Highly efficient asymmetric hydrogenation of α,β-unsaturated carboxylic acids catalyzed by ruthenium(II)-dipyridylphosphine complexes

Article abstract of DOI:10.1002/adsc.200600410

Two types of catalysts [RuL(benzene)Cl]Cl and Ru(OCOCH₃) ₂L with the dipyridylphosphine ligands P-Phos and Xyl-P-Phos were applied in the asymmetric hydrogenation of α,β-unsaturated carboxylic acids. The cationic complexes [RuL(benzene)Cl]Cl were found to be superior to the corresponding neutral complex Ru(OCOCH₃)₂L in this type of reactions. The catalysts exhibited excellent activities and enantioselectivities (up to 97% ee) in the asymmetric hydrogenation.

Full text of DOI:10.1002/adsc.200600410

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DOI: 10.1002/adsc.200600410
Highly Efficient Asymmetric Hydrogenation of a,b-Unsaturated
Carboxylic Acids Catalyzed by Ruthenium(II)-Dipyridylphos-
phine Complexes
Liqin Qiu,a,b Yue-Ming Li,a,b Fuk Yee Kwong,a,b Wing-Yiu Yu,a,b Qing-Hua Fan,c
and Albert S. C. Chana,b,*
a
State Key Laboratory of Chinese Medicine and Molecular Pharmacology, Shenzhen, Peopleꢀs Republic of China
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis, and
b
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon,
Hong Kong SAR, Peopleꢀs Republic of China
Fax : (+852)-23-649-932; e-mail: bcachan@polyu.edu.hk
Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, Peopleꢀs Republic of
c
China
Received: August 15, 2006
Dedicated to Professor Masakatsu Shibasaki on the occasion of his 60th birthday.
Abstract: Two types of catalysts [RuL-
(benzene)Cl]Cl and Ru(OCOCH3)2L with the di-
pyridylphosphine ligands P-Phos and Xyl-P-Phos
were applied in the asymmetric hydrogenation of
a,b-unsaturated carboxylic acids. The cationic com-
the asymmetric hydrogenation leading to high-valued
products.[7] Recently, SFDP ligands bearing a spirobi-
fluorene structure with a large dihedral angle were
developed and their ruthenium complexes gave excel-
lent results in the asymmetric hydrogenation of a,b-
unsaturated carboxylic acids.[8] Rhodium-catalyzed
asymmetric hydrogenations of cinnamic acid deriva-
tives were also carried out using a combination of
monodentate phosphoramidite and PPh3 ligands.[9]
The pyridylphosphine ligand P-Phos and its deriva-
tives can be conveniently prepared and have been
successfully used in a variety of asymmetric catalytic
reactions such as the asymmetric hydrogenation of b-
keto esters and ketones, the asymmetric hydrosilyla-
tion of ketones, the asymmetric Pauson–Khand reac-
tion and the asymmetric carbocyclization reaction.[10]
The transition metal complexes containing these li-
gands are quite air-stable even in solution, making
their application in organic synthesis very convenient
A
ACHTREUNG
plexes [RuL(benzene)Cl]Cl were found to be supe-
G
rior to the corresponding neutral complex
Ru(OCOCH3)2L in this type of reactions. The cata-
lysts exhibited excellent activities and enantioselec-
tivities (up to 97% ee) in the asymmetric hydroge-
nation.
Keywords: asymmetric hydrogenation; dipyridyl-
phosphine; P-Phos; ruthenium complexes; a,b-un-
saturated carboxylic acids; Xyl-P-Phos
Optically active carboxylic acids are important build- and the expansion of their scope of application attrac-
ing blocks for the synthesis of new materials such as tive. Herein we report the application of P-Phos and
ferroelectric liquid crystals (FLCs),[1] non-steroidal Xyl-P-Phos ligands in the enantioselective hydrogena-
anti-inflammatory (NSAI) agents[2] and other bioac- tion of a,b-unsaturated carboxylic acids.
tive compounds.[3] The enantioselective hydrogenation
of a,b-unsaturated carboxylic acids provides a simple, [RuL
straightforward and quantitative route to this type of following similar procedures as previously descri-
important compound. Ru
(BINAP)-type catalysts bed,[7b,11] and were directly used for the asymmetric
Two types of catalysts Ru
A
AHCTREUNG
AHCTREUNG
were found to be highly effective in this class of reac- hydrogenation of a,b-unsaturated carboxylic acids
tions,[4] and H8-BINAP was later proved to be superi- without further purification (Scheme 1). The corre-
or to BINAP as the chiral ligand for these reactions.[5] sponding saturated carboxylic acids were obtained in
Other types of effective ligands also have been re- essentially quantitative yields in most cases (Table 1).
ported for this type of asymmetric hydrogenation.[6]
It is noteworthy that [RuL
From both scientific and practical points of view, it is 1b) were found to be more effective than
of high interest to develop more effective catalysts for Ru(OCOCH3)2L (2a and 2b) (L=P-Phos or Xyl-P-
A
AHCTREUNG
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517

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Liqin Qiu et al.
10, 17 and 20). The activity of the catalyst system with
the Xyl-P-Phos ligand also was found to surpass those
of Ru
N
N
SFDP.[5a,b,8] In the hydrogenation of 2-methylcinnamic
acid (4e) the reactivity and enantioselectivity of the
present catalysts decreased significantly. A similar
effect was previously observed with the BINAP sys-
tem.[5b] The reaction proceeded very slowly at room
temperature, giving less than 10% conversion after
65 h. The target compound 5e was obtained with
moderate ees when the reaction temperature was
raised to 608C.
The hydrogenation of b,b-disubstituted acrylic acids
such as fluorinated 4f required higher hydrogen pres-
sure for high product ees. When catalyst 1b was used,
product 5f with 97% ee was obtained (entry 31). To
our knowledge, this is the highest ee obtained for 5f
through asymmetric hydrogenation. When catalysts
2b and 3 were used, 96% ee and 87% ee, respectively,
were obtained (entries 32 and 33).
Figure 1. Structures for catalysts 1–3.
Catalysts 1a and 1b were also used for the hydroge-
nation of substrate 6 (Scheme 2), whose product (7)
Scheme 1. Asymmetric hydrogenation of a,b-unsaturated
carboxylic acids.
Scheme 2. Asymmetric hydrogenation of 2-(4-isobutylphe-
nyl)propenoic acid.
Phos) in these reactions. This is in sharp contrast to with the (S)-configuration is an effective anti-inflam-
the Ru(BINAP)-type catalysts, e.g., Ru(OCOCH3)2- matory agent [(S)-ibuprofen]. It was noteworthy that
H8-BINAP was reported to be superior to [Ru-H8- P-Phos was superior to Xyl-P-Phos in the hydrogena-
BINAP(benzene)Cl]Cl in both activity and enantiose- tion of 6 (92% ee vs. 89% ee, entries 34 and 35).
lectivity.[5a,b] As shown in Table 1, in the presence of
In summary, we have applied two types of P-Phos
0.25 mol% of catalyst 1a or 1b, the hydrogenation of catalysts, [RuL(benzene)Cl]Cl and Ru(OCOCH3)2L
A
ACHTREUNG
ACHTREUNG
A
ACHTREUNG
tiglic acid (4a) proceeded smoothly at room tempera- (L=Xyl-P-Phos and P-Phos), in the asymmetric hy-
ture and under low hydrogen pressure (6 bar), afford- drogenation of a,b-unsaturated carboxylic acids. The
ing (S)-2-methylbutanoic acid (5a) in high ees (96% experimental results indicated that the cationic com-
and 97%, respectively, entries 1 and 2). Compound plexes [RuL
ACHTREUNG
(S)-5a and its esters are important materials for pre- tral species Ru
AHCTREUNG
paring fruit flavors (e.g., apple, strawberry, grape). ferent from other previously reported systems. The
Substrates 4a–e were found to give high ees under catalysts exhibited excellent activity and enantioselec-
low hydrogen pressure. Similarly high ees (95–97%) tivities (up to 97% ee).
were also obtained in the hydrogenation of other (E)-
2-alkyl-2-alkenoic acids (4b–d) when 1b was used as
catalyst. The reaction temperature had little effect on
the enantioselectivity even though a higher reaction
Experimental Section
temperature was indeed beneficial to the rate of hy-
drogenation. The substrates were fully converted to
the corresponding products at 508C even when S/C
General Procedure for Asymmetric Hydrogenation of
a,b-Unsaturated Carboxylic Acids
ratios were increased to up to 10,000/1 without caus-
ing a notable change in enantioselection (entries 5, a,b-unsaturated carboxylic acid (0.1 mmol, unless otherwise
A glass-lined stainless steel autoclave was charged with an
518
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Asymmetric Hydrogenation of a,b-Unsaturated Carboxylic Acids
Table 1. Asymmetric Ru-catalyzed hydrogenation of a,b-unsaturated carboxylic acids.[a]
Entry
Substrate
Catatalyst
S/C ratio
H2, [bar]
Time [h]
Conversion [%]
ee[b] [%]
Configuration
1
2
3
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4c
4c
4c
4c
4c
4c
4c
4d
4d
4d
4d
4d
4e
4e
4e
4e
4e
4e
4e
4f
4f
4f
4f
6
1a
1b
2b
3
1b
1a
1b
2b
3
1b
1a
1b
3
1b
1b
2b
1b
1a
1b
1b
2b
3
1a
1b
3
1a
1b
2b
3
1a
1b
2b
3
1a
1b
2a
3
400
400
400
400
10,000
500
500
500
500
10,000
400
400
400
400
400
400
10,000
400
400
10,000
400
400
400
400
400
400
400
400
400
400
400
400
400
200
200
200
200
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
36
36
36
36
24
36
36
36
36
40
36
36
36
36
36
36
24
36
36
36
36
36
65
65
65
24
24
24
24
16
16
16
16
8
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
1%
>99
>99
>99
>99
>99
>99
>99
7.2
96
97
94
88
96
92
96
91
84
95
93
97
82
94
nd
92
95
94
95
96
94
88
nd
nd
nd
55
77
76
36
95
97
96
87
92
89
89
88
(S)
(S)
(S)
(R)
(S)
(S)
(S)
(S)
(R)
(S)
(S)
(S)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
4
5[c]
6
7
8
9
10[c]
11
12
13
14[d]
15[e]
16
17[c]
18
19
20[c]
21
22
23
24
25
26[f]
27[f]
28[f]
29[f]
30
31
32
33
34
35
36
37
4.1
2.7
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
(S)
(S)
(S)
(R)
(+)
(+)
(+)
(À)
(S)
(S)
(S)
(R)
6
95
95
100
100
100
100
100
100
6
6
6
8
8
8
[a]
Reaction conditions: 0.1 mmol for substrates 4a–f except for entries 5, 10, 17 and 20 (2.5 mmol substrates), 0.05 mmol for
substrate 6; 700 mL MeOH as solvent; room temperature reaction unless otherwise stated.
The ee values were determined by chiral HPLC analysis with an OD-H column for the anilide derivative of 5a, an OB
[b]
column for the anilide derivative of 5e, an OJ-H column for the anilide derivative of 5f (the anilide derivatives were pre-
pared by reaction of 5a, 5e and 5f with aniline) or by chiral GC with a 25 m”0.25 mm CP-CYCLODEX b 236M column
for 5b–d, or a 25 m”0.25 mm Chirasil-DEX CB column for the methyl ester of 7. The optical roation of 5f was deter-
mined in CHCl3.
At 508C.
Non-degassed solvent was used.
Charged in air.
At 608C.
[c]
[d]
[e]
[f]
stated) and a catalyst according to the given S/C ratio in
antiomeric excess of the product was determined by chiral
HPLC or chiral GC (either directly or after derivatization
to the corresponding methyl ester or anilide followed by
silica gel column purification). The absolute configuration
was determined by comparison with the corresponding
known compound described in the literature.
methanol (0.7 mL) under a nitrogen atmosphere. After
purging three times with H2, the autoclave was pressurized
to the desired pressure with H2. The solution was magneti-
cally stirred well at the given temperature for 8–65 h. After
releasing the hydrogen pressure, the conversion of the sub-
1
strate was determined by H NMR analysis of the residue
obtained on concentration of the reaction mixture. The en-
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We thank the University Grants Committee Areas of Excel-
lence Scheme in Hong Kong (AoE P/10–01) and the Hong
Kong Polytechnic University Area of Strategic Development
Fund for financial support.
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520
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Adv. Synth. Catal. 2007, 349, 517 – 520