Asymmetric hydrogenation of ketones with ruthenium complexes of rac- and enantiopure (S,S)-1,2-bis((diphenylphosphino)methyl)cyclohexane: A comparative study with rac- and (R)-BINAP

Article abstract of DOI:10.1021/om070129i

Ruthenium(II) complexes of the type trans-[RuCl₂-{1,2- bis((diphenylphosphino)methyl)cyclohexane}(diamine)]based on the inexpensive and easy-to-prepare rac- and (S,S)-1,2-bis-((diphenylphosphino)methyl) cyclohexaneform highly active and enantioselective catalysts for the asymmetric hydrogenation of a wide range of aryl and heteroaryl ketones, in most cases giving ee's that exceed those obtained with their BINAP counterparts. Although precatalysts based on 1,2-bis((diphenylphosphino)-methyl)cyclohexane slowly isomerize in solution to afford the thermodynamically favored isomer with a cis arrangement of chlorides, catalysts generated from both isomers afford similar enantioselectivities.

Full text of DOI:10.1021/om070129i

Organometallics 2007, 26, 2465-2468
2465
Asymmetric Hydrogenation of Ketones with Ruthenium Complexes
of rac- and Enantiopure
(S,S)-1,2-Bis((diphenylphosphino)methyl)cyclohexane:
A Comparative Study with rac- and (R)-BINAP
Simon Doherty,* Julian G. Knight,* Adam L. Bell, Ross W. Harrington, and William Clegg
School of Natural Sciences, Chemistry, Bedson Building, Newcastle UniVersity,
Newcastle upon Tyne NE1 7RU, U.K.
ReceiVed February 9, 2007
Summary: Ruthenium(II) complexes of the type trans-[RuCl2-
{1,2-bis((diphenylphosphino)methyl)cyclohexane}(diamine)] based
on the inexpensiVe and easy-to-prepare rac- and (S,S)-1,2-bis-
((diphenylphosphino)methyl)cyclohexane form highly actiVe and
enantioselectiVe catalysts for the asymmetric hydrogenation of
a wide range of aryl and heteroaryl ketones, in most cases giVing
ee’s that exceed those obtained with their BINAP counterparts.
Although precatalysts based on 1,2-bis((diphenylphosphino)-
methyl)cyclohexane slowly isomerize in solution to afford the
thermodynamically faVored isomer with a cis arrangement of
chlorides, catalysts generated from both isomers afford similar
enantioselectiVities.
For example, complexes based on rac-2,2′-bis(ditolylphos-
phino)-1,1′-binaphthyl (rac-tolBINAP) and (S,S)-1,2-diphenyl-
ethylenediamine ((S,S)-DPEN) were found to catalyze the
asymmetric hydrogenation of 2,4,4-trimethyl-2-cyclohexenone
to afford the corresponding alcohol in 95% ee, which was similar
to the ee obtained with the (R)-tolBINAP/(S,S)-DPEN combina-
tion. In comparison, a catalyst based on the mismatched
combination of (S)-tolBINAP and (S,S)-DPEN gave an ee of
only 26%. In an elegant extension of these studies,6 the same
researchers substituted the conformationally flexible tropos
diphosphine
2,2′-[(3,5-dimethylphenyl)phosphino]biphenyl
(DM-BIPHEP) for the rac-tolBINAP ligand to afford [RuCl2-
(DM-BIPHEP){(S,S)-DPEN}] and revealed a marked depen-
dence of the enantioselectivity on the diastereoisomeric ratio
of the precatalyst, with the 1:1, 2:1, and 3:1 mixtures giving
enantioselectivities of 63, 73, and 84%, respectively. Moreover,
the catalyst generated from DM-BIPHEP gave a higher enan-
tioselectivity than its rac-DMBINAP counterpart.
While a number of related reports on the use of an achiral or
racemic diphosphine in the ruthenium-catalyzed asymmetric
hydrogenation of ketones have appeared,7 the vast majority of
catalysts that have been developed for this transformation are
based on an enantiopure diphosphine,8 which is often either
relatively expensive and/or has to be prepared via a multistep
synthesis. As part of an ongoing program aimed at developing
the applications of inexpensive, readily accessible, conforma-
tionally flexible and racemic ligands in asymmetric catalysis,9
we became interested in exploring the use of rac- and (S,S)-
1,2-bis((diphenylphosphino)methyl)cyclohexane (rac-1 and (S,S)-
1) in the ruthenium-catalyzed hydrogenation of ketones, rea-
soning that there was a clear and direct analogy between these
diphosphines and rac- and (R)-BINAP, respectively (Chart 1).
Moreover, both rac- and (S,S)-1,2-bis((diphenylphosphino)-
methyl)cyclohexane are inexpensive and straightforward to
prepare on a multigram scale from readily available starting
Introduction
During the past decade, asymmetric catalysis has evolved into
an indispensable and highly valuable tool for the synthesis of
nonracemic intermediates and products.1 The design of catalysts
for asymmetric synthesis was initially guided by the premise
that a rigid, conformationally restricted, enantiopure ligand was
required to obtain high ee’s. However, alternative strategies have
now begun to emerge which involve the use of a conforma-
tionally flexible, meso, or racemic ligand to convey asymmetry
in enantioselective catalysis.2 In the last case, a chiral additive
is used to selectively activate one enantiomer of a racemic
catalyst, a strategy that has been successfully applied to the
ruthenium-catalyzed asymmetric hydrogenation of unfunction-
alized ketones.3 Having first demonstrated that ruthenium(II)
complexes of the type [RuCl2(diphosphine)(diamine)], based on
an enantiopure diphosphine and amine, form catalysts that are
highly active and enantioselective for the asymmetric reduction
of a wide range of ketones,4 Noyori and co-workers proceeded
to show that ruthenium(II) complexes of racemic BINAP
derivatives could be activated by a nonracemic 1,2-diamine.5
* To whom correspondence should be addressed.
(1) (a) Seyden-Penne, J. Chiral Auxillaries and Ligands in Asymmetric
Catalysis: Wiley: New York, 1995. (b) Noyori, R. Asymmetric Catalysis
in Organic Synthesis; Wiley: New York, 1994. (c) Ojima, I., Ed. Catalytic
Asymmetric Synthesis, 2nd ed.; Wiley-VCH: New York, 2000. (d) Jacobsen,
E. N. Pfaltz, A. Yamamoto, H. ComprehensiVe Asymmetric Catalysis;
Springer: Berlin, 1999; Vols. I-III.
(2) For recent reviews see: (a) Walsh, P. J.; Lurain, A. E.; Balsells, J.
Chem. ReV. 2003, 103, 3297. (b) Mikami, K.; Terada, M.; Korenaga, T.;
Matsumoto, Y.; Ueki, M.; Angelaud, R. Angew. Chem., Int. Ed. 2000, 39,
3533. (c) Mikami, K.; Terada, M.; Korenaga, T.; Matsumoto, Y.; Mat-
sukawa, S. Acc. Chem. Res. 2000, 33, 391.
(3) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 41.
(4) (a) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1995, 117, 2675. (b) 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.
(5) Ohkuma, T.; Doucet, H.; Pham, T.; Mikami, K.; Korenaga, T.; Terada,
M.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 1086.
(6) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.;
Noyori, R. Angew. Chem., Int. Ed. 1999, 38, 495.
(7) (a) Mikami, K. Wakabayashi, K.; Aikawa, K. Org. Lett. 2006, 8,
1517. (b) Xia, Y. Q. Tang, Y. Y.; Liang, Z. M.; Yu, C. B.; Zhou, X. G.; Li,
R. X.; Lim X. J. J. Mol. Catal. A: Chem. 2005, 240, 132. (c) Subongkoj,
S.; Lange, S.; Chen, W.; Xiao, J. J. Mol. Catal. A: Chem. 2003, 196, 125.
(d) Mikami, K.; Wakabayashi, K.; Yusa, Y.; Aikawa, K. Chem. Commun.
2006, 2365.
(8) (a) Burk, M. J.; Hems, W.; Herzberg, D.; Malan, C.; Zanotti-Gerosa,
Org. Lett. 2000, 2, 4173. (b) Dominguez, B.; Zanotti-Gerosa, A.; Hems,
W. Org. Lett. 2004, 6, 1927. (c) Xie, J. H.; Wang, L. W.; Fu, Y.; Zhu, S.
F.; Fan, B. M.; Duan, H. F.; Zhou, Q. L. J. Am. Chem. Soc. 2003, 125,
4404. (d) Xie, J.-H.; Liu, S.; Huo, X. H.; Cheng, X.; Duan, H. F.; Fan, B.
M.; Wang, L. X.; Zhou, Q. L. J. Org. Chem. 2005, 70, 2967.
10.1021/om070129i CCC: $37.00 © 2007 American Chemical Society
Publication on Web 03/24/2007

2466 Organometallics, Vol. 26, No. 9, 2007
Notes
materials. Herein, we report that ruthenium complexes of these
diphosphines form highly efficient catalysts for the asymmetric
hydrogenation of a range of aryl and heteroaryl ketones and
give ee’s that either rival or exceed those obtained with their
BINAP counterparts.
Chart 1
Figure 1. Molecular structure of cis-[RuCl2{(S,S)-1}{(R,R)-
DPEN}], showing the cis arrangement of chloride ligands and the
λ configuration at ruthenium. Hydrogen atoms and the dichlo-
romethane molecule of crystallization have been omitted for clarity.
Ellipsoids are at the 30% probability level. Selected bond lengths
(Å) and angles (deg): Ru-P(1), 2.2794(10); Ru-P(2), 2.2634-
(10); Ru-N(1), 2.141(3); Ru-N(2), 2.171(3); Ru-Cl(1), 2.45289-
(10); Ru-Cl(2), 2.5278(10); P(1)-Ru-P(2), 92.07(3); N(1)-Ru-
N(2), 79.44(11); Cl(1)-Ru-Cl(2), 89.77(4), P(1)-Ru-N(2),
172.31(8); Cl(1)-Ru-N(1), 164.25(8); P(2)-Ru-Cl(2), 176.00-
(3).
Results and Discussion
Diphosphines rac- and (S,S)-1 were synthesized on a multi-
gram scale by reaction of rac- or (S,S)-1,2-bis(bromomethyl)-
cyclohexane with lithium diphenylphosphide, rather than from
the ditosylate or mesylate as previously described.10 In the case
of (S,S)-1, the corresponding dibromide was prepared via the
Lewis acid catalyzed diastereoselective Diels-Alder reaction
between (-)-menthyl fumarate and 1,3-butadiene.11 The enan-
tiopurity of (S,S)-1 was established by comparison of its [R]D
value with that reported in the literature.10 Although ruthenium
complexes of the type trans-[RuCl2(diphosphine)(diamine)] are
typically prepared from [RuCl2(benzene)]2, according to the
procedure originally described by Noyori,4b we chose to use
[RuCl2(py)2(nbd)] as the precursor, following a protocol devel-
oped by Bergens12 for the synthesis of a range of diphosphine-
diamine complexes (Scheme 1). In a typical procedure, addition
of (S,S)-1 to a chloroform solution of [RuCl2(py)2(nbd)] results
in rapid and quantitative formation of trans-[RuCl2{(S,S)-1,2-
bis((diphenylphosphino)methyl)cyclohexane}(py)2] (2), which
can be isolated as a deep yellow crystalline solid by diffusion
of a dichloromethane solution layered with hexane or reacted
directly with an enantiopure diamine to afford diphosphine-
diamine complexes of the type 3. Interestingly, upon standing
in solution, 3 slowly converts into the thermodynamically
favored isomer 4, with a cis arrangement of chloride ligands.
The presence of only one pair of doublets in the 31P NMR
spectrum of 4 is entirely consistent with a highly diastereo-
selective isomerization to afford one of the two possible
diastereoisomers, which, in the case of cis-[RuCl2{(S,S)-1}-
{(R,R)-DPEN}], was identified by a single-crystal X-ray study;
the molecular structure is shown in Figure 1. In contrast, we
found no evidence for the corresponding isomerization of trans-
[RuCl2{(R)-BINAP}{(R,R)-DPEN}], even after standing in
solution for several weeks or heating at reflux. Interestingly,
James and co-workers recently reported that compounds of the
type [RuCl2(dppf)(diimine)], based on 2,2′-bipyridine or 1,10-
phenanthroline, exist exclusively as the cis-dichloride while
those based on a diamine such as ethylenediamine or 1,3-
diaminopropane have a trans arrangement of chloride ligands;13a
In the case of [RuCl2(dppb)(2,2′-bipy)], both trans- and cis-
dichloro complexes are accessible and correspond to the kinetic
and thermodynamic products, respectively.13b
Scheme 1
Reasoning that the catalytic behavior of enantiopure and
racemic 1,2-bis(diphenylphosphinomethyl)cyclohexane could
parallel that of enantiopure and racemic BINAP, we first
undertook comparative catalyst testing with each of these
diphosphines and chose acetophenone as the model substrate
and trans-[RuCl2(1)(diamine)] (3) as the precatalyst. Examina-
tion of the results in Table 1 reveals that the catalyst based on
(S,S)-1/(R,R)-DPEN is slightly more enantioselective than the
(R)-BINAP/(R,R)-DPEN combination, giving 1-phenylethanol
in 90% and 86% ee, respectively (entries 1 and 3). Gratifyingly,
(9) (a) Doherty, S.; Knight, J. G.; Robins, E. G.; Scanlan, T. H.;
Champkin, P. A.; Clegg, W. J. Am. Chem. Soc. 2001, 123, 5110. (b)
Doherty, S.; Newman, C. R.; Rath, R. K.; van den Berg, J.-A.; Hardacre,
C.; Nieuwenhuyzen, M.; Knight, J. G. Organometallics 2004, 23, 1055.
(c) Doherty, S.; Newman, C. R.; Rath, R. K.; Luo, H.-K.; Nieuwenhuyzen,
M.; Knight, J. G. Org. Lett. 2003, 5, 3863. (d) Doherty, S.; Knight, J. G.;
Hardacre, C.; Luo, H.-K.; Newman, C. R.; Rath, R. K.; Campbell, S.;
Nieuwenhuyzen, M. Organometallics 2004, 23, 6127. (e) Doherty, S.;
Goodrich, P.; Hardacre, C.; Luo, H.-K.; Nieuwenhuyzen, M.; Rath, R. K.
Organometallics 2005, 24, 5945.
(10) Hayashi, T.; Tanaka, M.; Ikeda, Y.; Ogata, I. Bull. Chem. Soc. Jpn.
1979, 52, 2605.
(11) Solladie´, G.; Lohse, O. J. Org. Chem. 1993, 58, 4555.
(12) Akotsi, O. M.; Metera, K.; Reid, R. D.; McDonald, R.; Bergens, S.
H. Chirality 2000, 12, 514.
(13) (a) Ma, G.; McDonald, R.; Ferguson, M.; Cavell, R. G.; Patrick, B.
O.; James, B. R.; Hu, T. Q. Organometallics 2007, 26, 846. (b) Queiroz,
S. L.; Batista, A. A.; Oliva, G.; Gambardella, M. T. d. P.; Santos, R. H. A.;
MacFarlane, K. S.; Rettig, S. J.; James, B. R. Inorg. Chim. Acta 1998, 267,
206.

Notes
Organometallics, Vol. 26, No. 9, 2007 2467
Table 1. Asymmetric Hydrogenation of Acetophenone Using
trans-[RuCl2(diphosphine)(diamine)] Precatalysts Based on
(S,S)-1, rac-1, (R)-BINAP, and rac-BINAPa
Table 2. Asymmetric Hydrogenation of Ketones Using
trans-[RuCl2(diphosphine)(diamine)] (3) Precatalysts Based
on (S,S)-1 and rac-1a
diphosphine
entry
diphosphine
diamine
ee (%)b
(S,S)-1
rac-1
1
2
3
4
5
6
7
8
9
(S,S)-1
(S,S)-1
(R)-BINAP
(R)-BINAP
rac-1
(R,R)-DPEN
(R,R)-DACH
(R,R)-DPEN
(R,R)-DACH
(R,R)-DPEN
(R,R)-DACH
(R,R)-DPEN
(R,R)-DACH
(R,R)-DPEN
(R,R)-DPEN
90 (S)
84 (S)
86 (S)
84 (S)
86 (S)
82 (S)
48 (S)
46 (S)
18 (S)
32 (R)
Ar or
conversn
conversn
entry
diamine
ketone
ee (%)b
(%)c
ee (%)b
(%)c
1
2
3
4
5
6
7
8
9
(R,R)-DPEN Ph
(R,R)-DACH Ph
90 (S)
84 (S)
90 (S)
85 (S)
85 (S)
83 (S)
92 (S)
88 (S)
94 (S)
90 (S)
88 (S)
85 (S)
88 (S)
85 (S)
89 (S)
83 (S)
>99
>99
>99
99
98
92
99
94
99
99
99
99
>99
>99
99
98
89
87
94
86 (S)
76 (S)
88 (S)
77 (S)
80 (S)
72 (S)
88 (S)
75 (S)
89 (S)
80 (S)
85 (S)
73 (S)
79 (S)
73 (S)
85 (S)
60 (S)
29 (S)
15 (S)
90 (S)
76 (S)
75 (S)
50 (S)
65 (S)
55 (S)
84 (S)
73 (S)
>99
>99
97
97
>99
96
96
94
99
99
99
97
>99
>99
99
98
90
90
>99
95
(R,R)-DPEN 1-naphthyl
(R,R)-DACH 1-naphthyl
(R,R)-DPEN p-ClC6H4
(R,R)-DACH p-ClC6H4
(R,R)-DPEN o-ClC6H4
(R,R)-DACH o-ClC6H4
(R,R)-DPEN o-BrC6H4
rac-1
rac-BINAP
rac-BINAP
(R,R)-1
10
(S)-BINAP
a Reactions were conducted with 0.17 M solutions of ketone in 2-propanol
with S/C ) 1000/1 unless otherwise noted, with added t-BuOK at 20-22
°C and 10 atm of H2 pressure for 12 h. b The ee’s were determined by
chiral GC, and the absolute configuration was determined by comparison
of the sign of the optical rotation or the retention time with literature data.
Average of three runs.
10 (R,R)-DACH o-BrC6H4
11 (R,R)-DPEN p-CH3C6H4
12 (R,R)-DACH p-CH3C6H4
13 (R,R)-DPEN p-CH3OC6H4
14 (R,R)-DACH p-CH3OC6H4
15 (R,R)-DPEN propiophenone
16 (R,R)-DACH propiophenone
the corresponding catalyst containing rac-1 and (R,R)-DPEN
gave a markedly higher enantioselectivity than its rac-BINAP/
(R,R)-DPEN counterpart, with ee values of 86% and 48%,
respectively (entries 5 and 7). Although the ee obtained with
rac-BINAP was lower than anticipated, related studies have
typically employed a subtituted BINAP derivative such as
tolBINAP or DM-BINAP to acheive optimum enantioselectivi-
ties, which necessarily precludes a meaningful comparison with
literature values. In this regard, studies are currently underway
to investigate the influence of aryl substitution on catalyst
performance with the aim of optimizing enantioselectivities.4a
Further analysis of the ee values reveals that hydrogenation of
acetophenone via the (S,S)-1/(R,R)-DPEN cycle occurs ca. 20
times faster than the (R,R)-1/(R,R)-DPEN cycle, whereas the
relative rate for the corresponding BINAP system is ca. 2. A
similar pattern of enantioselectivities was also obtained with a
catalyst based on (S,S)-1 and (R,R)-1,2-diaminocyclohexane
((R,R)-DACH). The 1-phenylethanol generated with (S,S)-1/
(R,R)-DPEN precatalyst was shown to have an S absolute
configuration, and in this regard (S,S)-1 behaves in a manner
similar to (R)-BINAP. This is not surprising, since the four-
carbon tethers of (S,S)-1 and (R)-BINAP both adopt a λ
conformation and in combination with the λ conformation of
(R,R)-DPEN will present similar chiral molecular surfaces for
differentiating the enantiofaces of aromatic ketones.14 These
results clearly suggest that easy-to-prepare and inexpensive
diphosphines such as 1 could prove to be practical alternatives
to more expensive and synthetically demanding enantiopure
ligands.
17 (R,R)-DPEN isobutyrophenone 28 (S)
18 (R,R)-DACH isobutyrophenone 16 (S)
19 (R,R)-DPEN 2-thienyl
20 (R,R)-DACH 2-thienyl
21 (R,R)-DPEN 3-pyridyl
22 (R,R)-DACH 3-pyridyl
23 (R,R)-DPEN 4-pyridyl
24 (R,R)-DACH 4-pyridyl
25 (R,R)-DPEN 2-furyl
26 (R,R)-DACH 2-furyl
94 (S)
86 (S)
84 (S)
82 (S)
81 (S)
80 (S)
92 (S)
86 (S)
94
99
97
99
96
99
96
98
99
99
97
99
97
a Reactions were conducted in 2-propanol with S/C ) 1000/1 unless
otherwise noted, with added t-BuOK at 20-22 °C and 10 atm of H2 pressure
for 12 h. b The ee’s were determined by chiral GC, and the absolute
configurations were determined by comparison of the sign of the optical
rotation or retention time with literature data. c Determined by GC or H
1
NMR. Average of three runs.
terpart, although both catalysts gave similar patterns of enan-
tioselectivities across the entire range of substrates. Closer
inspection of the results reveals that methyl ketone substrates
containing an ortho-substituted aromatic ring gave the highest
ee’s. For example, o-chloro- and o-bromoacetophenone were
reduced using the precatalyst [RuCl2{(S,S)-1}{(R,R)-DPEN}]
in 92 and 90% ee, respectively, whereas their para-substituted
counterparts were reduced in only 85 and 84% ee, respectively.
An increase in the size of the nonaromatic substituent in aryl/
alkyl ketones was accompanied by a reduction in enantioselec-
tivity. While the drop in enantioselectivity between acetophe-
none and propiophenone was relatively small, larger substituents
were less well tolerated and a significant drop in ee was
observed when an isopropyl group was introduced, for both
precatalysts examined (entries 17 and 18).
Encouraged by the enantioselectivities obtained in these
preliminary studies, we next extended our investigations to
include asymmetric hydrogenation of a range of aryl and
heteroaryl substrates using a catalyst generated from trans-
[RuCl2{(S,S)-1}(diamine)] (3). The results in Table 2 demon-
strate that a range of aryl-substituted methyl ketones can be
hydrogenated with good to very high enantioselectivities and
that, for each substrate examined, the catalyst based on (S,S)-
1/(R,R)-DPEN consistently outperformed its (R,R)-DACH coun-
The combination of RuII/(S,S)-1 with (R,R)-DPEN or (R,R)-
DACH also proved effective for the hydrogenation of hetero-
cyclic ketones, giving the corresponding alcohols in good to
high enantioselectivity (81-94%). For instance, hydrogenation
of 2-acetylthiophene and furan with the (S,S)-1/(R,R)-DPEN-
based catalyst was particularly efficient and gave ee’s in excess
of 90%, slightly higher than the ee of 86% obtained with its
DACH counterpart. In contrast, the same catalyst systems were
slightly less effective for the hydrogenation of 2- and 4-acetylpy-
ridine, which were converted to the alcohol in 84 and 81% ee,
respectively. Noyori has previously reported ee’s as high as 99%
for the asymmetric hydrogenation of heteroaromatic ketones
(14) (a) Abdur-Rashid, K.; Clapham, S. E.; Hadzovic, A.; Harvey, J.
N.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2002, 124, 15104. (b)
Sandoval, C. A.; Ohkuma, T.; Muniz, K.; Noyori, R. J. Am. Chem. Soc.
2003, 123, 13490.

2468 Organometallics, Vol. 26, No. 9, 2007
Notes
using a catalyst based on (R)-xylylBINAP and (R)-DAIPEN,
now widely accepted as the optimum system for a range of
substrates.15
ization to afford a cis arrangement of chlorides, catalysts
generated from both isomers gave similar levels of stereocontrol.
Once optimized, these catalysts could prove to be practical
alternatives to more expensive enantiopure systems for the
asymmetric hydrogenation of ketones and/or C-C and C-het-
eroatom bond formation via bifunctional transition-metal-based
catalysis.16
On the basis of the impressive enantioselectivities reported
for the hydrogenation of aryl/methyl ketones with a catalyst
generated from a 1:1 mixture of diastereoisomeric [RuCl2(rac-
tolBINAP){(S,S)-DPEN)}],5 we next examined the efficacy of
the corresponding catalysts based on rac-1 for asymmetric
hydrogenation of the same series of substrates, full details of
which are presented in the last two columns of Table 2.
Gratifyingly, for the majority of substrates examined, the ee’s
were only marginally lower than those obtained with enantiopure
(S,S)-1 and showed a similar trend in enantioselectivity across
the range of substrates. Moreover, as for (S,S)-1, the catalyst
based on rac-1/(R,R)-DPEN consistently outperformed its (R,R)-
DACH counterpart.
Finally, in a comparative study with acetophenone as
substrate, the performance of the catalyst generated from the
cis precatalyst 4 matched that of its trans counterpart. For
example, asymmetric hydrogenation of acetophenone with the
catalyst generated from cis-[RuCl2{(S,S)-1}{(R,R)-DPEN}] gave
1-phenylethanol in 89% ee, while the catalyst generated from
cis-[RuCl2(rac-1){(R,R)-DPEN}] and cis-[RuCl2{(S,S)-1)/{(S,S)-
DPEN}] gave ee’s of 85 and 15%, respectively. Not surprisingly,
the catalyst generated from a mixture of trans and cis isomers
gave the same ee’s as those obtained with the pure isomer.
In conclusion, ruthenium(II) complexes of inexpensive and
easy-to-prepare racemic and enantiopure diphosphines based on
a 1,2-bis(dimethyl)cyclohexyl tether form highly efficient and
selective catalysts for the asymmetric hydrogenation of a range
of ketones, giving ee’s and conversions that rival or exceed those
obtained with BINAP. The performance of these catalysts is
quite surprising, since enantioselectivities obtained with diphos-
phines which form conformationally flexible seven-membered
chelate rings are often significantly lower than those obtained
with catalysts based on biaryl diphosphines. Interestingly, while
the trans-dichloride precatalyst undergoes a quantitative isomer-
Experimental Section
General Experimental Procedure for the Asymmetric Hy-
drogenation of Acetophenone. A flame-dried Schlenk flask was
charged with propan-2-ol (10 mL), acetophenone (0.206 g, 1.72
mmol), and catalyst (0.00172 mmol) and the resulting mixture
degassed by three successive freeze-thaw cycles. A solution of
t-BuOK in propan-2-ol (0.026 mL, 0.0258 mmol, 1 M solution)
was added and the resulting solution transferred to a 50 mL Parr
stainless steel benchtop reactor. The vessel was pressurized to 10
atm with hydrogen and left to stand for 10 s before releasing the
gas though an outlet valve. After this sequence was repeated six
times, the reactor was pressurized to ca. 10 atm and the solution
stirred vigorously at 20-22 °C for 16 h. The pressure was released,
and the resulting mixture was filtered through a short silica plug,
diluted with diethyl ether, and analyzed by chiral GC (Supelco Beta
DEX column, 0.25 mm i.d. × 25 m, injection temperature 200 °C,
column conditions 35 °C for 5 min, ramp to 115 °C at 5 °C/min,
hold for 20 min, ramp to 170 °C at 5 °C/min, hold for 10 min,
pressure 18.9 psi): tR of R enantiomer, 26.1 min; tR of S enantiomer,
27.2 min.
Acknowledgment. We gratefully acknowledge Johnson
Matthey for generous loans of ruthenium salts.
Supporting Information Available: Text and figures giving
experimental procedures and characterization data for all compounds
and GC analysis of the reduction products and a CIF file giving
crystal data for compound 4. This material is available free of charge
via the Internet at http://pubs.acs.org.
OM070129I
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