Aerobic oxidative kinetic resolution of racemic secondary alcohols with chiral bifunctional amido complexes

Article abstract of DOI:10.1002/anie.200705875

(Chemical Presented) Up for air: The aerobic oxidative kinetic resolution of racemic secondary alcohols with chiral bifunctional Ir, Rh, and Ru catalysts proceeds smoothly under mild conditions to provide chiral alcohols with up to 99% ee, and O₂ serves as an excellent hydrogen acceptor.

Full text of DOI:10.1002/anie.200705875

Angewandte
Chemie
DOI: 10.1002/anie.200705875
Aerobic Oxidation
Aerobic Oxidative Kinetic Resolution of Racemic Secondary Alcohols
with Chiral Bifunctional Amido Complexes**
Sachiko Arita, Takashi Koike, Yoshihito Kayaki, and Takao Ikariya*
Catalytic hydrogen transfer between alcohols and ketones
offers a great opportunity to explore an attractive molecular
transformation because of its low cost and operational
simplicity.[1] We have developed chiral bifunctional Ru, Rh,
and Ir hydride complexes—[RuH(Tsdpen)(h6-arene)] and
[Cp*MH(Tsdpen)] (TsDPEN: N-(p-toluenesulfonyl)-1,2-
diphenylethylenediamine, Cp* = 1,2,3,4,5-pentamethylcyclo-
pentadienyl, M = Rh, Ir) as practical catalysts for the
asymmetric transfer hydrogenation of ketones.[1a–d,2] The
amine–hydrido complex has a sufficiently acidic NH proton
to activate ketones, leading to the amido complex along with
the formation of the reduction products. The resulting amido
complex readily dehydrogenates alcohols to regenerate the
amine–hydrido complex (Scheme 1). Because of its intrinsic
the amido complex. Based on the present new finding,[6] we
could successfully apply the aerobic oxidation to the kinetic
resolution of racemic secondary alcohols with chiral bifunc-
tional Ir, Rh, and Ru catalysts, in which O2 serves as a
hydrogen acceptor.
The newly developed {Cp*Ir} hydride complex 1a[7]
bearing a C–N chelate primary amine ligand prepared from
triphenylmethylamine reacts rapidly with O2 or air under mild
conditions to give the corresponding amido complex 2a
(Scheme 2). Monitoring a solution of 1a in [D8]THF under air
Scheme 2. Reaction of 1a with oxidants including O2, H2O2, and
tBuOOH.
at room temperature by 1H NMR spectroscopy showed a
rapid decrease in the intensity of a hydride signal at d =
À13.12 ppm and an increase in the characteristic signal due
to the NH moiety of 2a at d = 8.37 ppm, indicating the smooth
conversion to the amido complex (70% yield based on 1a) by
the action of O2.
Other oxidants like hydroperoxides also promoted the
transformation to 2a. The reaction of 1a with an equimolar
amount of H2O2 in [D8]THF for 24 h gave 2a in 95% yield in
Scheme 1. Hydrogen transfer with bifunctional molecular catalysts.
reversible nature, both forward and reverse reactions can be
utilized as the reduction of ketones and oxidation of alcohols,
respectively. However, the dehydrogenative oxidation reac-
tion with the related amine/amido catalysts has been inves-
tigated less, mainly because of the lack of appropriate
hydrogen acceptors, except for ketones for the kinetic
resolution of racemic alcohols,[3] intramolecular redox iso-
merization,[4] and other oxidative transformations.[5] We have
extended a conceptually new hydrogen-transfer protocol with
bifunctional catalysts and found that molecular oxygen
readily reacts with the amine–hydrido complex leading to
À
addition to a detectable amount of H2O. The O O bond
cleavage of peroxides with the hydrido complex 1a was also
clearly demonstrated in the treatment of tBuOOH, which
afforded 2a and tBuOH (26% yield). Although the precise
mechanism of the formation of 2a from 1a in the presence of
O2 has remained unclear, these findings as well as recently
reported results[6] imply that the reaction of 1a with O2 might
proceed through O2 insertion into the metal–hydride bond[8]
to form an amine–hydroperoxo complex, followed by the
release of 2a and H2O2.[9] The H2O2 product then reacts with
1a to provide 2a and water.
[*] S. Arita, Dr. T. Koike, Dr. Y. Kayaki, Prof. Dr. T. Ikariya
Department of Applied Chemistry
Graduate School of Science and Engineering
Tokyo Institute of Technology
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552 (Japan)
Fax: (+81)3-5734-2637
Encouraged by the rapid conversion of 1a with O2 into 2a,
we next examined the catalytic aerobic dehydrogenative
oxidation of 1-phenylethanol with Ir complexes bearing C–N
chelate ligands; representative results are shown in Scheme 3.
Exposure of a THF solution containing 1-phenylethanol and
1a (S/C = 10:1) to air at room temperature gave acetophe-
none in 63% yield after 3 h.[10] Comparable catalyst perfor-
mance was observed for the reaction with the amido complex
E-mail: tikariya@apc.titech.ac.jp
[**] This work was financially supported by a Grant-in-Aid fromthe
Ministry of Education, Culture, Sports, Science and Technology
(Japan) (No. 18065007) and partially supported by The 21st Century
COE and G-COE Programs.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
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under dilute conditions. The desired R alcohol with 98% ee
was recovered in 48% yield and the kf/ks value was up to 90
(entry 5, Table 1). A 1-phenylethanol derivative having an
electron-donating CH3O group at the para position was
efficiently resolved with catalyst 2d (entry 6, Table 1).
Similarly, the R enantiomers with > 99% ee and with 46–
50% yields were readily obtainable from the reactions of 1-
indanol and 1-tetralol at ambient temperature (entries 7 and
8, Table 1).
The reaction with the binary catalyst system including
=
[Cp*IrCl((S,S)-Tscydn)] (4) (TsCYDN N-(p-toluenesul-
fonyl)-1,2-cyclohexanediamine) and tBuOK proceeded
equally well to provide (R)-1-phenylethanol with an excellent
ee value of 98% in 45% recovered yield (entry 9, Table 1).
Additionally, the added base did not promote any harmful
Scheme 3. Aerobic oxidation of 1-phenylethanol using C–N chelate
complexes.
2a. Notably, the hydrido complex 3 bearing an N,N-dimethyl-
amino group did not catalyze the
Table 1: Aerobic oxidative kinetic resolution of secondary alcohols.[a]
oxidation under otherwise identical
conditions, indicating that the
metal/NH units possibly participate
in the activation of O2 to facilitate
transformation to the amido com-
plex.
This aerobic oxidation of alco-
hols is more appealing when
applied to the kinetic resolution of
racemic secondary alcohols with
chiral amido catalysts.[11,12] The effi-
ciency is significantly influenced by
the redox properties of the alcohols
and the reaction conditions as well
as the chiral catalyst performance.
When a THF solution of race-
mic 1-phenylethanol (1.0m) and the
chiral Ir complex 2b derived from
(R)-1-naphthylethylamine (S/C =
10) was treated with air at 308C
for 4 h, (R)-1-phenylethanol was
recovered with a 48% yield and
14% ee (entry 1, Table 1). The same
reaction but at higher dilution (0.1m
substrate) led to a marked increase
in the ee value, up to 42% (entry 2,
Table 1). Noticeably, the use of the
chiral amido Ir complex bearing an
N-sulfonylated diamine ligand,
[Cp*Ir((S,S)-Tsdpen)] (2c),[2] sig-
nificantly improved the enantio-
mer-discrimination ability, and (R)-
1-phenylethanol was recovered in
39% yield and 86% ee with a kf/ks
ratio[13] of 9, although a prolonged
reaction time was necessary for
completion (entry 3, Table 1). Fur-
ther improvement in the stereo-
chemical outcome of the reaction
was possible when the reaction with
[Cp*Ir((S,S)-Msdpen)] (2d) (Ms =
Entry
1
Alcohol
Conc.
[m]
Cat.
t
[h]
Unreacted alcohol
recov. [%][b]
ee [%][c]
kf/ks[d]
1.0
2b
4
48
14
1.5
2
3
4
5
0.1
1.0
1.0
0.2
2b
2c
2d
2d
75
24
22
38
48
39
44
48
42
86
84
98
3.3
9.1
12.6
91.3
6
0.2
2d
19
6
38
98
17.2
7
8
9
0.1
0.1
1.0
2d
2d
4[e]
50
46
45
>99
>99
98
>100
6.5
77.6
40.8
24
10
11
1.0
1.0
5[e]
6[e]
3.5
12
46
78
93
23
28.9
12.3
[a] Reaction conditions: The reaction was carried out with a solution of alcohol (1.1 mmol) in THF and a
substrate/catalyst ratio of 10 under air. [b] Recovered starting material; determined by GC using durene
as an internal standard. [c] Determined by HPLC on a Daicel Chiralcel OD column. [d] ln[1ÀC)(1Àee)]/
methanesulfonyl) was carried out ln[(1ÀC)(1+ee)]. [e] tBuOK (1.5 equiv) was added.
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Chemie
side reactions as observed in our previous work.[3a] The
resolution with the chiral amido Rh catalyst generated
analogously from [Cp*RhCl((S,S)-Tsdpen)] (5) and the base
proceeded faster to completion, providing the desired chiral
alcohols with 93% ee (entry 10, Table 1), while the related
chiral Ru complex, [RuCl((S,S)-Tsdpen)(p-cymene)] (6) gave
unsatisfactory results (entry 11, Table 1).
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[6] During the preparation of this manuscript, studies on the
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In summary, we found facile hydrogen transfer from the
amine–hydrido complex to the oxygen molecule, generating
the corresponding amido complex. Based on the finding that
O2 is a promising hydrogen acceptor, we successfully demon-
strated the first example of aerobic oxidative kinetic reso-
lution of racemic secondary alcohols with well-defined
bifunctional catalysts, providing chiral alcohols with up to
99% ee. The present aerobic oxidative transformation with
the bifunctional catalysts is a clean process that proceeds
under mild conditions with high efficiency and minimal
organic waste. Further efforts to improve the rate of the
reaction and to clarify the mechanism for the hydrogen
transfer to oxygen and to expand further the scope of the
aerobic oxidation are now underway.
[7] Details of the synthesis and structures of {Cp*Ir} complexes
examined will be published separately; S. Arita, T. Koike, T.
Ikariya, manuscript in preparation; see also the Supporting
Information.
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Experimental Section
General procedure for the aerobic kinetic resolution of secondary
alcohols: A 20-mL Schlenk flask was charged with the catalysts
(0.11 mmol), durene (0.024 mg, 1.1 mmol; an internal standard), and
THF (1.1 mL) under Ar atmosphere. After the secondary alcohols
(1.1 mmol) had been introduced, the flask was evacuated and filled
with air. The reactions were carried out at 308C under an air balloon
and monitored by gas chromatography and HPLC to determine the
conversion and ee values. The methods utilized for the determination
of enantiomeric excesses are summarized in Table S1 in the
Supporting Information.
[9] Facile protonation of alkoxo ligands by acidic coordinated amine
protons on the amine–alkoxo complexes to give the correspond-
ing amido complexes has been reported; T. Koike, T. Ikariya,
Organometallics 2005, 24, 724 – 730.
Received: December 21, 2007
Published online: February 22, 2008
[10] Indirect reoxidation of Ru hydrides by molecular oxygen by
electron transfer was reported by Bäckvall and co-workers: G.
Csjernyik, A. H. Éll, L. Fadini, B. Pugin, J.-E. Bäckvall, J. Org.
Chem. 2002, 67, 1657 – 1662.
[11] Pd-catalyzed aerobic oxidative kinetic resolution of alcohols:
a) D. R. Jensen, J. S. Pugsley, M. S. Sigman, J. Am. Chem. Soc.
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Res. 2006, 39, 221 – 229. See also references therein.
[12] Other examples of the asymmetric aerobic oxidation of alcohols:
a) A. T. Radosevich, C. Musich, F. D. Toste, J. Am. Chem. Soc.
2005, 127, 1090 – 1091; b) H. Shimizu, S. Onitsuka, H. Egami, T.
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Nakamura, H. Egami, K. Matsumoto, T. Uchida, T. Katsuki,
Tetrahedron 2007, 63, 6383 – 6387, and references therein.
[13] V. S. Martin, S. S. Woodard, T. Katsuki, Y. Yamada, M. Ikeda,
K. B. Sharpless, J. Am. Chem. Soc. 1981, 103, 6237 – 6240.
Keywords: alcohols · homogeneous catalysis · iridium ·
kinetic resolution · oxidation
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