COMMUNICATION
Ruthenium-catalysed asymmetric hydrogenation of ketones using
QUINAPHOS as the ligand
Simon Burk,a Giancarlo Francio`a and Walter Leitner*ab
Received (in Cambridge, UK) 13th April 2005, Accepted 18th May 2005
First published as an Advance Article on the web 9th June 2005
DOI: 10.1039/b505195a
catalytic runs are summarised in Table 1. As benchmark
substrates, acetophenone 2a, 4-fluoro-acetophenone 2b and
4-methoxyacetophenone 2c have been chosen. The catalyst was
prepared in situ from [RuCl2(C6H6)]2, the ligand, a diamine co-
catalyst, and sodium tert-butoxide as activator following the
procedure described by Genov and Ager.6 In a first series of
experiments (entries 1–8), ethylendiamine 4 was used as the co-
catalyst. Using (Ra,RC)-1, 1-phenylethanol 3a was obtained with
moderate conversion (45%) and an ee of 65% under standard
reaction conditions{ (entry 1). By increasing the amount of base
from 4 mol% to 10 mol% almost quantitative conversion was
achieved with the same ee (entry 2). By using (Ra,SC)-1 as the
ligand under otherwise identical conditions, the hydrogenation of
2a was accomplished with similar conversion but with a
significantly higher ee of 80% (entry 3). Remarkably, an opposite
absolute configuration of the alcohol was found (R vs. S; entry 3
vs. entry 2) indicating that the transfer of the chiral information
from the ligand to the substrate is mainly controlled by the
stereocenter in the dihydroquinoline backbone. The same level of
enantioselectivity is retained also using a S/C of 5000. After 18 h,
31% conversion was achieved which corresponds to an average
TOF of 86 h21 (entry 4). An optimisation of the reaction
parameters towards higher catalyst activity was not pursued at this
stage of the investigation.
Highly enantioselective ruthenium-catalysed hydrogenation of
aromatic ketones is achieved with (Ra,SC)-QUINAPHOS in
the presence of achiral and chiral diamines as co-catalysts.
Asymmetric hydrogenation of ketones is an extremely useful
synthetic route to chiral alcohols. In contrast to functionalised
ketones in which a secondary coordination to the metal centre
enhances the reactivity and facilitates the transfer of the chiral
information, unfunctionalised ketones are much more
challenging substrates.1,2 It was not until the introduction of
[(diphosphine)RuCl2(diamine)] as catalyst systems3 that this
method gained an important place in the tool-box of the organic
chemist. Notably, the most effective ligands for this transformation
such as BINAP and its derivatives, PennPhos, DIOP, BDDP and
BICP are C2-symmetric.1 Very recently, it was shown that
monodentate phosphonites can serve as excellent ligands for
asymmetric hydrogenation of ketones.4 In some cases, an
enhancement of the stereoselectivity was observed by using
C1-symmetric diamines5 or achiral thioamines6 as co-catalysts.
The hydrogenation of substrate 2b bearing an electron with-
drawing group proceeded more slowly with both diastereomers of
QUINAPHOS leading to conversions between 32 and 34% after
16 h. With this substrate, (Ra,RC)-1 and (Ra,SC)-1 led to similar
enantioselectivities (albeit with opposite sign) of 69% (S) and 73%
(R), respectively (entries 5 and 6).
Recently, we introduced QUINAPHOS 1, a phosphine–
phosphoramidite ligand based on the 1,2-dihydroquinoline back-
bone.7 This bidentate ligand8 with two dissimilar phosphorous
donors was originally designed for rhodium catalysed asymmetric
hydroformylation. Indeed, QUINAPHOS accomplished the
asymmetric hydroformylation of styrene with good enantioselec-
tivities (ee up to 74%) and remarkable regioselectivities (.96%). At
the same time, high activities as well as high enantioselectivities
have been achieved in the hydrogenation of dimethyl itaconate and
methyl 2-acetoamidoacrylate (ee up to 99.4% and 97.8%,
The hydrogenation of 4-methoxy-substituted acetophenone 2c
carried out in the presence of (Ra,RC)-1 afforded 3c with 65%
conversion and an ee of 67% (S) (entry 7), whereas full conversion
and an ee of 86% (R) resulted by using (Ra,SC)-1 (entry 8). For
comparison, the hydrogenation of 1-acetonaphthone with the
system (S)-BINAP–ethylendiamine affords the corresponding
alcohol with an ee of only 57% (R).9 More recently, enantioselec-
tivities in the same range of those obtained with (Ra,SC)-1/4 have
been reported for a system comprising an achiral thioamine and
BICP.6
respectively; TOF . 35 000 h21 for dimethyl itaconate).7
A
strong cooperative effect of the two elements of chirality in these
two applications was observed. Whereas (Ra,SC)-1 was the
preferred ligand for hydroformylation, the (Ra,RC) diastereomer
works best in CLC hydrogenation.
We want to disclose here a further application of QUINAPHOS
in asymmetric catalysis, namely the highly enantioselective Ru-
catalysed hydrogenation of unfunctionalised ketones. Selected
In the next set of experiments the chiral diamine (S,S)-5 was
used as a co-catalyst (entries 9–14). Full conversion was obtained
in all cases, indicating that the amine has a pronounced influence
on reactivity and selectivity. The combination (Ra,RC)–1/(S,S)-5
afforded 3a almost as a racemic mixture (entry 9). The value of
6% ee (R) obtained in this experiment reflects two opposite
contributions. On one side, the system chiral phosphorous
ligand/achiral diamine (Ra,RC)-1/4 led to 3a with 65% ee (S)
*leitner@itmc.rwth-aachen.de
3460 | Chem. Commun., 2005, 3460–3462
This journal is ß The Royal Society of Chemistry 2005