling, S. Barreiros, Biotechnol.
Bioeng. 2002, 77, 296 – 305.
1999, 142, 367 – 372; d) A. Watanabe, T. Uchida, R. Irie, T.
Katsuki, Proc. Natl. Acad. Sci. USA 2004, 101, 5737 – 5742.
[15] For calculation of relative reaction rates, see the Supporting
Information.
[16] For experimental details, see the Supporting Information
(Table S2).
[12] a) H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18, 249 – 330;
b) C. J. Sih, S.-H. Wu, Top. Stereochem. 1989, 19, 63 – 125; c) See
Ref.[1c]; d) E. Vedejs, M. Jure, Angew. Chem. 2005, 117, 4040 –
4069; Angew. Chem. Int. Ed. 2005, 44, 3974 – 4001.
[13] D. G. Blackmond, J. Am. Chem. Soc. 2001, 123, 545 – 553.
[14] Metal complexes of the second and third transition series can
adopt a seven-coordinate pentagonal bipyramidal geometry:
a) F. Corazza, E. Solari, C. Florlani, A. Chiesi-Villa, C. Guastini,
J. Chem. Soc. Dalton Trans. 1990, 1335 – 1344; b) T. Repo, M.
Klinga, P. Pietikꢃinen, M. Leskelꢃ, A.-M. Uusitalo, T. Pakkanen,
K. Hakala, P. Aaltonen, B. Lçfgren, Macromolecules 1997, 30,
171 – 175; c) Z. Gross, A. Mahammed, J. Mol. Catal. A: Chem.
[17] M. M. Whittaker, J. W. Whittaker, Biochemistry 2001, 40, 7140 –
7148.
[18] See the Supporting Information (Figures S3 and S4).
[19] In our previous paper on the OKR of secondary alcohols with
1 under irradiation (Reference [4c]), we determined the relative
rate constants at a substrate concentration of 0.1m. Based on the
present result, we reinvestigated the oxidation rate of 1-phenyl-
ethanol with 1 at several concentrations under irradiation and
observed substrate inhibition (see the Supporting Information).
It is thus likely that the reported krel values correspond to the
kSKS/kRKR values.
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