Asymmetric hydrogenation of α-ethylstyrenes catalyzed by chiral ruthenium complexes

Article abstract of DOI:10.1016/S0040-4039(00)01613-0

A combined system of RuCl₂[(R,R)-Me-DuPhos](dmf)(n) and t-C₄H₉OK catalyzes the asymmetric hydrogenation of α-ethylstyrene derivatives. The reaction proceeds with a substrate to catalyst molar ratio of up to 2600 in 2-propanol at 8 atm and room temperature to give the chiral saturated products in 81-89% ee. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01613-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9471–9475
Asymmetric hydrogenation of a-ethylstyrenes catalyzed by
chiral ruthenium complexes†
Grant S. Forman, Takeshi Ohkuma, William P. Hems and Ryoji Noyori*
Department of Chemistry and Research Center for Materials Science, Nagoya University, Chikusa,
Nagoya 464-8602, Japan
Received 30 August 2000; revised 13 September 2000; accepted 18 September 2000
Abstract
A combined system of RuCl2[(R,R)-Me-DuPhos](dmf)n and t-C4H9OK catalyzes the asymmetric
hydrogenation of a-ethylstyrene derivatives. The reaction proceeds with a substrate to catalyst molar ratio
of up to 2600 in 2-propanol at 8 atm and room temperature to give the chiral saturated products in
81–89% ee. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: a-substituted styrenes; asymmetric hydrogenation; Me-DuPhos–Ru complex.
Asymmetric hydrogenation of simple aromatic olefins has been a challenging subject since
1968, when Horner1 reported the first trial using chiral phosphine–Rh complexes. Despite
numerous efforts, currently available catalyst systems, with one notable exception,2 are not
suitable for the reaction of simple a-alkylated styrenes because of the low reactivity and/or
enantioselectivity. Ru and Rh complexes possessing a chiral diphosphine ligand act as excellent
precatalysts of asymmetric hydrogenation of functionalized olefins such as enamides, allylic or
homoallylic alcohols, and a,b- or b,g-unsaturated carboxylic acids.3,4 The reaction occurs via an
olefin/metal p complex which is stabilized by additional ligation of a heteroatom to the metallic
center.3–5 Asymmetric hydrogenation of a-alkylstyrenes is difficult because such highly organized
chelate complexes are not accessible.4d,6–9 Chiral Ir complexes are known to catalyze the
enantioselective hydrogenation of certain tri- and tetrasubstituted aromatic olefins (S/C=25–
1000, 50 atm, 81–98% ee),10 while the reaction of a-alkylated styrenes is unknown. The high
reactivity of a-alkylstryenes is obtainable with early transition metal-11 and lanthanide-based
catalysts, and the best result was recorded in a chiral Sm-catalyzed hydrogenation of a-ethyl-
styrene, giving 96% ee at 1 atm and −80°C or 64% ee at 25°C (S/C=100–1000).2,12 We here
describe a new method for activating chiral Ru complexes for the asymmetric hydrogenation of
a-alkylated styrene derivatives.
* Corresponding author. Tel: +81-52-789-2956; fax: +81-52-783-4177; e-mail: noyori@chem3.chem.nagoya-u.ac.jp
†
Respectfully dedicated to Professor Harry H. Wasserman on the occasion of his 80th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01613-0

9472
Ru complexes of type RuCl2(diphosphine)(dmf)n13 have a low reactivity for the hydrogenation
of styrene derivatives, but the catalytic activity is markedly enhanced by the addition of an
14,15
alkaline base in 2-propanol. Thus, in the presence of RuCl2[(R,R)-Me-DuPhos](dmf)n
and
t-C4H9OK (1:20) in 2-propanol, a series of a-ethylstyrenes 1 were smoothly hydrogenated at 8
atm and at room temperature in an enantioselective manner (Scheme 1). The reaction was
performed with S/C of up to 2600 to give the chiral products (R)-2 in 81 to 89% ee.16,17
Examples of the asymmetric hydrogenation are given in Table 1. The absolute configuration of
the meta- or para-halogenated products was determined after dehalogenation with a LiAlH4–
CeCl3 mixture18 or hydrogenolysis catalyzed by 10% Pd/C.19 Hydrogenation of the meta- or
para-substituted substrates gave the chiral 2-arylbutanes with consistently high selectivity. The
highest value, 89%, was obtained with m-chloro-a-ethylstyrene (1g). The enantioselectivity was
found to be relatively insensitive to the substituents. However, the ortho-brominated analogue
1i gave only moderate chemical and optical yield. When the relative reactivities of the
para-substituted olefins (independent experiments) are plotted against the | value, a linear
relationship with z=0.10 is obtained, indicating a very low sensitivity to substituent effects.
p-Hydroxy-a-ethylstyrene was inert to the standard conditions. A 2:1 mixture of cis- and
trans-2-(p-bromophenyl)-2-butene was recovered without hydrogenation, suggesting that reac-
tion of a-ethylstyrenes occurs directly without isomerization to the internal olefins. The
electron-donating Me-DuPhos,14 as the catalyst ligand, appears to greatly facilitate the reaction.
The bulkier Et-DuPhos or BINAP, a fully aromatic phosphine, was not effective. Replacement
of 2-propanol solvent by methanol or t-butyl alcohol sharply decreased the chemical and/or
enantioselectivity. The presence of a strong base was crucial. Otherwise, the reactivity was
significantly reduced, and the sense of enantioselection was reversed. For example, hydrogena-
tion of 1e without t-C4H9OK (S/C=660, 8 atm) proceeded ca. ten times more slowly (initial
rate) than in the presence of base, giving the S-configurated product in 21% ee.
(R,R)-Me-DuPhos–Ru
t-C4H9OK
+
H2
X
X
(CH3)2CHOH
1
2
a: X = H
f: X = p-CF3
g: X = m-Cl
m-Br
b: X = p-CH3
c: X = p-F
P
P
h: X =
i: X = o-Br
d: X = p-Cl
e: X = p-Br
(R,R)-Me-DuPhos
Scheme 1.
It is well known that the treatment of Ru halides with an alkaline base in 2-propanol
generates Ru hydride species that are capable of catalyzing the transfer hydrogenation of
carbonyl compounds.4d,20 However, the present system does not promote saturation of styrene
derivatives without H2. Both H2 and 2-propanol are necessary for high reactivity. The reaction
of 1e using D2 and (CH3)2CHOH (S/C=500, 10 atm, 25°C, 16 h) gave the corresponding vicinal
1
dideuterio compound selectively (ca. 90% at a position and >95% at b position by H NMR
analysis, 83% ee), confirming the net hydrogenation.

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Table 1
Asymmetric hydrogenation of a-ethylstyrenes catalyzed by (R,R)-Me-DuPhos–Ru complexa
Olefin
S/Cb
% Conv.c
Product 2
% Yieldd
% Eee
Config.f
1a
1b
1c
1d
1e
1f
1g
1h
1i
200
330
660
1380
660
2620
520
100
87
97
92
86g
87
R
R
83h
83
82i
85
Rj
Rj
Rj
R
94
88h
89
100
99.5
87
83k
81l
89
93
81h
Rj
Rj
Rj
520
390
100m
33
89m
86n
69
o
–
a Unless otherwise stated, reactions were conducted at 8 atm of H2 and 18–25°C for 16 h using a 2.0–2.5 M solution
of 1 (95–99% pure) in 2-propanol containing RuCl2[(R,R)-Me-DuPhos](dmf)n and t-C4H9OK (1:20 molar ratio).
b Substrate:catalyst molar ratio.
c GC analysis.
d Isolated yield after bulb-to-bulb distillation.
e Chiral GC analysis (b-cyclodextrin phase).
f Determined by the sign of rotation of the pure or substrate-contaminated product.
g Determined by the rotation value, [h]2D2 −24.5° (c 0.53, 95% C2H5OH); lit. Lardicci, L.; Menicagli, R.; Salvadpri,
P. Gazz. Chim. Ital. 1968, 98, 738–759, [h]2D5 +28.4° (c 1.00, 95% C2H5OH) for (S)-2a.
h Contaminated with ca. 5% of 1.
i [h]2D0 −22.8° (c 2.5 C2H5OH).
j Determined after conversion to 2a.
k [h]2D2 −15.1° (c 2.5, C2H5OH).
l See Ref. 16.
m Formation of 1% cis- and trans-2-(m-bromophenyl)-2-butene was observed.
n [h]1D7 −22.1° (c 1.0, 95% C2H5OH).
o A 67:33 mixture of 1i and 2i.
The present chiral catalyst system hydrogenates certain aromatic olefins under mild reaction
conditions and with respectable enantioselectivity. The reactivity and chiral efficiency are better
than those accessible with the conventional Ru or Rh catalysts.4,6
Acknowledgements
We are grateful to ChiroTech for supplying a sample of (R,R)-Me-DuPhos. G.S.F. and
W.P.H. thank the JSPS postdoctoral fellowship. This work was financially supported by
grants-in-aid from the Ministry of Education, Science, Sports and Culture of Japan (Nos.
07CE2004 and 11440188).
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(Knowles, W. S.; Sabacky, M. J. Chem. Commun. 1968, 1445–1446) presented the first examples of asymmetric
hydrogenation of olefins.

9474
2. (a) Conticello, V. P.; Brard, L.; Giardello, M. A.; Tsuji, Y.; Sabat, M.; Stern, C. L.; Marks, T. J. J. Am. Chem.
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bis(diphenylphosphino)-1,1%-binaphthyl.
8. The reactivity of Ru-catalyzed hydrogenation is highly dependent on the substitution pattern of olefins (Hallman,
P. S.; McGarvey, B. R.; Wilkinson, G. J. Chem. Soc. A 1968, 3143–3150) and decreases in the order of terminal
alkenes>styrenes>a-alkylstyrenes.
9. A cationic diphosphine–Rh complex in benzene is activated by tetrabutylammonium iodide. See: Buriak, J. M.;
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8105–8107. The reported optical yield of 96% was actually 77%.6 See also: Paquette, L. A.; Sivik, M. R.; Bzowej,
E. I.; Stanton, K. J. Organometallics 1995, 14, 4865–4878.
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olefins (S/C=13–20, 68–136 atm, rt to 65°C, 83“>99% ee). See: (a) Broene, R. D.; Buchwald, S. L. J. Am. Chem.
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14. Me-DuPhos=1,2-bis(2,5-dimethylphospholano)benzene. Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R.
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15. Preparation of RuCl2[(R,R)-Me-DuPhos](dmf)n: (R,R)-Me-DuPhos (99.8 mg, 0.326 mmol) and [RuCl2(C6H6)]2
(82.0 mg, 0.164 mmol) were placed in a 100-mL Schlenk flask. After the air was replaced with argon, dry
degassed DMF (2 mL) was added and the mixture was stirred under argon at 100°C for 2 h to form a brown
solution. The solvent was evaporated under reduced pressure, and the residue was dissolved in a 1:1 mixture of
ether and CH2Cl2 (5 mL). The turbidity was removed by filtration under argon, and the filtrate was concentrated
to approximately 3 mL. The turbidity was again removed by filtration. Hexane (3 mL) was added, and the
turbidity was removed by filtration. Upon concentration of the filtrate to approximately 2 mL, a bright yellow
powder precipitated. The supernatant was removed, and the resulting solid was dried under reduced pressure to
give oligomeric RuCl2[(R,R)-Me-DuPhos](dmf)n (83.1 mg). 31P NMR (202 MHz, C6D6): l 97.9 (d, J=26 Hz),
99.1 (d, J=30 Hz), 99.5 (d, J=28 Hz), 102.4 (d, J=32 Hz). This complex should be stored under an argon
atmosphere.
16. RuCl2[(R,R)-Me-DuPhos](dmf)n (1.5 mg, 0.0024 mmol, calculated as n=2) was placed in a 100-mL glass
autoclave equipped with a Teflon-coated magnetic stirring bar, and the air in this apparatus was replaced with
argon. 2-Propanol (1.2 mL), 1f (1.26 g, 6.29 mmol), and a 1.0 M t-C4H9OK solution in t-butyl alcohol (47 mL,
0.047 mmol) were added to the autoclave, and the mixture was degassed. Hydrogen was introduced into the
autoclave at a pressure of 8 atm. The reaction mixture was vigorously stirred at 20°C for 16 h. The conversion
determined by GC was 99.5%. GC [Chirasil-DEX CB, df=0.25 mm, 0.32 mm i.d.×25 m, CHROMPACK; carrier
gas, helium (26 kPa); column temp., 89°C; retention time (tR) of (R)-2f, 34.0 min (90.0%); tR of S isomer 32.9
min (9.5%); tR of 1f, 42.9 min (0.5%)]. After the reaction, the solvent was removed under reduced pressure, and
the residue was purified by bulb-to-bulb distillation to give (R)-2f (1.18 g, 93% yield, 81% ee). No starting

9475
substrate was detected. [h]2D2 −17.0° (c 3.0, C6H6), lit. [h]D22 +19.6° (c 5, C6H6), 94% ee (S), Capillon, J.; Guette´,
J. P. Tetrahedron 1979, 35, 1807–1815.
17. Hydrogenation of p-bromo-a-ethylstyrene in 2-propanol containing RuCl2[(R,R)-Me-DuPhos][NH2(CH2)2NH2]
and t-C4H9OK (S/C=1000, 10 atm, rt, 12 h) gave the R-enriched product in 80% ee but in only 7% yield.
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.