Highly efficient asymmetric transfer hydrogenation of ketones catalyzed by chiral 'roofed' cis-diamine-Ru(II) complex

Article abstract of DOI:10.1016/j.tetlet.2005.03.165

A new type of chiral Ru(II) complex, prepared from a conformationally rigid, sterically bulky 'roofed' cis-diamine and [RuCl₂(benzene)] ₂, functions as an efficient catalyst for the asymmetric transfer hydrogenation of a wide variety of aryl ketones, including sterically bulky ketones, when the reaction is conducted in the presence of 5HCO ₂H?2NEt₃.

Full text of DOI:10.1016/j.tetlet.2005.03.165

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3645–3648
Highly efficient asymmetric transfer hydrogenation of ketones
catalyzed by chiral ꢀroofedꢁ cis-diamine–Ru(II) complex
*
Hirofumi Matsunaga, Tadao Ishizuka and Takehisa Kunieda
Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
Received 14 February 2005; revised 18 March 2005; accepted 23 March 2005
Available online 8 April 2005
Abstract—A new type of chiral Ru(II) complex, prepared from a conformationally rigid, sterically bulky ꢀroofedꢁ cis-diamine and
[
RuCl
including sterically bulky ketones, when the reaction is conducted in the presence of 5HCO
2005 Elsevier Ltd. All rights reserved.
2
(benzene)]
2
, functions as an efficient catalyst for the asymmetric transfer hydrogenation of a wide variety of aryl ketones,
2
HÆ2NEt
3
.
ꢀ
5
a
The asymmetric catalytic transfer hydrogenation of ke-
tones represents a viable method, not only in the labora-
tory, but also on a commercial scale, because of its ease
of handling, lower cost, and safety, compared with the
typically used expensive, hazardous, and dangerous re-
agents such as borane reagents and high-pressure hydro-
with anthracene followed by optical resolution. These
compounds have proven to be excellent chiral auxiliaries
for asymmetric C–C bond formations, including the
a-alkylation of carbonyl compounds and the Diels–Al-
5
der reaction. The perfect stereoselectivities obtained in
these reactions prompted us to apply ring-opened cis-
diamines to catalytic asymmetric reactions as chiral
ligands.
1
gen gas. Some noteworthy achievements in this area
include the preparation of the chiral trans-N-tosyl-1,2-
diphenylethylenediamine–Ru (p-cymene) complex 2,
by Noyori et al., which can be used in the presence of
2-propanol or a formic acid-triethylamine azeotrope as
2
a hydrogen donor (Scheme 1).
In this paper, we report the ꢀroofedꢁ cis-diamine as an
excellent ligand for the Ru(II)-catalyzed asymmetric
transfer hydrogenation of ketones, leading to both a
high catalytic activity and enantioselectivity.
Focusing on the configuration of 1,2-diamine ligands, a
number of trans-diamines have been used to obtain the
corresponding secondary alcohols in good to excellent
The ꢀroofedꢁ cis-1,2-diamine 6 was readily obtained from
chiral 2-imidazolidinone 5 by hydrolytic ring cleavage
with Ba(OH) in refluxing ethanol (Scheme 2).
3
yields and enantioselectivities.
2
cis-1,2-Diaminoindane derivatives, established by Wills
et al., represent the only case of a cis-diamine–Ru(II)
The diamine–ruthenium(II) complexes 7 and 8 were pre-
2
b,6
pared in situ, following Noyoriꢁs procedure.
We first
(
4) catalyzed asymmetric transfer hydrogenation of
ketones but the reaction resulted in lower enantioselec-
tested the activity of benzene complex 7 toward acetophen-
one 1 in the presence of an azeotropic mixture of
5HCO HÆ2NEt as a hydrogen source at 25 ꢁC (Table
4
tivities than Noyoriꢁs results (Scheme 1).
2
3
1
, entry 1). The reaction proceeded smoothly to give
We recently developed chiral ꢀroofedꢁ 2-imidazoli-
dinones, which are conformationally rigid and sterically
bulky, from the thermal [4+2] cycloaddition of a simple
the corresponding secondary alcohol 3 in 98% yield
and 93% ee. To the contrary, the Ru(II) (p-cymene)
complex 8 showed a lower reactivity and only a moder-
ate ee value (entry 2).
5
-membered heterocycle, 1,3-dihydro-2-imidazolone,
We also investigated co-solvent effects (Table 1, entries
2
m,4,7
3–8).
The reactions proceeded in the presence of
Keywords: Asymmetric transfer hydrogenation; cis-Diamine–Ru(II)
complex; Aryl ketones; 5HCO HÆ2NEt
Corresponding author. Tel.: +81 96 371 4394; fax: +81 96 362
692; e-mail: tstone@gpo.kumamoto-u.ac.jp
CH Cl , THF, and DMF to give 91–93% eeꢁs, but a
slightly longer time was required to complete the reac-
tion. The addition of IPA required a longer reaction
2
3
.
2
2
*
7
0
040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.165

3646
H. Matsunaga et al. / Tetrahedron Letters 46 (2005) 3645–3648
OH
2
(0.5 mol%)
>
99% yield
8% ee
9
O
Ph
Ph
Me
Ts
N
Ru
Ts
N
(
(
R)
R)
(R)
(S)
(
R)-3
Ph
Ph
5
HCO H•2NEt
28 ˚C, 20 h
2
3
Ph
Me
RuCl(p-cymene)
OH
N
H
N
1
Cl
H2
4
2
9
6% yield
4
(0.5 mol%)
8
3% ee
2
Me
S)-3
Wills et al.
(
Noyori et al.
Scheme 1.
Ba(OH) •8H O (5 eq.)
2
2
NH
NH2
NH
Ts
9
8% yield
EtOH-H O (5:1)
N
2
O
reflux, 18 h
Ts
5
6
Scheme 2.
Table 1. Asymmetric transfer hydrogenation of acetophenone 1 catalyzed by chiral ruthenium(II) complexes (7, 8)
Chiral Ru cat.
(
R)
NH2
O
OH
(
0.5 mol %)
(
S)
N
RuClAr
5
2
HCO H•2NEt3
Ph
Ph
Me
Me
*
3
2
5 ˚C,Time
Ts
1
7
8
: Ar = benzene
: Ar = p-cymene
a
b
b
Entry
Catalyst
Co-solvent
Time (h)
Yield (%)
Ee (%)
Configuration
1
2
3
4
5
6
7
8
7
8
7
7
7
7
7
7
(None)
(None)
15
67
19
19
19
24
48
43
98
53
97
91
91
95
62
>99
93
86
93
93
91
94
90
90
S
S
S
S
S
S
S
S
2 2
CH Cl
THF
DMF
IPA
DMSO
2
H O
a
Isolated yields.
Determined by HPLC.
b
time than standard conditions, but gave 94% ee. DMSO
retarded the reaction and only a moderate yield and 90%
ee resulted after 48 h. It is interesting to note that the
addition of water did not seriously affect either the yield
or the enantioselectivity.
quantitative yield after a 20 h reaction. Another cyclic
substrate, b-tetralone, gave an inferior ee value,
although the reaction time was quite short. Substitution
of the benzene ring with electron-withdrawing or elec-
0
tron-donating groups at the 4 -position (entries 10–13)
had only minor effects on the reaction time and ee val-
ues. Unfortunately, a dialkylketone such as benzyl ethyl
ketone with 7 showed a lower ee value, similar to 11.
Table 2 summarizes the results of some transfer hydro-
genation reactions with various ketones 9 in the pres-
ence of catalyst 7 and the 5HCO HÆ2NEt azeotrope.
2
3
Corresponding results using Noyori-type catalysts 11
and 2 are also listed for comparison. In general, the cat-
alytic activity of 7 is superior to Noyoriꢁs catalysts 11
and 2. This is especially true for isobutyrophenone (en-
Although the precise structures of the catalyst 7 and the
9
corresponding hydride species are unknown, we specu-
late the most likely hydride catalyst, depicted in Figure
1. Thus, the hydride has two candidates, 12 and 15,
and 12 looks feasible as an active catalyst because
another candidate 15 would be difficult to approach
the ketones toward ruthenium hydride because of steric
shielding of ꢀroofꢁ moiety. Arylketones easily approach
from the ꢀnon-shieldedꢁ side, the site opposite the ꢀroofꢁ
moiety, of the hydride catalyst 12 to subsequently
tries 4–6), 2,2-dimethylpropiophenone (entries 7–9), and
0
1 -acetonaphthone (entries 14, 15) which are sterically
bulky, where 7 showed higher reactivities and enantio-
8
selectivities than the others. The cyclic substrate, a-tetra-
lone, was also converted to the corresponding alcohol
with the highest enantioselectivity (99% ee) and in a

H. Matsunaga et al. / Tetrahedron Letters 46 (2005) 3645–3648
3647
Table 2. Chiral ruthenium(II) complexes (2, 7, and 11)—catalyzed asymmetric transfer hydrogenation of various ketones 9
H2
(
R)
(
R)
NH2
Ph
Ph
N
Chiral Ru cat.
0.5 mol %)
O
OH
(
RuClAr
(S)
N
RuClAr
N
Ts
R1
R2
5HCO H•2NEt
R1
R2
(R)
2
3
*
10
Ts
25 ˚C,Time
9
7: Ar = benzene
11: Ar = benzene
2
: Ar = p-cymene
1
R
2
R
a
b
b
Entry
Catalyst
Time (h)
Yield (%)
ee (%)
Configuration
1
2
Ph
Ph
Ph
Me
Me
Me
7
15
16
20
98
98
93
96
98
S
11
2
R
R
c
3
>99
4
5
Ph
Ph
Ph
i-Pr
i-Pr
i-Pr
7
24
24
—
85
12
41
84
48
83
S
11
2
R
R
d
6
7
8
Ph
Ph
Ph
t-Bu
t-Bu
t-Bu
7
24
24
—
68
6
65
19
—
S
11
2
R
—
d
9
<1
1
0
1
4-ClC
4-ClC
6
H
H
4
4
Me
Me
7
2
17
24
>99
>99
89
95
S
c
c
c
c
c
c
1
6
R
1
1
2
3
4-MeOC
4-MeOC
6
6
H
4
Me
Me
7
2
24
60
91
>99
92
97
S
H
4
R
1
1
4
5
1-Naphthyl
1-Naphthyl
Me
Me
7
2
20
60
>99
93
92
83
S
R
1
1
6
7
2-Naphthyl
2-Naphthyl
Me
Me
7
2
20
22
>99
>99
90
96
S
R
1
1
8
9
a-Tetralone
a-Tetralone
7
2
20
48
>99
>99
99
99
S
R
2
2
0
1
b-Tetralone
b-Tetralone
7
2
7
80
>99
70
66
82
S
R
2
2
2
3
Bn
Bn
Et
Et
7
11
24
24
92
92
28
23
R
S
a
b
c
Isolated yields.
Determined by HPLC.
See Ref. 2b.
d
Reactions at 40 ꢁC; see Ref. 1b.
H
(R)
Ts
H
(
S)
N
Ts
OH
(
S)
N
H
(R)
Ru
H
N
H
Ru
N
H2
7
H2
4
Ph (S)
R
H
1
3
14
1
2
ketone
ketone
ketone
Ts
N
H
Ru
N
H2
1
5
Figure 1.
produce the (S)-alcohol 13. Meanwhile, as reported by
4
to 14 in the production of the (S)-alcohol 13. It is note-
worthy that both hydride catalysts 12 and 14, which
,10
Willsꢁ,
the hydride form of 4 appears to be similar

3648
H. Matsunaga et al. / Tetrahedron Letters 46 (2005) 3645–3648
contain cis-diamine ligands with opposite configur-
ations, form the (S)-alcohol 13. These characteristics
must be caused by the chiral ꢀroofedꢁ cis-1,2-diamine
structure, which is both conformationally rigid and ste-
rically congested.
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997, 38, 2275–2278; (j) Touchard, F.; Fache, F.; Lemaire,
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roofedꢁ cis-1,2-diamine–Ru (II) complex, which is both
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hydrogenation of ketones. Further studies are currently
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Acknowledgements
This work was supported in part by a grant from the
TAKEDA SCIENCE FOUNDATION and a Grant-
in-Aid for Scientific Research (No. 15790013) from the
Ministry of Education, Science, Sports, and Culture of
Japan.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
8
. General procedure for asymmetric transfer hydrogenation
537.
6
2
005.03.165.
of ketone catalyzed by 7: A mixture of benzeneruthenium
(
II) chloride dimer (2.5 mg, 0.005 mmol, 0.25 mol%), N-
tosyl-ꢀroofedꢁ diamine 6 (3.9 mg, 0.01 mmol, 0.5 mol%),
and triethylamine (2.8 lL, 0.02 mmol, 1 mol%) in 2-
propanol (1 mL) was refluxed for 1 h under an argon
atmosphere. After removal of the solvent in vacuo,
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5HCO HÆ2NEt azeotrope (1 mL) and ketone (2 mmol)
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25 ꢁC. The reaction was monitored by TLC until
substantial completion. After the addition of satd
2
NaHCO
20 mL · 3), washed (brine, 10 mL · 3), dried (anhyd
Na SO ), and evaporated in vacuo followed by the
3
aq (5 mL), the product was extracted (EtOAc,
2
4
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gel to afford the corresponding alcohol. Enantiomeric
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