A new NCN pincer ruthenium complex and its catalytic activity for enantioselective hydrogenation of ketones

Article abstract of DOI:10.1039/b800387d

New bis(oxazolinyl)phenyl-ruthenium(ii) complexes, which were synthesized by C-H bond activation with RuCl₃·3H₂O in zinc powder and 1,5-cyclooctadine followed by ligand exchange reaction with sodium acetylacetonate or acetylacetone,

Full text of DOI:10.1039/b800387d

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A new NCN pincer ruthenium complex and its catalytic activity for
enantioselective hydrogenation of ketonesw
Jun-ichi Ito, Satoshi Ujiie and Hisao Nishiyama*
Received (in College Station, MA, USA) 10th January 2008, Accepted 18th February 2008
First published as an Advance Article on the web 12th March 2008
DOI: 10.1039/b800387d
New bis(oxazolinyl)phenyl–ruthenium(II) complexes, which were
synthesized by C–H bond activation with RuCl3ꢀ3H2O in zinc
powder and 1,5-cyclooctadine followed by ligand exchange
reaction with sodium acetylacetonate or acetylacetone, exhibited
enantioselective hydrogenation of ketones in up to 90% ee.
which has a dimeric constitution of [(Phebox-ip)Ru(CO)Cl]2-
(ZnCl2) (Scheme 1).11 The dimeric complex was in turn treated
with sodium acetylacetonate [Na(acac)] at room temperature
for 12 h to furnish (Phebox-ip)Ru(CO)(acac) 2a in 90% yield.
In place of Na(acac), acetylacetone can also be used. Alter-
natively, direct addition of acetylacetone at room temperature
to a reaction mixture of RuCl3ꢀ3H2O and 1a in EtOH and
further stirring for 20 h produced the complex 2a in 47% total
yield in two steps. Similarly, phenyl-substituted complex 2b
could be synthesized in 45% yield from 1b by the sequential
method with acetylacetone.z
Chiral nitrogen-based pincer-type ligands such as NNN,
NCN, NNC, NPN, NNP etc. have successfully been applied
to ruthenium catalysed enantioselective hydrogenation and
transfer hydrogenation reactions of ketones.1,2 As we reported
that rhodium and platinum catalysts with bis(oxazolinyl)phe-
nyl (= Phebox) ligand of NCN type pincers have been applied
for highly enantioselective reactions,3 for example, allylation
of aldehydes,4 Michael addition,5 conjugate reduction,6 re-
ductive aldol reactions,7 and direct aldol reaction,8 we were
encouraged to synthesise a ruthenium complex of Phebox for
enantioselective hydrogenation of carbonyl compounds. It is
of note that the bis(oxazolinyl) moiety of Phebox, which
provides a C2-symmetric and meridional environment around
the metal center, would create a suitable catalyst to distinguish
prochiral faces of substrates. To our best knowledge, only one
example of an in situ ruthenium catalyst bearing a bis(oxazo-
linyl)benzene moiety was demonstrated for enantioselective
cylcopropanation as disclosed by Iwasa and co-workers.9 We
report here the first synthesis and structural characterization
of a Phebox–ruthenium(II) complex [abbreviated as (Phebox)-
Ru] and its application for enantioselective hydrogenation and
transfer hydrogenation.
The molecular structure of 2a was confirmed by X-ray
diffraction (Fig. 1). The Ru center is described to have a
distorted octahedral geometry with meridionally coordinated
Phebox-ip ligand and bidentate acetylacetonato ligand. The
CO ligand is perpendicular to the Phebox plane.
Next, asymmetric hydrogenation of several simple ketones
was attempted with chiral (Phebox)Ru complexes 2a and 2b.
An initial reaction was carried out using para-methoxyphenyl
methyl ketone 3a in isopropyl alcohol (IPA) with 1 mol% of 2
and 20 mol% of NaOMe at 40 1C for 24 h under 30 atm of
hydrogen pressure.z The corresponding alcohol 4a, (S)-1-
(para-methoxyphenyl)-1-ethanol, was successfully obtained
We started by choosing the 4,6-dimethyl derivative of chiral
1,3-bis(oxazolinyl)benzene 1 as a precursor for complex for-
mation with ruthenium atom via C–H bond activation at the
2-position.10 The dimethyl substitution at 4- and 6-positions
could block undesirable metallation by C–H bond activation
at those positions. Simple heating of a mixture of RuCl3ꢀ3H2O
and 1a (R = i-Pr) in refluxing EtOH with Et3N resulted in the
formation of complicated solid mixtures to give no isolable
ruthenium complexes. Reactions of 1a with common ruthe-
nium(II) complexes, such as [RuCl2(COD)]2 (COD = 1,5-
cyclooctadiene) and [RuCl2(C6H6)]2, also failed. However,
zinc powder in the presence of COD with RuCl3ꢀ3H2O and
1a successfully afforded a ruthenium complex in 65% yield,
Department of Applied Chemistry, Graduate School of Engineering,
Nagoya University, Chikusa, Nagoya 464-8603, Japan. E-mail:
hnishi@apchem.nagoya-u.ac.jp; Fax: +81-52-789-3209
w Electronic supplementary information (ESI) available: Experimental
section and analytical data. CCDC 673251. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/b800387d
Scheme 1 Synthesis of (Phebox)Ru complexes.
Chem. Commun., 2008, 1923–1925 | 1923
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Scheme 3 Asymmetric transfer hydrogenation of ketone.
Fig. 1 ORTEP diagram of 2a with 50% probability level. Hydrogen
atoms are omitted for clarity. Selected bond lengths (A) and angle (1):
Ru1–C1 1.976(3), Ru1–C26 1.813(5), Ru1–N1 2.095(3), Ru1–N2
2.126(3), Ru1–O3 2.125(3), Ru1–O4 2.201(3); N1–Ru1–N2 156.52(11).
in 98% yield and 65% ee with 2a and in 87% yield and 56% ee
with 2b, respectively (Scheme 2). Other base sources such as
NaOEt, NaOt-Bu, KOt-Bu, and LiOMe provided similar
results, 98–99% yields and 51–63% ees, whereas use of
K2CO3 and Cs2CO3 resulted in low yields (3–11%) and low
selectivity (22–37% ees). The hydrogenation did not proceed
in the absence of the bases. Under the same reaction condition,
several ketones, o-MeOC6H4COMe 3b, 2-NaphCOMe 3c,
PhCOi-Pr 3d, and PhCOn-C5H11 3e, were examined to give
Fig. 2 Hypothetical stereochemical course.
the corresponding secondary alcohols, 4b–4e in 81–90% ees.
The enantioselectivity thus changed depending on the combi-
nation between the substituents of ketones and substituents of
the ligands.
In the absence of hydrogen, the transfer hydrogenation of
the ketone 3c with catalyst 2b (1 mol%) at 80 1C was found to
proceed giving the alcohol (S)-4c in 95% yield with 81% ee
(Scheme 3). However, use of catalyst 2a drastically decreased
the ee to 15%.
The hydrogenation and the transfer hydrogenation with
(Phebox)Ru catalysts afforded alcohols with the same
S-absolute configuration. We propose a hypothetical reaction
course for the hydrogenations as follows: the monohydride
species (Phebox)Ru(H)(CO) may be formed by elimination of
acac ligand from 2, followed by activation of molecular
hydrogen by a base. Alternatively, b-H elimination of a
Ru–OCH(CH3)2 intermediate, which is generated by exchange
of the acac ligand with NaOiPr, may provide the hydride
intermediate in the case of transfer hydrogenation. Judging
from the S-absolute configuration of the product alcohols, the
transition state I that apical hydride attacks Re-face of ketone
could be proposed (Fig. 2).
In summary, the first synthesis of ruthenium complexes with
the bis(oxazolinyl)phenyl moiety has been described via C–H
activation using commercially available ruthenium chloride in
the presence of zinc powder. It was also found that the
(Phebox)Ru complex catalyses the enantioselective hydroge-
nation of ketones in isopropyl alcohol with NaOMe to afford
Scheme 2 Enantioselective hydrogenation of ketones.
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the corresponding S-alcohols with enantioselectivity up to
90% ee. We are now studying on the scope and limitations
of the hydrogenations and further applications of the
(Phebox)Ru complex as a potential catalyst for a variety of
enantioselective reactions.
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This research was partly supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan (460:18065011), the
Japan Society for the Promotion of Science (18350049),
G-COE in Chemistry (Nagoya University).
Notes and references
z Procedure of the hydrogenation. To a stainless steel autoclave were
added 2 (0.010 mmol), NaOMe (0.20 mmol), isopropyl alcohol (10
mL) and ketone (1.0 mmol) under an argon atmosphere. After purging
with H2, the H2 pressure was adjusted to 30 atm. The mixture was
stirred at 40 1C for 24 h, and then the solvent was removed under
reduced pressure. The residue was purified by column chromatogra-
phy on silica gel (hexane–ethyl acetate, 10 : 1) to yield white solids of
the alcohol. The enantioselectivity was determined using HPLC with a
suitable chiral column; see ESI.w
1 D. Morales-Morales and C. M. Jensen, The Chemistry of Pincer
Compounds, Elsevier, Amsterdam, 2007.
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425; (b) Y. Jiang, Q. Jiang and X. Zang, J. Am. Chem. Soc., 1998,
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M. K. Tse, B. Bitterlich, K. Junge, G. Erre and M. Beller, Adv.
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Gossage, S. Gladiali and G. van Koten, Angew. Chem., Int. Ed.,
10 J. Ito, T. Shiomi and H. Nishiyama, Adv. Synth. Catal., 2006, 348,
1235.
11 The constitution of the complex was determined by elemental
analysis. The 1H NMR spectrum indicates an unsymmetric structure.
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