Highly efficient enantioselective synthesis of optically active carboxylic acids by Ru(OCOCH3)2[(S)-H8-BINAP]

Article abstract of DOI:10.1021/jo960426p

In the presence of a catalytic amount of Ru(OCOCH₃)₂[(S)-H₈-BINAP] [H₈-BINAP = 2,2′-bis-(diphenylphosphino)-5,5′,6,6′,7,7′,8,8′- octahydro-1,1′-binaphthyl], the asymmetric hydrogenation of α,β- and β,γ-unsaturated carboxylic acids afforded the corresponding saturated carboxylic acids in higher enantiomeric excesses and at faster reaction rates than those using the Ru(OCOCH₃)₂[(R)-BINAP] catalyst [BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]. The hydrogenation of (E)-2-alkyl-2-alkenoic acids by the H₈-BINAP catalyst system produced saturated acids in 95-97% ee. 2-Methylcinnamic acid was treated with H₈-BINAP-Ru(II) complex as a catalyst to yield a hydrogenated product in much higher ee than that produced by BINAP-Ru(II) (89 and 30% ee, respectively). This homogeneous catalysis using H₈-BINAP-Ru(II) established a promising synthetic route to (S)-ibuprofen in up to 97% ee. Asymmetric hydrogenation of β-disubstituted acrylic acids also proceeded smoothly with good enantioselectivities (70-93% ee). In addition, the hydrogenation of trisubstituted acrylic acids (up to 88% ee) was investigated. Hydrogen pressure effect on the sense and level of enantioselection was shown to be substrate dependent. The difference between the H₈-BINAP- and BINAP-Ru(II) complexes was also discussed.

Full text of DOI:10.1021/jo960426p

5510
J . Org. Chem. 1996, 61, 5510-5516
High ly Efficien t En a n tioselective Syn th esis of Op tica lly Active
Ca r boxylic Acid s by Ru (OCOCH3)2[(S)-H8-BINAP ]
Toshitsugi Uemura,† Xiaoyoung Zhang,‡ Kazuhiko Matsumura,‡ Noboru Sayo,‡
Hidenori Kumobayashi,‡ Tetsuo Ohta,*,§ Kyoko Nozaki,*,† and Hidemasa Takaya†,
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Sakyo-ku, Kyoto 606-01, J apan, Central Research Laboratory, Takasago International Corporation,
Nishiyawata, Hiratsuka, Kanagawa 254, J apan, and Department of Molecular Science and Technology,
Faculty of Engineering, Doshisha University, Tanabe, Kyoto 610-03, J apan
Received March 1, 1996X
In the presence of a catalytic amount of Ru(OCOCH3)2[(S)-H8-BINAP] [H8-BINAP ) 2,2′-bis-
(diphenylphosphino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl], the asymmetric hydrogenation of
R,â- and â,γ-unsaturated carboxylic acids afforded the corresponding saturated carboxylic acids in
higher enantiomeric excesses and at faster reaction rates than those using the Ru(OCOCH3)2[(R)-
BINAP] catalyst [BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]. The hydrogenation of (E)-
2-alkyl-2-alkenoic acids by the H8-BINAP catalyst system produced saturated acids in 95-97% ee.
2-Methylcinnamic acid was treated with H8-BINAP-Ru(II) complex as a catalyst to yield a
hydrogenated product in much higher ee than that produced by BINAP-Ru(II) (89 and 30% ee,
respectively). This homogeneous catalysis using H8-BINAP-Ru(II) established a promising
synthetic route to (S)-ibuprofen in up to 97% ee. Asymmetric hydrogenation of â-disubstituted
acrylic acids also proceeded smoothly with good enantioselectivities (70-93% ee). In addition, the
hydrogenation of trisubstituted acrylic acids (up to 88% ee) was investigated. Hydrogen pressure
effect on the sense and level of enantioselection was shown to be substrate dependent. The difference
between the H8-BINAP- and BINAP-Ru(II) complexes was also discussed.
In tr od u ction
(NSAI) agents7 and ferroelectric liquid crystals (FLCs).8
However, the need remains for improvement with respect
to catalytic activities and the application range of the
substrates. We previously prepared a new atropisomeric
bis(triarylphosphine), H8-BINAP,9 which possesses a
unique structural feature compared to conventional BI-
NAPs. We have already reported its outstanding asym-
metric induction ability in the H8-BINAP-Ir(I) complex-
catalyzed asymmetric hydrogenation of certain â-
thiacycloalkanones and benzocycloalkanones.10 We here
report that chiral Ru(OCOCH3)2(H8-BINAP) (2),9b the
analogous complex of 1, and [RuI(H8-BINAP)(p-cymene)]I
(3)9b are more effective catalysts than 1 and the related
complexes for the asymmetric hydrogenation of R,â-
unsaturated carboxylic acids.11
Asymmetric hydrogenation by chiral transition-metal
complexes has been one of the most powerful methods
for the synthesis of optically active organic compounds.1
We have already reported that BINAP-Ru(II) complexes
are effective catalysts for asymmetric hydrogenation of
a wide range of prochiral substrates.2 Dicarboxylate
complex 1,3 for example, catalyzes the enantioselective
hydrogenation of various mono- and disubstituted R,â-
unsaturated carboxylic acids to produce optically active
carboxylic acids with very high ee’s.3-6 These products
are very important building blocks for the synthesis of
new materials, such as non-steroidal anti-inflammatory
† Kyoto University.
‡ Takasago International Corp.
§ Doshisha University.
Deceased, October 5, 1995.
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) (a) Koenig, K. E. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press, Inc.: Orlando, FL 1985; Vol. 5, Chapter 3, p 71. (b)
Takaya, H.; Noyori, R. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8, Chapter
3.2, p 443. (c) Takaya, H.; Ohta, T.; Noyori, R. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993. (d) Noyori,
R. Asymmetric Catalysis in Organic Synthesis; J ohn Wiley & Sons,
Inc.: New York, 1994; Chapter 2.
(5) For the mechanism, see: (a) Ohta, T.; Takaya, H.; Noyori, R.
Tetrahedron Lett. 1990, 31, 7189. (b) Ashby, M. T.; Halpern, J . J . Am.
Chem. Soc. 1991, 113, 589.
(6) For asymmetric transfer hydrogenation of R,â-unsaturated car-
boxylic acids using related BINAP-Ru(II) complexes, see: (a) Brown,
J . M.; Brunner, H.; Leitner, W.; Rose, M. Tetrahedron: Asymmetry
1991, 2, 331. (b) Saburi, M.; Ohnuki, M.; Ogasawara, M.; Takahashi,
T.; Uchida, Y. Tetrahedron Lett. 1992, 33, 5783.
(7) (a) Shen, T. Y. Angew. Chem., Int. Ed. Engl. 1972, 11, 460. (b)
Lednicer, D.; Mitscher, L. A. The Organic Chemistry of Drug Synthesis;
Wiley: New York, 1977 and 1980; Vols. 1 and 2. (c) Rieu, J .-P.;
Boucherle, A.; Cousse, H.; Mouzin, G. Tetrahedron 1986, 42, 4095. (d)
Botteghi, C.; Paganelli, S.; Schionato, A.; Marchetti, M. Chirality 1991,
3, 355.
(2) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
(3) (a) Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori, R. To
be published. (b) Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori,
R. J . Org. Chem. 1987, 52. 3176. (c) Ohta, T.; Takaya, H.; Noyori, R.
Inorg. Chem. 1988, 27, 566.
(4) (a) Kitamura, M.; Tokunaga, M.; Noyori, R. J . Org. Chem. 1992,
57, 4053. (b) Genet, J . P.; Mallart, S.; Pinel, C.; J uge, S.; Laffitte, J . A.
Tetrahedron: Asymmetry 1991, 2, 43. (c) Alcock, N. W.; Brown, J . M.;
Rose, M.; Wienand, A. Tetrahedron: Asymmetry 1991, 2, 47. (d) Heiser,
B.; Broger, E. A.; Crameri, Y. Tetrahedron: Asymmetry 1991, 2, 51.
(e) Shao, L.; Takeuchi, K.; Ikemoto, M.; Kawai, T.; Ogasawara, M.;
Takeuchi, H.; Kawano, H.; Saburi, M. J . Organomet. Chem. 1992, 435,
133. (f) Saburi, M.; Takeuchi, H.; Ogasawara, M.; Tsukahara, T.; Ishii,
Y.; Ikariya, T.; Takahashi, T.; Uchida, Y. J . Organomet. Chem. 1992,
428, 155. (g) Saburi, M.; Shao, L.; Sakurai, T.; Uchida, Y. Tetrahedron
Lett. 1992, 33, 7877. (h) Manimaran, T.; Wu, T.-C.; Klobucar, W. D.;
Kolich, C. H.; Stahly, G. P.; Fronczek, F. R.; Watkins, S. E. Organo-
metallics 1993, 12, 1467.
(8) (a) Nohira, H.; Nakamura, S.; Kamei, M. Mol. Cryst. Liq. Cryst.
1990, 180B, 379. (b) Nakamura, S.; Nohira, H. Mol. Cryst. Liq. Cryst.
1990, 185, 199.
(9) (a) Zhang, X.; Mashima, K.; Koyano, K.; Sayo, N.; Kumobayashi,
H.; Akutagawa, S.; Takaya, H. Tetrahedron Lett. 1991, 32, 7283. (b)
Zhang, X.; Mashima, K.; Koyano, K.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S.; Takaya, H. J . Chem. Soc., Perkin Trans. 1 1994, 2309.
(10) Zhang, X.; Taketomi, T.; Yoshizumi, T.; Kumobayashi, H.;
Akutagawa, S.; Mashima, K.; Takaya, H. J . Am. Chem. Soc. 1993, 115,
3318.
(11) We have already reported a part of this work as a communica-
tion, see: Zhang, X.; Uemura, T.; Matsumura, K.; Kumobayashi, H.;
Sayo, N.; Takaya, H. Synlett 1994, 501.
S0022-3263(96)00426-4 CCC: $12.00 © 1996 American Chemical Society

Enantioselective Asymmetric Hydrogenation
J . Org. Chem., Vol. 61, No. 16, 1996 5511
Ta ble 1. Asym m etr ic Hyd r ogen a tion of 4a -f Ca ta lyzed
by H8-BINAP - a n d BINAP -Ru (II) Com p lexesa
hydrogen proceeded smoothly at room temperature,
giving exclusively 2-methylbutyric acid (5a ) in 97% ee.
Using the neutral complex (S)-2 (run 2) or the cationic
one (R)-3 (run 3) under 4.0 atm of hydrogen, 4a was
hydrogenated in 96% ee. This result is better than those
obtained with various chiral BINAP-Ru(II) complexes,
including 1 (which gives up to 92% ee,3a,b under similar
conditions).4bef,12 The high asymmetric induction ability
of (S)-2 was effectively demonstrated in the hydrogena-
tion of other (E)-2-alkyl-2-alkenoic acids, i.e., (E)-2-
methyl-2-pentenoic acid (4b, run 4), (E)-2-methyl-2-
hexenoic acid (4c, run 6), and (E)-2-ethyl-2-hexenoic acid
(4d , run 11). Using BINAP as a diphosphine ligand
resulted in lower enantioselectivities by 7-14% (runs 5,
10, and 12). As with 4c, a higher ee was achieved in a
10:1 mixture of methanol and water (run 7) than in
methanol (run 6). Furthermore, the elevated reaction
temperature (50 °C) resulted in acceleration of the
hydrogenation without causing a notable decrease in the
enantioselectivity (run 7 vs 8). While the substrate/
catalyst ratio had little effect on the enantioselectivity
(run 8 vs 9), the catalytic activity is much higher when
using H8-BINAP than when using BINAP (run 9 vs 10).
conditions
product
ee,e
sub-
run strate catalyst S/Cb atm
H2, time, conv,c yield,d
h
%
%
%
1
2
3
4
5
4a
4a
4a
4b
4b
4c
4c
4c
4c
4c
4d
4d
4e
4e
4e
4e
4e
4f
4f
4f
4f
4f
4f
4f
4f
4f
(S)-2
(S)-2
(R)-3
(S)-2
(R)-1
(S)-2
(S)-2
(S)-2
(S)-2
200
200
200
213
220
201
204
209
1074
1.5
4.0
4.0
1.5
1.5
1.5
1.5
4.0
4.0
4.0
1.5
1.5
1.8
20
15
15
24
24
20
22
3
100
100
94
100
75
100
100
100
59
85
83
73
89
69
98
90
83
56
26
80
95
93
82
91
87
29
97 (S)
96 (S)
96 (R)
96f (S)
84f (R)
94 (S)
96 (S)
94 (S)
93 (S)
79 (R)
95f (S)
88f (R)
86 (S)
82 (S)
75 (S)
89 (S)
30 (R)
75 (R)
68 (R)
61 (R)
73 (R)
74 (R)
71 (R)
73 (R)
70 (R)
72 (R)
6
7g
8g,h
9g,h
10g,h
11
12
13i
14i
15i
16
17
18j
19j
20j
21i
22i
23i
24k
25k
26k
4
4
(R)-1 1016
27
(S)-2
(R)-1
(S)-2
(S)-2
(S)-2
(S)-2
(R)-1
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
197
203
200
200 25
200 97
200
200
200
200 25
200 100
200
200 27
200 105
200
200 29
200 109
20
37
26
15
8
100
100
100
100
100
95
30
55
94
100
77
100
100
89
100
100
1.5
1.5
1.8 182
48
48
90
74
95
1.8 117
61
16
56
24
6
90
90
5.5
88
91
a
Hydrogenation was carried out in an autoclave at 10-25 °C
in methanol (solvent/substrate ) 5-50 mL/g) unless otherwise
stated, and the chemical selectivity of 5a -f was 100%, as given
b
by 1H NMR analysis. Substrate/catalyst ratio (mol/mol). c As
d
given by 1H NMR analysis. Isolation yield obtained on Kugelrohr
distillation. e Enantiomeric excess was determined by HPLC
analysis of the anilide of the saturated carboxylic acid with a
Daicel Chiralcel OB or OD column, unless otherwise indicated.
Absolute configuration was determined by the sign of optical
rotation value. f Measured by GLC analysis of the saturated
carboxylic acid with a Chrompack CP-cyclodextrin-â-236M-19
In the hydrogenation of 2-methylcinnamic acid (4e) and
2-phenylcinnamic acid (4f), which have a substitution
pattern similar to those of 4a -d , using BINAP as a
ligand, the catalytic activities were not as high, and
enantioselectivities, especially, were insufficient.3a We
describe the remarkable superiority of H8-BINAP over
BINAP for the hydrogenation of prochiral â-aryl-(E)-
acrylic acids. At room temperature, the reduction of 4e
catalyzed by (S)-2 yielded (S)-2-methyl-3-phenylpropanoic
acid (5e) with 95% conversion in 48 h and in 89% ee (run
16), significantly surpassing those (merely 30% conver-
sion and 30% ee) catalyzed by (R)-1 (run 17).
h
capillary column. g Solvent system was MeOH/H2O (10:1). At 50
i
j
k
°C. At 60 °C. At 30 °C. At 90 °C.
As for 2-substituted cinnamic acid (4e,f), the relation-
ship of ee and hydrogen pressure was the same for (E)-
2-alkyl-2-alkenoic acids. Enantiomeric excesses of 5e,f
improved at lower pressure when the reaction was
catalyzed by (S)-2. The hydrogenation of 4f was acceler-
ated by elevated temperature (60 and 90 °C), and the
enantioselectivities achieved were almost equal to that
at 30 °C. However, the effect of H2 pressure on ee at 90
or 60 °C, was unlike that at 30 °C. At 60 and 90 °C,
hydrogen pressure had little influence on enantioselec-
tivity (runs 21-26), while at 30 °C the lower pressure of
H2 brought about higher enantioselectivities. This dif-
ference is thought to depend on the isomerization of the
substrate in the reaction. However, only the reductant
and starting material were observed by the 1H NMR
analysis of the reaction mixture over the course of the
hydrogenation at 60 °C. Thus, there is no evidence to
Resu lts a n d Discu ssion
Asym m etr ic Hyd r ogen a tion of R,â-Disu bstitu ted
(E)-Acr ylic Acid s. Table 1 shows the results of the
hydrogenation of R-mono-â-monosubstituted (E)-acrylic
acids 4a -f. Hydrogenation of (E)-2-alkyl-2-alkenoic acids
(4a -d ) in methanol catalyzed by (S)-2 yielded quantita-
tively the corresponding saturated acids with exceedingly
high enantioselectivities (95-97% ee). In the presence
of a catalytic amount of (S)-2 (run 1), for instance, the
hydrogenation of tiglic acid (4a ) under 1.5 atm of
(12) Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki, K.;
Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.;
Takaya, H. J . Org. Chem. 1994, 59, 3064.

5512 J . Org. Chem., Vol. 61, No. 16, 1996
Uemura et al.
Ta ble 2. Asym m etr ic Hyd r ogen a tion of
2-(4-Isobu tylp h en yl)p r op en oic Acid (6) Ca ta lyzed by
H8-BINAP - a n d BINAP -Ru (II) Com p lexesa
Ta ble 3. Asym m etr ic Hyd r ogen a tion of 8a -c Ca ta lyzed
by H8-BINAP - a n d BINAP -Ru (II) Com p lexesa
conditions
product
ee,e
conditions
product
sub-
run strate catalyst S/Cb atm
H2, time, conv,c yield,d
H2,
atm
time,
h
conv,b
%
yield,c
%
ee,d
%
h
%
%
%
run
catalyst
1
2
3
4
5
6
7
8
9
8a
8a
8a
8b
8b
8b
8c
8c
8c
(S)-2
(S)-2
(R)-1
(S)-2
(S)-2
(R)-1
(S)-2
(S)-2
(R)-1
209
200 100
200 100
200
200 100
200 100
200
200 100
200
1.5
24
8
8
25
7
7
25
6
25
100
100
100
100
100
89
100
100
100
87
86
83
97
90
65 (+)
93 (+)
75 (-)
5 (R)
70 (S)
27 (R)
92 (R)
79 (R)
92 (S)
1
2
3
4
(S)-2
(S)-2
(S)-2
(R)-1
4.0
24
24
8
100
100
100
100
99
99
97
99
77 (S)
94 (S)
97 (S)
96 (R)
25
100
100
4.0
8
a
Hydrogenation was carried out in an autoclave at 10-25 °C
in methanol (solvent/substrate ) 25 mL/g, substrate/catalyst )
200), and the chemical selectivity of 7 was 100% as given by 1H
4.0
93
89
98
4.0
b
NMR analysis. As given by 1H NMR analysis. c Isolation yield
a
d
Hydrogenation was carried out in an autoclave at 10-25 °C
obtained on column chromatography. Enantiomeric excess was
in methanol (solvent/substrate ) 5-33 mL/g), and the chemical
selectivity of 9a ,b was 100% as given by 1H NMR analysis.
b,c,d,e See footnotes in Table 1.
determined by GLC analysis of 7 with a Chrompack CP-cyclodex-
trin-â-236M-19 capillary column. Absolute configuration was
determined by the sign of optical rotation value.
Ta ble 4. Asym m etr ic Hyd r ogen a tion of
3-P h en yl-3-bu ten oic a cid (10) Ca ta lyzed by H8-BINAP -
a n d BINAP -Ru (II) Com p lexesa
suggest that the isomerization of 4f occurs. To date, the
enantiomeric excess of 5f obtained under 1.8 atm of H2
(75% ee, run 18) was the highest ee in the data reported
for homogeneous or heterogeneous catalysts.13,14
Asym m et r ic H yd r ogen a t ion of R-Su b st it u t ed
Acr ylic Acid (Asym m etr ic Syn th esis of Ibu p r ofen ).
The hydrogenation of 2-(4-isobutylphenyl)propenoic acid
(6) using (S)-2 as a catalyst under 100 atm of initial
hydrogen pressure was completed in 8 h, producing the
important anti-inflammatory agent7 (S)-7 in 97% ee
(Table 2, run 3). The pressure effect on the hydrogena-
tion was similar to that of 2-arylpropenoic acids using
(S)- or (R)-1,3a in which higher hydrogen pressure results
in higher enantioselectivities. In the case of this sub-
strate, (R)-1 matched well (S)-2 in the enantiomeric
excess of 7 (run 4).15
conditions
product
time, conv,c yield,d ee,e
H2,
run catalyst S/Cb
atm
h
%
%
%
1
2
3
4
(S)-2
(S)-2
(S)-2
(R)-1
200
200
200 100
200 1.5
1.5
4.0
2
15
8
100
100
100
39
92
92
96
83 (R)
71 (R)
41 (R)
74 (S)
2
a
Hydrogenation was carried out in an autoclave at 10-25 °C
in methanol (solvent/substrate ) 31 mL/g), and the chemical
selectivity of 9b was 100%, as given by 1H NMR analysis. b,c,d,e See
footnotes in Table 1.
cases of 8a ,b, at high pressure (100 atm of H2), the
catalyst seemed to distinguish mainly the olefinic carbon
R to carboxylic acid moiety, because the â-enantioface
selectivities of 8b,8c were close [70% ee (S) for 8b and
79% ee (R) for 8c by (S)-2]. In other words, the arrange-
ment of phenyl and methyl substituents on carbon â to
carboxylic acid moiety showed a large effect on the
enantioselectivity at a low pressure of H2. For the
reduction of 8b,c, only the product and substrate were
1
observed by H NMR analysis, while the reduction was
not completed; therefore, E-Z isomerization did not
Asym m etr ic Hyd r ogen a tion of â-Disu bstitu ted
Acr ylic Acid . Fluorinated unsaturated acid 8a was
found to be converted by (S)-2 to 9a in 93% ee (Table 3,
run 2). Conversely, the use of the analogous complex
(R)-1 decreased the ee by 18% (run 3). As for 8a , the
enantioselectivities of the reaction became better at
higher pressure (runs 1 and 2). (E)-3-Phenyl-2-butenoic
acid (8b) showed the same pattern as 8a in the H2
pressure effect on the sense and degree of enantioselec-
tivity, in that â-enantioface selectivity (vide infra, Chart
1, I) was dramatically increased by (S)-2 at higher
pressure (runs 4 and 5). The superiority of H8-BINAP
over BINAP then became larger in ee by 43% (run 6).
On the other hand, the asymmetric hydrogenation of (Z)-
3-phenyl-2-butenoic acid (8c), the E-Z isomer of 8b,
showed a hydrogen pressure effect the reverse of that of
8b, and the lower H2 pressure resulted in a slightly
higher â-enantioface selectivity (runs 7 and 8). In the
significantly occur over the course of the hydrogenation.
Asym m etr ic Hyd r ogen a tion of â,γ-Un sa tu r a ted
Ca r boxylic Acid . To examine the catalytic performance
of H8-BINAP-Ru(II) and the isomerization of the sub-
strate during the course of the hydrogenation, â,γ-
unsaturated carboxylic acid 10 was studied (Table 4).4f,16
3-Phenyl-3-butenoic acid (10) was hydrogenated by (S)-2
under 1.5 atm of hydrogen to yield 9b in 83% ee, and
this reaction was completed within 2 h because the CdC
moiety was not so crowded (run 1). Considering this
substrate, the hydrogen pressure effect17 is similar to that
of the reduction of 8c, (Z)-isomer, and the absolute
(13) In this connection, reduction of 4f by (S)-1 gave 5f in 41% ee
(S/C ) 136, an initial H2 pressure of 4.0 atm, 40 °C, 100 h).3a
(14) For heterogeneous catalysts, see: Nitta, Y.; Ueda, Y.; Imanaka,
T. Chem. Lett. 1994, 1095.
(15) Previously, Stahly and co-workers obtained (S)-7 in 91% ee by
reduction of 6 catalyzed by (S)-1 or in-situ-generated Ru(acac)2[(S)-
binap] (S/C ) 800, H2 68 atm).4h
(16) For asymmetric hydrogenation of 10 catalyzed by DIOP-Rh-
(I) complexes, see: Yamamoto, K.; Ikeda, K.; Yin, L. L. J . Organomet.
Chem. 1989, 370, 319.

Enantioselective Asymmetric Hydrogenation
J . Org. Chem., Vol. 61, No. 16, 1996 5513
Ta ble 5. Asym m etr ic Hyd r ogen a tion of 11a ,b Ca ta lyzed by H8-BINAP - a n d BINAP -Ru (II) Com p lexesa
conditions
H2, atm
product
sub-
strate
run
catalyst
solvent
S/Cb
time, h
conv,c %
yield,d
%
ee,e %
59 (S)
88 (S)
82 (R)
68 (S)
72 (S)
76 (S)
50 (2S,3S)
55 (2S,3S)
58 (2S,3S)
53 (2R,3R)
1
2
3
4
5
6
7
8
9
11a
11a
11a
11a
11a
11a
11b
11b
11b
11b
(S)-2
(S)-2
(R)-1
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(R)-1
THF
THF
THF
MeOH
i-PrOH
CH2Cl2
MeOH
MeOH
THF
600
600
600
600
600
600
200
200
200
200
4.0
100
100
100
100
100
4.0
100
100
100
93
3
44
3
100
100
100
100
100
100
100f
100f
100f
50f
89
95
90
77
86
5
23
24
5
18
19
95
10
THF
a
Hydrogenation was carried out in an autoclave at 10-25 °C in methanol (solvent/substrate ) 10 mL/g), and the chemical selectivity
of 12a was 100%, as given by 1H NMR analysis. b,c,d,e See footnotes in Table 1. f The chemical selectivity of 12b was 92% (run 7), 100%
(run 8), and 98% (run 9 and 10). The rest was erythro isomer.
Ch a r t 1
configurations of the products are also the same (runs
1-3). In addition, for this â,γ-unsaturated carboxylic
acid, H8-BINAP was superior to BINAP in both ee and
1
reaction rate (run 1 vs 4). We carried out the H NMR
analysis of the incomplete reaction mixture and found
only 10 and 9b. There seems to be no isomerization
between 8b,c, and 10 under the hydrogenation conditions
using 1 or 2 as a catalyst.
H2 P r essu r e Effects on En a n tiofa ce Selectivities
a n d En a n tiom er ic Excesses in th e Hyd r ogen a tion
of Su bstitu ted Acr ylic Acid s. The H2 pressure effect
on enantioface selectivities and ee’s were summarized
with three classes of substrates. First, a better â-enan-
tioface selectivity (Chart 1, I) of the hydrogenation by
(S)-2 was observed for R,â-disubstituted substrates (4)
at lower hydrogen pressure. Second, the hydrogenation
of 6, R-substituted acrylic acid, by (S)-2 proceeded in the
Asym m et r ic H yd r ogen a t ion of Tr isu b st it u t ed
Acr ylic Acid s. Finally, we carried out the reduction of
manner of higher R-enantioface selection (Chart 1, II) at
higher H2 pressure. Third, in the case of â-disubstituted
trisubstituted acrylic acids (tetrasubstituted olefins,
acrylic acids, 8b,c, the trend of the H2 pressure effect on
Table 5). Although the optically active reductants of
ee’s is not clear. In other words, a higher hydrogen
those acids have wide applicability, there are few reports
pressure caused a higher ratio of â-enantioface selectivity
where high enantiomeric excesses were obtained.18
for 8b, while a slightly higher ee and the same enantio-
The hydrogenation of trimethyl-substituted acrylic acid
face selectivity were observed under lower hydrogen
11a smoothly proceeded under high H2 pressure to yield
pressure for 8c. Namely, if substrates have an R-sub-
12a in 88% ee, while the phenyl-substituted acrylic acid
stituent, then the ratio of â-enantioface selectivity be-
11b was converted to 12b with moderate enantioselec-
tivity. A series of reductions of tiglic acid (4a ) showed
that alcoholic solvents, especially methanol, were the best
comes higher under a lower pressure of H2. On the other
hand, the H2 pressure effect for substrates without an
R-substituent depends on the type of â-substituents.
choice.3a However, for the hydrogenation of 2,3-dimethyl-
P ossible Mech a n ism . Although the mechanism of
2-butenoic acid (11a ), tetrahydrofuran was a better
this catalysis is not yet clear, Scheme 1 shows a possible
solvent choice than alcoholic solvents, methylene chloride
pathway. As earlier reported,5 the monohydride species
(runs 2 vs 4-6), or their variable mixtures. This result
indicates that it is not only the polarity of the solvent
that influences the enantiomeric excess of the reductant.
In this case, the higher pressure of H2 caused higher ee
(runs 1 and 2). The complex (S)-2 as a catalyst was more
effective than (R)-1 in ee and, above all, in the reaction
seem to be important intermediates in the catalytic cycle
of the hydrogenation of R,â-unsaturated carboxylic acid
by BINAP-Ru(II) diacetate complexes. Important ob-
servations of the H2 pressure effect on enentioselectivities
could be affected by the equilibrium between the complex
coordinated through the olefin part and the alkyl com-
rate (run 2 vs 3).
plex. Namely, the reaction under high pressure produced
kinetically favorable products, while thermodynamic
equilibrium influences the reaction under low pressure.
The special feature of the H8-BINAP-metal complexes
compared to BINAP-metal complexes is the value of the
dihedral angle of the axial biaryl groups. Unfortunately,
no X-ray structure of the H8-BINAP-Ru complex is
available; however, the structure of H8-BINAP- and
BINAP-Rh complexes could be used as models. The
(17) For the reduction of 10, lower H2 pressure caused ee of 9b to
dihedral angle (80.3°) of the two tetralin rings in [Rh-
increase, but this trend is not applied to the all cases of the reduction
((S)-H8-BINAP)(cod)]ClO49b is wider than those of the two
naphthalene rings in the BINAP-Rh complexes reported
(71.0s75.5°).19 This difference is a reflection of the larger
steric hindrance of the hydrogen atoms attached to sp3
of other â,γ-unsaturated carboxylic acids.3a
(18) Previously, high ee was obtained for the hydrogenation of 2-aryl-
3-disubstituted acrylic acids catalyzed by
ferrocenylphosphine-Rh(I) complex, see: Hayashi, T.; Kawamura, N.;
Ito, Y. J . Am. Chem. Soc. 1987, 109, 7876.
a chiral (aminoalkyl)-

5514 J . Org. Chem., Vol. 61, No. 16, 1996
Uemura et al.
Sch em e 1
dination of olefin to ruthenium becomes better than that
in the BINAP-Ru complex because of the crowded
equatorial site, and the hydrogenolysis of the Ru-C bond
by H2 becomes faster due to a wide apical one.
Although the more electron-donating H8-BINAP ligand
could increase the hydridity of metal hydrides and
accelerate the reaction, ruthenium complexes having
p-Tol-BINAP and p-MeO-BINAP, which also seemed
more electron-donating than BINAP, showed catalytic
activities and selectivities similar to those of the BINAP-
Ru catalyst.
Con clu sion
In conclusion, the catalytic action of the H8-BINAP-
Ru(II) complex 2 has proven to be superior to that of the
ruthenium complexes having BINAPs. We have obtained
the highest enantiomeric excesses ever reported in the
asymmetric hydrogenation of various mono- and disub-
stituted R,â-unsaturated carboxylic acids by using the
dicarboxylate complex 2 as a catalyst. The substitution
pattern, both type and arrangement, affects the pressure
effect on the sense and degree of asymmetric induction.
F igu r e 1. Models of (S)-BINAP-Ru (left) and (S)-H8-BINAP-
Ru (right) complexes. Circles show apical coordination sites,
and squares show equatorial coordination sites.
carbon atoms in tetralin rings than that of hydrogen
atoms on sp2 carbon atoms in naphthalene rings.
Exp er im en ta l Section
In turn, a similar difference in the dihedral angles of
the axial biaryl groups between the H8-BINAP- and
BINAP-Ru(II) could be assumed. Simple models of
these are shown in Figure 1. From the models, the
arrangements of four phenyls on the phosphorous atoms
are influenced. These conformational changes made the
equatorial coordination sites of the H8-BINAP-Ru com-
plex more crowded than that of the BINAP-Ru complex
and the apical ones wider. Thus, in the case of the H8-
BINAP-Ru complex, the enantioselectivity on the coor-
Gen er a l. 1H NMR (270 MHz) spectra were recorded on a
J EOL J NM-EX270 spectrometer with a TMS internal refer-
ence. Optical rotations were measured on a J ASCO DIP-360
instrument. Gas chromatographic (GLC) analyses were con-
ducted on a Shimadzu GC-15A equipped with a flame ioniza-
tion detector on a Chrompack CP-cyclodextrin-â-236M-19
capillary column (0.25 mm id × 25 m df). HPLC analyses were
performed with a Toso CO-8000 chromatograph using a Toso
UV-8000 detector (column, Daicel Chiralcel OB, OD, or OJ ,
25 cm × 0.46 cm id; detection, 254-nm light). All melting
points were determined with a Yanako MP-500D melting point
apparatus and were not corrected.
(19) (a) Toriumi, K.; Ito, T.; Takaya, H.; Souchi, T.; Noyori, R. Acta
Crystallogr., Sect. B 1982, 38, 807. (b) Tani, K.; Yamagata, T.; Tatsuno,
Y.; Yamagata, Y.; Tomita, K.; Akutagawa, S.; Kumobayashi, H.;
Otsuka, S. Angew. Chem., Int. Ed. Engl. 1985, 24, 217. (c) Yamagata,
T.; Tani, K.; Tatsuno, Y.; Saito, T. J . Chem. Soc., Chem. Commun. 1988,
466; 1989, 67.
Ma ter ia ls. All manipulations involving air- and moisture-
sensitive organometallic compounds were carried out with the
standard Schlenk technique under argon atmosphere, purified
by passing it through a BASF-Catalyst R3-11 column. Ru-
(OAc)2((R)-BINAP) [(R)-1],3c Ru(OAc)2((S)-H8-BINAP) [(S)-2],9b

Enantioselective Asymmetric Hydrogenation
J . Org. Chem., Vol. 61, No. 16, 1996 5515
and [RuI((R)-H8-BINAP)(p-cymene)]I [(R)-3]9b were prepared
according to previously reported methods. Tiglic acid (4a ), (E)-
2-methyl-2-pentenoic acid (4b), N,N ′-dicyclohexylcarbodiim-
ide, and 4-(dimethylamino)pyridine were used as purchased.
(E)-2-Methyl-2-hexenoic acid (4c), (E)-2-ethyl-2-hexenoic acid
(4d ), 3-(trifluoromethyl)-2-butenoic acid (8a ), and aniline were
distilled under argon before use. 2-Methylcinnamic acid (4e)
and 2-phenylcinnamic acid (4f) were recrystallized from
benzene prior to use. 2-(4-Isobutylphenyl)propenoic acid (6),20
3-phenyl-3-butenoic acid (10),16 ethyl (E)- and (Z)-3-phenyl-2-
butenoate,21 ethyl 2,3-dimethyl-2-butenoate,22 and ethyl (E)-
2-methyl-3-phenyl-2-butenoate23 were prepared according to
the literature methods. For calibration purposes, racemic
2-methylbutyric acid ((()-5a ), 2-methylpentanoic acid ((()-5b),
2-methylhexanoic acid ((()-5c), 2-ethylhexanoic acid ((()-5d ),
and 2-(4-isobutylphenyl)propanoic acid ((()-7) were purchased
and used without purification. 2-Methyl-3-phenylpropanoic
acid ((()-5e), 2,3-diphenylpropanoic acid ((()-5f), 3-(trifluo-
romethyl)butyric acid ((()-9a ), 3-phenylbutyric acid ((()-9b),
2,3-dimethylbutyric acid ((()-12a ), and threo-2-methyl-3-phen-
ylbutyric acid ((()-12b) were prepared by the standard hy-
drogenation technique by 10% Pd/C. All solvents were dried
by standard methods and distilled under argon.
Asym m etr ic Hyd r ogen a tion of (E)-2-Meth yl-2-h exen o-
ic Acid (4c). Typical reaction conditions: Ru(OAc)2[(S)-H8-
BINAP] [(S)-2, 12.6 mg, 14.8 × 10-3 mmol], (E)-2-methyl-2-
hexenoic acid (4c, 387.3 mg, 3.02 mmol, S/C ) 204 mol/mol),
dry methanol/H2O (10:1, 1.9 mL, S/S ) 5 mL/g), an initial
hydrogen pressure of 1.5 atm, room temperature, 22 h.
Conversion (100%) of 4c and chemical selectivity (100%) to
1
2-methylhexanoic acid (5c) were determined by H NMR and
by GLC analysis with a Neutra bond-1 capillary column
(programmed from 100 to 140 °C at a rate of 4 °C/min). 5c:
354.0 mg, 2.72 mmol, 90% yield, a colorless liquid (Kugelrohr
distillation), [R]24D ) +19.00 (neat) [lit.26 [R]25D ) +18.7 (neat)
for (S)-2-methylhexanoic acid]. Enantiomeric excess (96%, S)
of the anilide of 5c was determined by HPLC analysis with a
Chiralcel OB column [hexane/2-propanol 92:8; flow rate, 1.0
mL/min; tR ) 10.67 (S) and 15.15 (R) min].
Asym m etr ic Hyd r ogen a tion of (E)-2-Eth yl-2-h exen oic
Acid (4d ). Typical reaction conditions: Ru(OAc)2[(S)-H8-
BINAP] [(S)-2, 9.7 mg, 11.4 × 10-3 mmol], (E)-2-ethyl-2-
hexenoic acid (4d , 320.2 mg, 2.25 mmol, S/C ) 197 mol/mol),
dry methanol (11.0 mL, S/S ) 34 mL/g), an initial hydrogen
pressure of 1.5 atm, room temperature, 20 h. Conversion
(100%) of 4d and chemical selectivity (100%) to 2-ethylhexanoic
acid (5d ) were determined by 1H NMR analysis. 5d : 261.4
mg, 1.81 mmol, 80% yield, a colorless liquid (Kugelrohr
distillation), [R]24 ) +8.52 (neat) [lit.27 [R]25 ) -4.20 (neat)
Asym m etr ic Hyd r ogen a tion of Tiglic Acid (4a ). This
procedure is illustrative for all asymmetric hydrogenation. To
a mixture of Ru(OAc)2[(S)-H8-BINAP] [(S)-2, 10.7 mg, 12.6 ×
10-3 mmol] and tiglic acid (4a , 252.1 mg, 2.52 mmol; S/C
(substrate/catalyst) ) 200 mol/mol) was added dry methanol
(12.5 mL; S/S (solvent/substrate) ) 50 mL/g). After the
resulting yellow solution was degassed by three freeze-thaw
cycles, it was transferred into a 100-mL autoclave and then
stirred under an initial hydrogen pressure of 1.5 atm at room
temperature for 20 h. Conversion (100%) of 4a and chemical
selectivity (100%) to 2-methylbutyric acid (5a ) were deter-
mined by 1H NMR analysis of the residue obtained on
concentration of the yellow reaction mixture. Kugelrohr
distillation of the residue afforded 5a (214.5 mg, 2.10 mmol,
D
D
for (R)-2-ethylhexanoic acid]. Enantiomeric excess (95%, S)
of 5d was directly determined by GLC analysis with
a
Chrompack CP-cyclodextrin-â-236M-19 capillary column [110
°C; He 1.3 kg/cm2; tR ) 20.28 (S) and 21.3 (R) min].
Asym m etr ic Hyd r ogen a tion of 2-Meth ylcin n a m ic Acid
(4e). Typical reaction conditions: Ru(OAc)2[(S)-H8-BINAP]
[(S)-2, 12.2 mg, 14.4 × 10-3 mmol], 2-methylcinnamic acid (4e,
467.4 mg, 2.88 mmol, S/C ) 200 mol/mol), dry methanol (14.4
mL, S/S ) 31 mL/g), an initial hydrogen pressure of 1.5 atm,
room temperature, 48 h. Conversion (95%) of 4e and chemical
selectivity (100%) to 2-methyl-3-phenylpropanoic acid (5e)
were determined by 1H NMR analysis. 5e: 410.5 mg, 2.50
mmol, 87% yield, a colorless liquid (Kugelrohr distillation),
[R]22 ) +24.88 (neat) [lit.28 [R]16 ) +18.4 (neat) for (S)-2-
83% yield) as a colorless liquid: [R]23 ) +20.36 (neat) [lit.24
D
[R]25 ) +18.9 (neat) for (S)-2-methylbutyric acid]. The
D
product (37.7 mg, 0.37 mmol) was condensed with aniline (51.1
mg, 0.55 mmol) in the presence of 4-(dimethylamino)pyridine
(8.0 mg) and N,N ′-dicyclohexylcarbodiimide (91.4 mg, 0.44
mmol) in THF (5 mL) for 21 h at room temperature. The
precipitate was filtered off, and the filtrate was evaporated.
The residue was chromatographed on silica gel (15 g), eluted
with diethyl ether to afford the anilide of 2-methylbutyric acid
as colorless crystals in quantitative yield. Enantiomeric excess
(97%, S) of this anilide was determined by HPLC analysis with
a Chiralcel OD column using an authentic sample of the
anilide of (()-2-methylbutyric acid as a reference [hexane/2-
propanol 485:15; flow rate, 0.5 mL/min; tR ) 64.37 (S) and
68.92 (R) min].
D
D
methyl-3-phenylpropanoic acid]. Enantiomeric excess (89%,
S) of the anilide of 5e was determined by HPLC analysis with
a Chiralcel OB column [hexane/2-propanol 96:4; flow rate, 1.0
mL/min; tR ) 43.32 (S) and 71.88 (R) min].
Asym m etr ic Hyd r ogen a tion of 2-P h en ylcin n a m ic Acid
(4f). Typical reaction conditions: Ru(OAc)2[(S)-H8-BINAP]
[(S)-2, 4.7 mg, 5.5 × 10-3 mmol], 2-phenylcinnamic acid (4f,
246.7 mg, 1.10 mmol, S/C ) 200 mol/mol), dry methanol (5.0
mL, S/S ) 20 mL/g), an initial hydrogen pressure of 27 atm,
60 °C, 61 h. Conversion (100%) of 4f and chemical selectivity
(100%) to 2,3-diphenylpropanoic acid (5f) were determined by
1H NMR analysis. 5f: 226.0 mg, 1.00 mmol, 90% yield,
colorless crystals (Kugelrohr distillation), mp 78.0-79.2 °C,
[R]24 ) -104.26 (c 0.525, acetone) [lit.28 mp 83-84 °C, [R]20
Asym m et r ic H yd r ogen a t ion of (E)-2-Met h yl-2-p en -
ten oic Acid (4b). Typical reaction conditions: Ru(OAc)2[(S)-
H8-BINAP] [(S)-2, 14.3 mg, 16.8 × 10-3 mmol], (E)-2-methyl-
2-pentenoic acid (4b, 409.0 mg, 3.58 mmol, S/C ) 213 mol/
mol), dry methanol (18.0 mL, S/S ) 44 mL/g), an initial
hydrogen pressure of 1.5 atm, room temperature, 24 h.
Conversion (100%) of 4b and chemical selectivity (100%) to
2-methylpentanoic acid (5b) were determined by 1H NMR
analysis. 5b: 370.5 mg, 3.19 mmol, 89% yield, a colorless
D
D
) +133.7 (c 0.535, acetone) for (S)-2,3-diphenylpropanoic acid
of 99% ee]. Enantiomeric excess (74%, R) of the anilide of 5f
was determined by HPLC analysis with a Chiralcel OD column
[hexane/2-propanol 97:3; flow rate, 1.0 mL/min; tR ) 48.86 (S)
and 56.42 (R) min].
Asym m etr ic Hyd r ogen a tion of 2-(4-Isobu tylp h en yl)-
p r op en oic Acid (6). Typical reaction conditions: Ru(OAc)2-
[(S)-H8-BINAP] [(S)-2, 5.0 mg, 5.9 × 10-3 mmol), 2-(4-
isobutylphenyl)propenoic acid (6, 240.5 mg, 1.18 mmol, S/C )
200 mol/mol), dry methanol (6.0 mL, S/S ) 25 mL/g), an initial
hydrogen pressure of 100 atm, room temperature, 8 h. Con-
version (100%) of 6 and chemical selectivity (100%) to 2-(4-
isobutylphenyl)propanoic acid (ibuprofen, 7) were determined
by 1H NMR analysis. Column chromatography of the residue
on silica gel (30 g) eluted with diethyl ether afforded 7 (235.1
mg, 1.14 mmol, 97% yield) as yellow crystals: mp 48.2-48.9
liquid (Kugelrohr distillation), [R]24 ) +17.56 (neat) [lit.25
D
[R]16 ) +18.4 (neat) for (S)-2-methylpentanoic acid]. Enan-
D
tiomeric excess (96%, S) of 5b was directly determined by GLC
analysis with a Chrompack CP-cyclodextrin-â-236M-19 capil-
lary column [100 °C; He 1.0 kg/cm2; tR ) 16.80 (S) and 19.59
(R) min].
(20) Kurtz, R. R.; Houser, D. T. J . Org. Chem. 1981, 46, 202.
(21) Takahashi, H.; Fujiwara, K.; Ohta, M. Bull. Chem. Soc. J pn.
1962, 35, 1498.
(22) Ceccherelli, P.; Curini, M.; Marcotullio, M.; Rosati, O. Synth.
Commun. 1991, 21, 17.
(23) Gallagher, G., J r.; Webb, R. L. Synthesis 1974, 122.
(24) Korver, O.; Gorkom, M. Tetrahedron 1974, 30, 4041.
(25) Helmchen, G.; Nill, G.; Flockerzi, D.; Youssef, M. S. K. Angew.
Chem., Int. Ed. Engl. 1979, 18, 63.
(26) Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J . Am. Chem.
Soc. 1976, 98, 567.
(27) Levene, P. A.; Rothen, A.; Meyer, G. M. J . Biol. Chem. 1936,
115, 401.
(28) Watson, M. B.; Youngson, G. W. J . Chem. Soc. (C) 1968, 258.

5516 J . Org. Chem., Vol. 61, No. 16, 1996
Uemura et al.
°C, [R]22D ) +51.63 (c 2.08, ethanol) [lit.29 mp 50-52 °C, [R]20
added ethyl 2,3-dimethyl-2-butenoate (2.87 g, 20.19 mmol),
potassium hydroxide (5.15 g, 78.05 mmol), H2O (20 mL), and
ethanol (15 mL). The mixture was stirred at reflux for 4 h.
The organic solvent was removed by distillation. The residue
was acidified until pH < 2 with 1 N HCl. The organic acid
was extracted with diethyl ether (50 mL × 4). The organic
layer was washed with water (50 mL), dried over anhydrous
MgSO4, and concentrated. The residue was purified by short-
column chromatography on silica gel (25 g) with diethyl ether
as an eluent to give 2,3-dimethyl-2-butenoic acid (11a ) as
colorless crystals (610.0 mg, 5.34 mmol). 1H NMR spectra were
in accordance with the reported data.16
D
) +59 (c 2, ethanol) for ibuprofen of 99% ee]. Enantiomeric
excess (97%, S) of ibuprofen was directly determined by GC
analysis with a Chrompack CP-cyclodextrin-â-236M-19 capil-
lary column [170 °C; He 2.0 kg/cm2; tR ) 15.64 (S) and 16.64
(R) min].
Asym m etr ic Hydr ogen ation of (E)-3-(Tr iflu or om eth yl)-
2-bu ten oic Acid (8a ). Typical reaction conditions: Ru(OAc)2-
[(S)-H8-BINAP] [(S)-2, 8.4 mg, 9.9 × 10-3 mmol], (E)-3-
(trifluoromethyl)-2-butenoic acid (8a , 305.8 mg, 1.98 mmol, S/C
) 200 mol/mol), dry methanol (10.0 mL, S/S ) 33 mL/g), an
initial hydrogen pressure of 100 atm, room temperature, 8 h.
Conversion (100%) of 8a and chemical selectivity (100%) to
3-(trifluoromethyl)butyric acid (9a ) were determined by 1H
NMR analysis. 9a : 267.0 mg, 1.71 mmol, 86% yield, a
colorless liquid (Kugelrohr distillation), [R]22D ) -19.88 (c 1.02,
chloroform). Enantiomeric excess (93%, (-)) of the anilide of
9a was determined by HPLC analysis with a Chiralcel OJ
Asym m etr ic Hyd r ogen a tion of 2,3-Dim eth yl-2-bu ten o-
ic Acid (11a ). Typical reaction conditions: Ru(OAc)2[(S)-H8-
BINAP] [(S)-2, 3.8 mg, 4.5 × 10-3 mmol], 2,3-dimethyl-2-
butenoic acid (11a , 308.2 mg, 2.70 mmol, S/C ) 600 mol/mol),
dry THF (3.1 mL, S/S ) 10 mL/g), an initial hydrogen pressure
of 100 atm, room temperature, 3 h. Conversion (100%) of 11a
and chemical selectivity (100%) to 2,3-dimethylbutyric acid
column [hexane/2-propanol 98:2; flow rate, 1.0 mL/min; tR
46.49 (-) and 55.74 (+) min].
)
1
(12a ) were determined by H NMR analysis. 12a : 298.2 mg,
Syn th esis of (E)- a n d (Z)-3-P h en yl-2-bu ten oic Acid
(8b,c) fr om Eth yl (E)- a n d (Z)-3-P h en yl-2-bu ten oa te.
Spinning-band distillation of an 84:16 mixture of ethyl (E)-
and (Z)-3-phenyl-2-butenoate gave pure (E)- and (Z)-esters,
respectively. Pure (E)-acid was obtained by recrystallization
from pentane at -20 °C after treatment of pure (E)-ester with
a mixture of aqueous sodium hydroxide and ethanol at reflux
temperature. (Z)-Acid was also obtained in a similar manner.
1H NMR spectra of these acids were in accordance with the
reported data.30
2.57 mmol, 95% yield, a colorless liquid (Kugelrohr distilla-
tion), [R]26 ) +18.72 (neat) [lit.32 [R]25 ) -18.9 (neat) for
D
D
(R)-2,3-dimethylbutyric acid]. Enantiomeric excess (88%, S)
of the anilide of 12a was determined by HPLC analysis with
a Chiralcel OD column [hexane/2-propanol 98:2; flow rate, 1.0
mL/min; tR ) 43.01 (S) and 49.88 (R) min].
Syn th esis of (E)-2-Meth yl-3-p h en yl-2-bu ten oic Acid
(11b) fr om Eth yl (E)-2-Meth yl-3-p h en yl-2-bu ten oa te. In
a 100-mL flask were added ethyl (E)-2-methyl-3-phenyl-2-
butenoate (4.99 g, 24.42 mmol), potassium hydroxide (5.52 g,
98 mmol), H2O (30 mL), and methanol (10 mL). The mixture
was stirred at reflux for 23 h. Two-thirds of the solvent was
removed by distillation. The residue was acidified until pH
< 2 with 1 N HCl. The organic acid was extracted with diethyl
ether (40 mL × 5) and benzene (50 mL × 2). Combined organic
layer was washed with water (50 mL), dried over anhydrous
MgSO4, and concentrated. The residue was chromatographed
on silica gel (170 g) with a 10:1 mixture of hexane and ethyl
acetate. The yellow solid obtained was washed with hexane
to give (E)-2-methyl-3-phenyl-2-butenoic acid (11b) as colorless
crystals (2.55 g, 14.47 mmol). 1H NMR spectra were in
accordance with the reported data.33
Asym m etr ic Hyd r ogen a tion of (E)-3-P h en yl-2-bu ten o-
ic Acid (8b). Typical reaction conditions: Ru(OAc)2[(S)-H8-
BINAP] [(S)-2, 3.5 mg, 4.1 × 10-3 mmol], (E)-3-phenyl-2-
butenoic acid (8b, 133.0 mg, 0.82 mmol, S/C ) 200 mol/mol),
dry methanol (2.7 mL, S/S ) 20 mL/g), an initial hydrogen
pressure of 100 atm, room temperature, 7 h. Conversion
(100%) of 8b and chemical selectivity (100%) to 3-phenylbutyric
acid (9b) were determined by 1H NMR analysis. 9b: 120.7
mg, 0.74 mmol, 90% yield, colorless liquid (Kugelrohr distil-
lation), [R]24 ) +38.81 (c 2.72, benzene) [lit.31 [R]25 ) -57.6
D
D
(c 2.7, benzene) for (R)-3-phenylbutyric acid]. Enantiomeric
excess (70%, S) of the anilide of 9b was determined by HPLC
analysis with a Chiralcel OB column [hexane/2-propanol 95:
5; flow rate, 1.0 mL/min; tR ) 34.4 (S) and 56.22 (R) min].
Asym m etr ic Hyd r ogen a tion of (Z)-3-P h en yl-2-bu ten o-
ic Acid (8c). Typical reaction conditions: Ru(OAc)2[(S)-H8-
BINAP] [(S)-2, 3.0 mg, 3.5 × 10-3 mmol], (Z)-3-phenyl-2-
butenoic acid (8c, 113.5 mg, 0.70 mmol, S/C ) 200 mol/mol),
dry methanol (2.3 mL, S/S ) 20 mL/g), an initial hydrogen
pressure of 4.0 atm, room temperature, 25 h. Conversion
(100%) of 8c and chemical selectivity (100%) to 3-phenylbutyric
acid (9b) were determined by 1H NMR analysis. 9b: 107.4
Asym m etr ic Hyd r ogen a tion of (E)-2-Meth yl-3-p h en yl-
2-bu ten oic Acid (11b). Typical reaction conditions: Ru-
(OAc)2[(S)-H8-BINAP] [(S)-2, 3.3 mg, 3.9 × 10-3 mmol], (E)-
2-methyl-3-phenyl-2-butenoic acid (11b, 137.5 mg, 0.78 mmol,
S/C ) 200 mol/mol), dry methanol (1.4 mL, S/S ) 10 mL/g),
an initial hydrogen pressure of 100 atm, room temperature, 5
h. Conversion (100%) of 11b and chemical selectivity (100%)
to threo-2-methyl-3-phenylbutyric acid (12b) were determined
1
by H NMR analysis. 12b: 132.1 mg, 0.74 mmol, a colorless
liquid (Kugelrohr distillation), [R]24 ) +53.37 (c 0.540,
D
mg, 0.65 mmol, 93% yield, [R]23 ) -51.73 (c 2.69, benzene),
methanol) [lit.34 [R]22 ) +53.1 (c 1.17) for (2S, 3S)-2-methyl-
D
D
93% ee (R).
3-phenylbutyric acid]. Enantiomeric excess (55%, 2S,3S) of
the anilide of 12b was determined by HPLC analysis with a
Chiralcel OD column [hexane/2-propanol 98:2; flow rate, 1.0
mL/min; tR ) 48.01 (2S,3S) and 61.30 (2R,3R) min].
Asym m etr ic Hyd r ogen a tion of 3-P h en yl-3-bu ten oic
Acid (10). Typical reaction conditions: Ru(OAc)2[(S)-H8-
BINAP] [(S)-2, 8.4 mg, 9.9 × 10-3 mmol], 3-phenyl-3-butenoic
acid (10, 321.4 mg, 1.98 mmol, S/C ) 200 mol/mol), dry
methanol (9.9 mL, S/S ) 31 mL/g), an initial hydrogen
pressure of 1.5 atm, room temperature, 2 h. Conversion
(100%) of 10 and chemical selectivity (100%) to 3-phenylbutyric
acid (9b) were determined by 1H NMR analysis. 9b: 301.0
Ack n ow led gm en t. Financial support from the Min-
istry of Education, Science, Sports and Culture, J apan
(No. 05236106), and the Grant-in-Aid for Developmental
Scientific Research (No. 06555272) are acknowledged.
The authors also appreciate financial support from the
Mitsubishi Foundation.
mg, 1.83 mmol, 92% yield, [R]25 ) -48.32 (c 2.69, benzene),
D
83% ee (R).
Syn th esis of 2,3-Dim eth yl-2-bu ten oic Acid (11a ) fr om
Eth yl 2,3-Dim eth yl-2-bu ten oa te. In a 100-mL flask were
J O960426P
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