Highly enantioselective catalytic asymmetric hydrogenation of b-keto
esters in room temperature ionic liquids†
Helen L. Ngo, Aiguo Hu and Wenbin Lin*
Department of Chemistry, CB#3290, University of North Carolina, Chapel Hill, NC 27599, USA.
E-mail: wlin@unc.edu
Received (in Columbia, MO, USA) 7th March 2003, Accepted 3rd June 2003
First published as an Advance Article on the web 26th June 2003
Polar phosphonic acid-derived Ru-BINAP systems were
used to catalyze asymmetric hydrogenation of b-keto esters
in room temperature ionic liquids (RTILs) with complete
conversions and ee values higher than those obtained from
homogeneous reactions in MeOH (up to 99.3%), and were
recycled by simple extraction and used for four times
without the loss of activity and enantioselectivity.
H
4
)(DMF)
synthesized by treating L
[Ru(benzene)Cl
2
Cl
2
and Ru(L
2
–H
–H
4
)(DMF) precatalysts were
2
Cl
2
1
4
and L –H with 0.46 equiv of
2
4
2
]
2
in DMF at 100 °C, respectively.
Catalytic asymmetric hydrogenation reactions have been estab-
lished as one of the most versatile and powerful methods for the
synthesis of optically pure organic compounds. Ru and Rh
We have examined the utility of Ru–(R)–L
for asymmetric hydrogenation of b-keto esters in RTILs butyl-
3-methylimidazolium tetrafluoroborate (BMImBF ), butyl-
3-methylimidazolium hexafluorophosphate (BMImPF ), and
propyl-2,3-dimethylimidazolium bis(trifluoromethylsulfony-
l)amide (DMPIIm).‡ We first attempted to hydrogenate methyl
1 2
and Ru–(R)–L
1
complexes of 2,2A-bis(diphenylphosphino)-1,1A-binaphthalene
4
(
BINAP) have been shown to be particularly effective asym-
6
metric catalysts for the hydrogenation of prochiral olefins,
ketones and other carbonyl compounds. High costs of both the
2
BINAP ligand and group 8 metals as well as the toxicity of trace
metal contaminants in the organic products have hindered their
industrial applications. Immobilization of such homogeneous
acetoacetate with 1 mol% precatalyst Ru–(R)–L
O (1 : 1 v/v) biphasic system. After 36 h of reaction at 1500
psi of H pressure, 3-hydroxybutyrate was obtained at a
1
in a DMPIIm/
H
2
2
asymmetric catalysts presents an interesting solution to these
reasonable conversion of 76%, but a modest ee of 33%. When
the hydrogenation reaction was carried out in pure DMPIIm
with 0.5 equiv of MeOH (relative to methyl acetoacetate) for 24
h, 3-hydroxybutyrate was obtained in 38% yield and 50% ee.
The use of increased amount of MeOH has drastically improved
the catalytic activity and enantioselectivity. Hydrogenation of
obstacles.3
Room temperature ionic liquids (RTILs) have recently
received a great deal of attention as alternative reaction media.4
RTILs have been used as alternative solvents for asymmetric
hydrogenation of arylacrylic acids to generate anti-inflamma-
5
methyl acetoacetate with 1 mol% precatalyst Ru–(R)–L in a
tory drugs Ibuprofen and Naproxen and asymmetric hydro-
1
6
homogeneous mixture of DMPIIm–MeOH (1 : 1 v/v) for 22 h
genation of enamides to give a-amino acids. The organic
products from these reactions were separated by extraction with
afforded 3-hydroxybutyrate in quantitative yield and 93% ee.
All the subsequent reactions were carried out in an equal
volume homogeneous mixture of RTIL and MeOH.
2
nonpolar solvents or supercritical CO while the IL phase
containing active catalysts could be reused several times
without significant deterioration of activity and enantioselectiv-
ity. RTILs thus represent an effective means for the immobiliza-
tion of expensive asymmetric catalysts.
To facilitate the separation of active catalysts from the
organic products, we have designed two polar derivatives of Ru-
BINAP precatalysts. Herein we wish to report their application
in highly enantioselective asymmetric hydrogenation of b-keto
esters in RTILs. These polar asymmetric catalysts immobilized
in the IL phase can be readily recycled and reused.
1 2
As shown in Table 1, Ru–(R)–L and Ru–(R)–L are highly
active for catalytic asymmetric hydrogenation of a wide range
of b-keto esters in the homogeneous RTIL–MeOH systems.
Although complete conversions have been achieved with three
different RTILs for all the b-keto esters, the enantioselectivity is
quite sensitive to the nature of RTILs. For Ru–(R)–L
1
4
precatalyst, BMImBF is the best choice of RTIL and afforded
ee values comparable to those obtained from homogeneous
reactions in MeOH (with the exception of methyl 2,2-dimethy-
lacetoacetate). Ru–(R)–L
1
performed poorly with methyl
2
,2-dimethylacetoacetate in all of the three RTILs. Complete
conversions and comparable ee’s were also achieved with lower
precatalyst loadings. In fact, methyl acetoacetate was hydro-
genated to give 3-hydroxybutyrate with 0.1 mol% Ru–(R)–L in
1
quantitative yield and 99% ee in 22 h.
2
Interestingly, Ru–(R)–L catalyzed highly enantioselective
hydrogenation of b-keto esters in all three RTILs, with ee values
higher than those obtained from homogeneous reactions in
MeOH. All the b-keto esters in Table 1 were hydrogenated in
the homogeneous RTIL–MeOH systems to give b-hydroxy
esters in quantitative yields and ee values ranging from 94.9%
to 99.3%. As shown in Table 1, these ee values compare
favorably with those obtained with Ru-BINAP catalyst in the
homogeneous DMPIIm–MeOH system (1:1 v/v).
We have also demonstrated that both the RTILs and catalysts
can be recycled and reused several times for asymmetric
hydrogenation of methyl acetoacetate. At the end of each
hydrogenation run, 3-hydroxybutyrate was readily extracted
with degassed hexanes. The IL phase was washed two more
1 2
Scheme 1 Synthesis of precatalysts Ru-L and Ru-L .
2
,2A-Bis(diphenylphosphino)-1,1A-binaphthyl-6,6A-bis(phos-
phonic acid), L –H (Scheme 1), was synthesized in 3 steps
1
4
starting from previously reported 2,2A-dihydroxy-1,1A-bina-
7
phthyl-6,6A-bis(diethylphosphonate), while 2,2A-bis(diphenyl-
phosphino)-1,1A-binaphthyl-4,4A-bis(phosphonic acid), L
2
–H
1
4
,
–
8
was synthesized according to a literature procedure. Ru(L
†
Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b3/b302637j/
1
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CHEM. COMMUN., 2003, 1912–1913
This journal is © The Royal Society of Chemistry 2003