trans-RuH(η1-BH4)(binap)(1,2-diamine): A catalyst for asymmetric hydrogenation of simple ketones under base-free conditions

Article abstract of DOI:10.1021/ja026136+

(Chemical Equqtion Presentation) Reaction of a chiral RuCl₂(diphosphine)(1,2-diamine) complex and NaBH₄ forms trans-RuH(η¹-BH₄)(diphosphine)(1,2-diamine) quantitatively. The TolBINAP/DPEN Ru complex has been characterized by single crystal X-ray analysis as well as NMR and IR spectra. The new Ru complexes allow for asymmetric hydrogenation of simple ketones in 2-propanol without an additional strong base. Various base-sensitive ketones are convertible to chiral alcohols in a high enantiomeric purity with a substrate/catalyst ratio of up to 100 000 under mild conditions. Configurationally unstable 2-isopropyl- and 2-methoxycyclohexanone can be kinetically resolved with a high enantiomer discrimination. This procedure overcomes the drawback of an earlier method using RuCl₂(diphosphine)(diamine) and an alkaline base, which sometimes causes undesired reactions such as ester exchange, epoxy-ring opening, β-elimination, and polymerization of ketonic substrates. Copyright

Full text of DOI:10.1021/ja026136+

Published on Web 05/15/2002
trans-RuH(η1-BH4)(binap)(1,2-diamine): A Catalyst for Asymmetric
Hydrogenation of Simple Ketones under Base-Free Conditions
Takeshi Ohkuma,† Masatoshi Koizumi,† Kilian Mun˜iz,† Gerhard Hilt,† Chizuko Kabuto,‡ and
Ryoji Noyori*,†
Nagoya UniVersity, Department of Chemistry and Research Center for Materials Science, Chikusa,
Nagoya 464-8602, Japan, and Tohoku UniVersity, Instrumental Analysis Center for Chemistry,
Graduate School of Science, Aoba, Sendai 980-8578, Japan
Received March 8, 2002
Chiral RuCl2(diphosphine)(1,2-diamine) complexes1 catalyze
rapid, highly productive asymmetric hydrogenation of simple
ketones in 2-propanol containing an alkaline base such as KOH,
KO-i-C3H7, or KO-t-C4H9.2 A range of chiral alcohols is accessible
in high enantiomeric purity from aromatic, heteroaromatic, and
olefinic ketones by this method. Since the discovery of this
procedure in 1995,3 and more recently, as its high practicality
became recognized,2 we have been encouraged to develop a robust
(pre)catalyst that promotes the enantioselective reaction under base-
free conditions.4 Here we disclose useful chiral Ru complexes that
meet this demand. The asymmetric hydrogenation using a newly
devised RuH(η1-BH4)(binap)(1,2-diamine) complex proceeds with-
out any base, with a high substrate/catalyst molar ratio (S/C), up
to 100 000, and with a 3-4 M substrate concentration in 2-propanol.
Figure 1. ORTEP drawing of (R,RR)-1. Selected distances (Å) and bond
angles (deg): Ru-H1 1.52(5), Ru-H2 1.74(7), Ru-P1 2.219(3), Ru-P2
2.233(3), Ru-N1 2.140(8), Ru-N2 2.163(8), B-H2 1.32(7); H1-Ru-
H2 172(3), P1-Ru-P2 91.9(1), N1-Ru-N2 76.9(3). Only the ruthenium-
and borohydrides, and amino and methine protons of DPEN are shown.
the solution was stirred at 65 °C for 5 min and at 25 °C for 30 min
and then evaporated. Extraction of the residue with benzene
followed by concentration gave RuH(η1-BH4)[(R)-tolbinap][(R,R)-
dpen] [(R,RR)-1] as a yellow solid in a quantitative yield, dec 164
°C. Recrystallization from a THF-hexane mixture gave (R,RR)-
1‚THF‚n-C6H14. Single-crystal X-ray analysis (Figure 1) revealed
that the BH4 anion is bound to the Ru center in an η1 fashion6 and
is located trans to the hydride. The (R)-TolBINAP and (R,R)-DPEN
ligands are accommodated in the same Ru plane and have a λ
conformation. The Ru-H bond length, 1.52(5) Å, is very short,7
whereas the Ru-HBH3 length, 1.74(7) Å, is rather long. The BH4
ligand is further supported in the complex through BH‚‚‚HN
hydrogen bonds (1.8 and 2.0 Å). A benzene-d6 solution of (R,RR)-1
gave 31P{1H} NMR signals at 71.2 and 75.2 ppm (AB quartet, JP-P
) 41.4 Hz), and an 1H signal for Ru-H at δ -13.60 (triplet, JH-P
) 22.4 Hz). The BH4 moiety gave a broad signal at δ -0.79 in
toluene-d8 at room temperature, suggesting its fluxional behavior.
Its IR spectrum in toluene showed a characteristic Ru-H stretching
band6b at 1862 (s) cm-1 and B-H stretching bands at 2317 (s)
cm-1 as well as BH3 deformation frequencies at 1092 (s) and 1080
The requisite chiral catalyst can be synthesized in a straightfor-
(s) cm-1. In the same manner, various RuH(η1-BH4) complexes
ward fashion. RuCl2[(R)-tolbinap][(R,R)-dpen]1,5 and 25 mol equiv
including (S,SS)-2 and (S,RR)-2 were synthesized from the corre-
of NaBH4 were dissolved in a 1:1 benzene-ethanol mixture, and
sponding RuCl2 precursors. The new Ru-hydride complexes are
relatively stable. They can be quickly weighed in open air and stored
for a long time in an argon-sealed bottle below -30 °C, although
preparation directly prior to use is preferable.
* To whom correspondence should be addressed. E-mail: noyori@
chem3.chem.nagoya-u.ac.jp.
† Nagoya University.
‡ Tohoku University.
9
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J. AM. CHEM. SOC. 2002, 124, 6508-6509
10.1021/ja026136+ CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
Table 1. Asymmetric Hydrogenation of Ketones Catalyzed by
trans-RuH(η1-BH4)(binap)(dpen)a
8a] was hydrogenated with (S,RR)-2 (S/C ) 2000), the R enanti-
omer was consumed 28 times faster than was the S isomer. Thus,
after 53% conversion, unreacted (S)-8a in 91% ee was recovered,
together with (1R,2R)-9a, in 85% ee. More importantly, enantiomers
of 2-methoxycyclohexanone (8b) can be discriminated by a factor
of 38. Thus, hydrogenation of the racemate with (S,SS)-2 afforded,
at 53% conversion, (R)-8b (94% ee, 42% isolated yield), and
(1R,2S)-9b (91% ee, 50% isolated yield). No trans alcohol was
detected. The chiral R-alkoxy ketone (S)-8b is a key intermediate
for the synthesis of the potent antibacterial sanfetrinem.14,16
This alkaline base-free procedure using the new chiral Ru
complexes substantially expands the scope of asymmetric hydro-
genation of ketones. In the presence of an alkaline base, these
complexes are more reactive than the standard RuCl2 complexes.2,17
alcohol
ketone
Ru cat
S/Cb
time, h
% yieldc
%eed
confige
3f
3f
3
(R,RR)-1
(S,SS)-2
(S,SS)-2
(S,SS)-2
(S,SS)-2
(S,SS)-2
(S,SS)-2
(S,SS)-2
(S,SS)-2
100000
100000
2000
4000
4000
2000
2000
4000
4000
6g
7h
99.9
100
99.9
99.9
100
100
99
82
99
97
99
99
97j
99j
97
99
S
R
R
R
R
Rk
Rk
R
R
12i
12
15
16
14
12
16
3
4a
4b
5
6
7
100
95
a
Unless otherwise stated, reactions were conducted at 8 atm of H2 at
23-25 °C using a 1.0-2.0 M ketone solution in 2-propanol containing a
b
c
Ru catalyst. Substrate/catalyst molar ratio. GC or 1H NMR analysis.d
Acknowledgment. M.K., K.M., and G.H. thank the JSPS
Fellowships. This work was financially supported by grants-in-aid
from the Ministry of Education, Culture, Sports, Science, and
Technology of Japan (Nos. 07CE2004, 13440188, and 13024239)
and the Sumitomo Foundation.
e
f
Chiral GC or HPLC analysis. Determined by the sign of rotation.
g
Reaction using 102 g of 3 in 100 mL of 2-propanol (3.4 M). Reaction
temperature was increased to 38 °C by the heat of reaction. At 45 °C.i
h
j
k
At 1 atm of H2. Diastereomeric excess. See Supporting Information.
These complexes showed an excellent catalytic efficiency without
addition of any base. When a 3.4 M solution of acetophenone (3)
(102 g) in 2-propanol (106 mL) containing (S,SS)-2 (9.0 mg, S/C
) 100 000) was stirred under 8 atm of H2 at 45 °C for 7 h in a 1-L
stainless steel autoclave, (R)-1-phenylethanol was obtained quan-
titatively in 99% ee.8 Addition of 0.014 M KO-t-C4H9 increased
the catalytic activity by an order of magnitude, completing the
hydrogenation of 3 in 45 min under otherwise identical conditions
(R in 99% ee). The standard RuCl2/0.014 M KO-t-C4H9-combined
system2 required 2.5 h for the completion.
As shown in Table 1, this method also demonstrated excellent
performance in hydrogenation of some base-sensitive ketones. The
keto benzoate 4a and its hydrogenation product undergo ready
transesterification under our earlier conditions using KO-t-C4H9 in
2-propanol. The new base-free procedure effected hydrogenation
of 2.0 M 4a in 2-propanol containing (S,SS)-2 (S/C ) 4000) to
give only the ethyl (R)-4-(1-hydroxyethyl)benzoate in 99% ee in
100% yield, and without contamination of the isopropyl ester.9 This
feature is most beneficial in the reaction of some precious keto
esters. In the presence of (S,SS)-2, the R keto ester 4b was
hydrogenated in 2-propanol to the (R,R)-hydroxy ester with 97%
de quantitatively, and without transesterification.
Hydrogenation of the keto (R)-glycidyl ether 5 with (S,SS)-2 gave
the R,R alcohol with 99% de in 99% yield, leaving the base-labile
epoxy ring.10 Highly base-sensitive â-amino ketone 6 can be
hydrogenated without any special precautions. Thus, the reaction
using a 1.0 M 2-propanol solution of 6 and (S,SS)-2 gave the R
amino alcohol in 97% ee in 100% yield, which is convertible to
the antidepressant (R)-fluoxetine.11 No trace of 1-phenyl-1-propanol
was detected.12 3-Nonen-2-one (7) is a highly base-sensitive acyclic
ketone, prone to polymerize in the presence of an alkaline base.4
However, hydrogenation of 7 using (S,SS)-2 as catalyst occurred
easily, resulting in the R allylic alcohol in 99% ee and in 95%
yield. The substrate concentration, 2.0 M in 2-propanol, is much
higher than the 0.1 M used in the earlier method.4
The original procedure is useful for stereoselective hydrogenation
of R-substituted ketones12-14 via dynamic kinetic resolution.15
However, because of the basic conditions, it is unsuitable for access
to the configurationally labile ketones. Now the kinetic resolution
of such ketones is possible due to a very small degree of
racemization, if any. When racemic 2-isopropylcyclohexanone [(()-
Supporting Information Available: Preparative methods and
properties of 1 and 2, procedure for asymmetric hydrogenation of
ketones (PDF) and an X-ray crystallographic file (CIF) of complex 1.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa, M.;
Katayama, E.; England, A. F.; Ikariya, T.; Noyori, R. Angew. Chem., Int.
Ed. 1998, 37, 1703-1707.
(2) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40-73.
(3) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 2675-2676.
(4) Although this problem was partly solved by utilizing K2CO3, the reaction
became much slower than that with the strong base.2
(5) TolBINAP ) 2,2′-bis(di-4-tolylphosphino)-1,1′-binaphthyl. XylBINAP )
2,2′-bis(di-3,5-xylylphosphino)-1,1′-binaphthyl. DPEN ) 1,2-diphenyl-
ethylenediamine.
(6) (a) Holar, D. G.; Hughes, A. N.; Hui, B. C. Can. J. Chem. 1976, 54,
320-328. (b) Yoshida, T.; Adachi, T.; Ueda, T.; Akao, H.; Tanaka, T.;
Goto, F. Inorg. Chim. Acta 1995, 231, 95-101.
(7) Survey of more than 20 crystal structures of RuH(phosphine) complexes
recorded in the Cambridge Crystallographic Data Base indicates that the
Ru-H bond length is normally about 1.6 Å, with some exceptions.
(8) Use of a glass reaction vessel should be avoided to obtain a high catalytic
activity in hydrogenation with an S/C >5000. Reaction temperature of
45 °C was necessary to achieve a turnover number as high as 100 000 in
hydrogenation of 3 catalyzed by 2. 1 is more reactive, achieving a high
catalytic activity without heating.
(9) Hydrogenation of 4a with trans-RuCl2[(S)-xylbinap][(S)-daipen] and KO-
t-C4H9 in 2-propanol ([4a] ) 2.0 M, 4a:Ru:base ) 2000:1:8, 8 atm, 25
°C, 12 h) gave a 36:64 mixture of the hydroxy ethyl ester and the isopropyl
ester (both R in 99% ee, 100% yield). DAIPEN ) 1,1-di(4-anisyl)-2-
isopropyl-1,2-ethylenediamine.
(10) Hydrogenation of 5 with a RuCl2/KO-t-C4H9 catalyst gave the desired
alcohol in only 59% yield accompanied by various byproducts.
(11) Robertson, D. W.; Krushinski, J. H.; Fuller, R. W.; Leander, J. D. J. Med.
Chem. 1988, 31, 1412-1417 and references therein.
(12) Earlier, even strictly controlled conditions gave 2% of this compound,
which arose from â-elimination of dimethylamine followed by double
hydrogenation. See: Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R. J.
Am. Chem. Soc. 2000, 122, 6510-6511.
(13) Ohkuma, T.; Ooka, H.; Yamakawa, M.; Ikariya, T.; Noyori, R. J. Org.
Chem. 1996, 61, 4872-4873.
(14) Matsumoto, T.; Murayama, T.; Mitsuhashi, S.; Miura, T. Tetrahedron Lett.
1999, 40, 5043-5046.
(15) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68,
36-56 and references therein.
(16) Rossi, T.; Marchioro, C.; Paio, A.; Thomas, R. J.; Zarantonello, P. J. Org.
Chem. 1997, 62, 1653-1661.
(17) RuHCl(binap)(dpen) acts as an excellent catalyst in the presence of a strong
base. See: Abdur-Rashid, K.; Lough, A. J.; Morris, R. H. Organometallics
2001, 20, 1047-1049.
JA026136+
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