Palladium-catalyzed asymmetric hydrogenation of functionalized ketones

Article abstract of DOI:10.1021/ol051007u

(Chemical Equation Presented) A novel catalytic system for asymmetric hydrogenation of functionalized ketones has been developed using a Pd/bisphosphine complex as the catalyst in 2,2,2-trifluoroethanol. The reaction exhibits high enantioselectivity, and

Full text of DOI:10.1021/ol051007u

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3235-3238
Palladium-Catalyzed Asymmetric
Hydrogenation of Functionalized
Ketones
You-Qing Wang, Sheng-Mei Lu, and Yong-Gui Zhou*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan
Road, Dalian 116023, The People’s Republic of China
ygzhou@dicp.ac.cn
Received May 3, 2005
ABSTRACT
A novel catalytic system for asymmetric hydrogenation of functionalized ketones has been developed using a Pd/bisphosphine complex as
the catalyst in 2,2,2-trifluoroethanol. The reaction exhibits high enantioselectivity, and up to 92.2% ee was obtained.
Transition-metal-catalyzed asymmetric synthesis is one of
the most powerful methods for preparing a wide range of
enantiomerically pure compounds and has turned into one
of the most important fields at the interface between organic
synthesis and organometallic chemistry.1 Among the different
catalytic methods, asymmetric hydrogenation utilizing mo-
lecular hydrogen to reduce prochiral substrates is one of the
most efficient.1,2 In the past 30 years, there were many
successful examples and high enantioselectivities were
achieved in asymmetric hydrogenation of prochiral ketones
to yield optically active secondary alcohols by using chiral
Ru, Rh, and Ir complexes (eq 1).1-3
Although a large number of Pd-based catalytic systems have
been developed for many kinds of reactions of a wide range
of compounds,4,5 palladium chemistry has still not achieved
its full potential. The search for the improvement of
palladium-catalyzed reactions continues with the goal of
increasing the diversity of possible substrates and reaction
types. For example, very little attention has been paid to
palladium-catalyzed homogeneous asymmetric hydrogenation
reactions, although many successful examples of heteroge-
neous asymmetric hydrogenation reactions catalyzed by Pd-
(0) have been well documented in the literature.6 Amii and
co-workers reported a good enantioselective hydrogenation
of R-fluorinated iminoesters in 2,2,2-trifluoroethanol using
Pd(CF3CO2)2/BINAP as catalyst with up to 91% ee.7 In 2003,
(2) (a) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (b) Noyori,
R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40. (c) Knowles, W. S.
Angew. Chem., Int. Ed. 2002, 41, 1998. (d) Rossen, K. Angew. Chem., Int.
Ed. 2001, 40, 4611. (e) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(3) Ir-catalyzed asymmetric hydrogenation of ketones: Zhang, X.;
Taketomi, T.; Yoshizumi, T.; Kumobayashi, H.; Akutagawa, S.; Mashima,
K.; Takaya, H. J. Am. Chem. Soc. 1993, 115, 3318.
(4) (a) Tsuji, J. Palladium Reagents and Catalysis; John Wiley & Sons:
Chichester, 2004. (b) Negishi, E. Handbook of Organopalladium Chemitry
for Organic Synthesis; Wiley: Hoboken, NJ, 2002. (c) Heck, R. F.
Palladium Reagents in Organic Synthesis; Academic: New York, 1985.
(5) Recent reviews about Pd chemistry: (a) Special issue: Palladium
Chemistry in 2003: Recent Developments. J. Organomet. Chem. 2003, 687,
209-590. (b) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. ReV. 2004, 104, 3453.
Recently, Pd complexes have become indispensable tools
for both common and state-of-the art organic synthesis.4
(1) (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: New York, 1999. (b) Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York,
2000.
10.1021/ol051007u CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/24/2005

Alper et al. reported palladium-catalyzed asymmetric double
carbohydroamination of iodobenzene for the synthesis of
chiral R-aminoamides with high enantioselectivity. The
catalytic cycle they suggested involved palladium-catalyzed
asymmetric hydrogenation of R-iminoamide intermediates;
however, no evidence was given.8 More recently, Raja and
Thomas reported a heterogeneous asymmetric hydrogenation
of R-ketoesters with catalyst Pd(allyl)diamino triflate an-
chored to the inner wall of mesoporous supports by the
surface-bound triflate counterion with 67% ee, but in
homogeneous form, only 55% ee was obtained.9 So, the
search for an efficient homogeneous palladium catalytic
system for asymmetric hydrogenation of ketones is still a
challenge. In the course of our research on asymmetric
hydrogenation of heteroaromatic compounds,10 we became
interested in exploring Pd-catalyzed asymmetric hydrogena-
tion of ketones (eq 2). Herein, we report our preliminary
results of asymmetric hydrogenation of a class of function-
alized ketones using homogeneous palladium catalysts, where
up to 92.2% ee was achieved.
The enantioslective hydrogenantion of protected amino
ketones is one of the efficient methods to obtain the
corresponding chiral amino alcohols, which are important
compounds as biologically active molecules and chiral
auxiliaries.11 High enantioselectivity have been achieved
upon asymmetric hydrogenation of R-phthalimide ketones12
with Ru-phosphine complexes.13 We chose 2-phthalimide-
1-phenylethanone (1a) as a hydrogenation model substrate
and carried out our initial experiments employing a Pd-
(OCOCF3)2/(S)-SYNPHOS system in 2,2,2-trifluoroethanol
(TFE) under 1000 psi of hydrogen. It was pleasing to find
that a promising result (77.5% ee and conversion 91%) was
obtained (entry 1, Table 1).
We further performed a systematic investigation on the
asymmetric hydrogenation of 1a. The results are summarized
in Table 1. First, the effect of the temperature and the
pressure was studied. When the reaction was carried out at
50 °C, slightly lower enantioselectivities were obtained (entry
2). Hydrogen pressure had no dramatic effect on enantiose-
lectivity (entries 2-5). Second, the effect of solvent was also
investigated; it was found that this reaction was strongly
solvent-dependent (entries 4, 6-12). Only TFE is most
effective in terms of the conversion and enantioselectivity,
which agreed with Pd-catalyzed asymmetric hydrogenation
of R-fluorinated iminoesters reported by Amii et al.7a 1,2-
Dichloroethane (DCE) gave low conversion with similar
enantioselectivities (entry 10), and other solvents led to low
activity. Other Pd catalyst precursors were also tested in the
reaction (entries 13-16). Pd(CH3CO2)2 gave moderate
conversion with slightly lower ee (entry 13), whereas cationic
Pd(OTf)2 provided a result equivalent to that of Pd(CF3CO2)2
(entries 4 vs 14). Metal precursors with halide had also no
catalytic activity (entry 15), which might be ascribed to the
strong coordinated character of chloride ion, which occupied
the coordination site of the central metal palladium, which
might play an important role in the activity. Pd(0) species
was also unable to catalyze this reaction (entry 16).
Subsequently, we turned our attention to the effect of
various commercially available chiral ligands (Figure 1) on
Table 1. Optimizaion of Reaction Conditions for Pd-Catalyzed
Asymmetric Hydrogenation of R-Phthalimide Ketonea
entry Pd precursor solvent H2 (psi) conv (%)b ee (%)c
1d
2
3
4
5
6
7
8
9
10
11
12
13
14e
15e
16
Pd(CF3CO2)2 TFE
Pd(CF3CO2)2 TFE
Pd(CF3CO2)2 TFE
Pd(CF3CO2)2 TFE
Pd(CF3CO2)2 TFE
Pd(CF3CO2)2 i-PrOH
Pd(CF3CO2)2 EtOH
Pd(CF3CO2)2 MeOH
Pd(CF3CO2)2 THF
Pd(CF3CO2)2 DCE
Pd(CF3CO2)2 acetone
Pd(CF3CO2)2 toluene
Pd(CH3CO2)2 TFE
1000
1000
600
200
40
200
200
200
200
200
200
200
200
200
200
200
91
>95
>95
>95
>95
<5
<5
<5
<5
16
<5
<5
44
>95
<5
77.5
77.0
76.0
76.4
75.2
N/A
N/A
N/A
N/A
74.4
N/A
N/A
74.2
76.4
N/A
N/A
Figure 1. Various chiral ligands.
the asymmetric hydrogenation using Pd(CF3CO2)2 as metal
precursor in TFE under 200 psi of hydrogen at 50 °C (Table
2). The results showed that monophosphine ligand MOP (L2)
Pd(OTf)2
PdCl2
TFE
TFE
TFE
Pd2(dba)3
<5
(6) Recent literature on heterogeneous Pd enantioselective hydrogenation.
Reviews: (a) Studer, M.; Blaser, H.-U.; Exner, C. AdV. Synth. Catal. 2003,
345, 45. (b) Baiker, A. J. Mol. Catal. A: Chem. 2000, 163, 205.
Communications: (c) Glorius, F.; Spielkamp, N.; Holle, S.; Goddard, R.;
Lehmann, C. W. Angew. Chem., Int. Ed. 2004, 43, 2850. (d) Mhadgut, S.
C.; Bucsi, I.; Toeroek, M.; Toeroek, B. Chem. Commun. 2004, 984. (e)
Raynor, S. A.; Thomas, J. M.; Raja, R.; Johnson, B. F. G.; Bell, R. G.;
Mantle, M. D. Chem. Commun. 2000, 1925.
a Unless otherwise stated, reactions were performed on a 0.25-mmol
scale: Pd precursor 2 mol %, (S)-SYNPHOS 2.4-3.0 mol %, 12 h, 50 °C
(oil bath temperature). b Determined by 1H NMR analysis of the crude
product. c Determined by HPLC analysis. d The reaction was carried out at
room temperature. e Pure complex (2 mol %)14 was used.
3236
Org. Lett., Vol. 7, No. 15, 2005

Table 2. Ligand Screening for Pd-Catalyzed Asymmetric
Hydrogenation of R-Phthalimide Ketonea
Table 3. Asymmetric Hydrogenation of R-Phthalimide Ketones
Catalyzed by a Pd(OCOCF3)2/(R,R)-Me-DuPhos System15
entry
R of 1
C6H5 (1a)
temp (°C)a
conv (%)
ee (%)
entry
ligand
conv (%)b
ee (%)c
configurationd
1
2
3
4
5b
6
7
8
50
50
50
75
50
50
75
75
50
50
50
>95
>95
>95
>95
94
>95
>95
72
91.7
92.2
92.2
90.4
75.2
92.0
80.4
88.2
89.8
88.0
N/A
1
2e
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
>95
<5
<5
<5
22
76.4
N/A
N/A
N/A
48.6
74.3
79.3
91.7
58.4
S
p-FC6H4 (1b)
p-MeC6H4 (1c)
p-PhC6H4 (1d)
p-MeOC6H4 (1e)
m-MeOC6H4 (1f)
o-MeOC6H4 (1g)
2-naphthyl (1h)
Me (1i)
R
R
S
R
R
82
>95
>95
17
9
10
11
>95
>95
tBu (1j)
p-BrC6H4 (1k)
a Unless otherwise stated, reactions were performed on a 0.25-mmol
scale: Pd(CF3CO2)2 2 mol %, ligand 2.4 mol %, H2 200 psi, TFE, 12 h, 50
°C (Oil bath temperature). b Determined by 1H NMR analysis of the crude
products. c Determined by HPLC analysis. d Determined by comparison of
rotation sign with literature data. e L2 (4.4 mol %) was used.
a Oil bath temperature. b (S)-SYNPHOS was used.
(1k) with a bromo goup (entry 11), no desired product was
obtained under the standard condition; the reason might be
catalyst poisoning for oxidative addition of palladium and
aromatic bromine. It is noteworthy that this is the first
example with a Pd/bisphosphines complex as a homogeneous
asymmetric hydrogenation catalyst of ketones.
To further expand the utility of this Pd-catalyzed asym-
metric hydrogenation of ketones, other ketones have been
examined under standard condition (Figure 2).15 Hydrogena-
had almost no catalytic activity (entry 2). P,N-ligand L3 and
N-containing bisphosphine ligand L4 also showed very low
activity (entries 3 and 4). Those other chiral bisphosphine
ligands tested exhibited moderate to high conversion (entries
1, 5-9), whereas the best result (up to 91.7% ee with more
than 95% conversion) was achieved with electron-rich (R,R)-
Me-DuPhos L7 (entry 7).
Under optimized condition, a variety of substituted R-ph-
thalimide ketones were hydrogenated to yield their corre-
sponding secondary alcohols (Table 3).15 Both electron-
deficient and electron-rich aryl ketones can be hydrogenated
in high enantioselectivities (entries 1-8); up to 92.2% ee of
hydrogenated products were obtained for para-substituted
1b (entry 2) and 1c (entry 3). For o-methoxy-substituted aryl
ketone (1g), slightly lower enantioselectivities were obtained
(entry 7). Alkyl ketones and even simple methyl ketone gave
good asymmetric induction (entries 9 and 10). For substrate
Figure 2. Asymmetric hydrogenation of other ketones: 3, 4 with
Pd(CF3CO2)2/(R,R)-Me-DuPhos, and 5 with Pd(CF3CO2)2/(S)-
SYNPHOS.
(7) (a) Abe, H.; Amii, H.; Uneyama, K. Org. Lett. 2001, 3, 313. (b)
Suzuki, A.; Mae, M.; Amii, H.; Uneyama, K. J. Org. Chem. 2004, 69, 5132.
(8) Nanayakkara, P.; Alper, H. Chem. Commun. 2003, 2384.
(9) Raja, R.; Thomas, J. M.; Jones, M. D.; Johnson, B. F. G.; Vaughan,
D. E. W. J. Am. Chem. Soc. 2003, 125, 14982.
(10) (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou.; Y.-
G. J. Am. Chem. Soc. 2003, 125, 10536. (b) Yang, P.-Y.; Zhou, Y.-G.
Tetrahedron: Asymmetry 2004, 15, 1145.
(11) (a) Bergmeier, S. C.Tetrahedron 2000, 56, 2561. (b) Ager, D. J.;
Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835. (c) Cardillo, G.;
Tomasini, C. Chem. Soc. ReV. 1996, 25, 117. (d) Bogevig, A.; Pastor, I.
M.; Adolfsson, H. Chem. Eur. J. 2004, 10, 394. (e) Petra, D. G. I.; Reek,
J. N. H.; Handgraaf, J. W.; Meijer, E. J.; Dierkes, P.; Kamer, P. C. J.;
Brussee, J.; Schoemaker, H. E.; Van Leeuwen, P. W. N. M. Chem. Eur. J.
2000, 6, 2818. (f) Atkinson, R. S.; Kelly, B. J. J. Chem. Soc., Chem.
Commun. 1987, 1362.
tion of ketone 3 with a NHBz group gave the corresponding
alcohol with complete conversion and 74.6% ee, which is
(15) Typical Procedure for the Asymmetric Hydrogenation. (R,R)-
Me-DuPhos (1.8 mg, 0.006 mmol) and Pd(CF3CO2)2 (1.7 mg, 0.005 mmol)
were placed in a Schlenk tube under a nitrogen atmosphere, and degassed
anhydrous acetone was added. The mixture was stirred at room temperature
for about 1 h. The solvent was removed under vacuum to give the catalyst.
This catalyst was taken into a glovebox filled with nitrogen and dissolved
in dry TFE (1.2 mL), the catalyst solution was transferred by a syringe to
stainless steel autoclave, in which substrate 1 (0.25 mmol) was placed
beforehand. The autoclave was stirred under 200-400 psi of hydrogen at
oil bath temperature for 12-18 h. The autoclave was cooled to room
temperature, and the hydrogen was carefully released. The solvents were
removed. Conversion was directly by 1H NMR spectroscopy. The enan-
tiomeric excess was determined by HPLC after purification on silica gel
(hexane/EtOAc/CH2Cl2 ) 4/1/1). The absolute configuration of 2 was
determined by measurement of its optical rotation and comparison to the
literature value or by analogue.
(12) Phthalimide ketones are readily prepared from phthalimide and
halide substituted ketone in the presence of potassium carbonate (see
Supporting Information).
(13) Ru-Catalyzed asymmetric hydrogenation of R-phthalimide ke-
tones: (a) Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004,
126, 1626. (b) Hu, A.; Lin, W. Org. Lett. 2005, 7, 455.
(14) For preparation of complex, see Supporting Information.
Org. Lett., Vol. 7, No. 15, 2005
3237

lower than with the corresponding R-phthalimide ketones.
Hydrogenation of â-ketoester 4 gave the corresponding
alcohol with complete conversion and 47.9% ee. Interest-
ingly, simple ketone 5 can also be hydrogenated by Pd(CF3-
CO2)2/(S)-SYNPHOS to obtain 90% conversion and 51.9%
ee.
It is noted that the asymmetric induction sense of the
palladium-catalyzed asymmetric hydrogenation of ketones
is the same as the corresponding Ru complexes with the same
ligand. For example, for hydrogenation of 1a, Pd(CF3CO2)2/
(S)-MeO-Biphep (entry 9, Table 2) and RuCl2/(S)-MeO-
Biphep13a gave the product with the same R configuration.
In conclusion, we have described the highly enantiose-
lective homogeneous hydrogenation of functionalized ketones
using a chiral Pd complex in TFE. This is the first example
with a Pd/bisphosphines complex as a homogeneous asym-
metric hydrogenation catalyst of ketones. This approach will
provide principles and insights into the developing area of
Pd-catalyzed reaction chemistry. Our ongoing experiments
are focused on the asymmetry hydrogenation of other
substrates and expanding other Pd-catalyzed asymmetric
reactions. The role of TFE16,17 and the mechanism in this
reaction is also under investigation.
Acknowledgment. We are grateful for the financial sup-
port from National Science Foundation of China (20302005)
and Talent Scientist Program, the Chinese Academy of
Sciences.
Supporting Information Available: Specroscopic date,
GC, HPLC spectra, and experimental details. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL051007U
(16) TFE as a solvent stabilizes the active catalysts: (a) Milani, B.;
Anzilutti, A.; Vicentini, L.; Santi, A. S.; Zangrando, E.; Geremia, S.;
Mestroni, G. Organometallics 1997, 16, 5064. (b) Milani, B.; Corso, G.;
Mestroni, G. Organometallics 2000, 19, 3435.
(17) TFE as a solvent influences the chemical character of substrates:
(a) Teunissen, H. T.; Elsevier, C. J. Chem. Commun. 1998, 1367. (b)
Whitfield, H. J.; Griffin, R. J.; Hardcastle, I. R.; Henderson, A.; Meneyrol,
J.; Mesguiche, V.; Sayle, K. L.; Golding, B. T. Chem. Commun. 2003, 2802.
3238
Org. Lett., Vol. 7, No. 15, 2005