A chiral "roofed" cis-diamine-Ru(II) complex: An efficient catalyst for asymmetric transfer hydrogenation of ketimines

Article abstract of DOI:10.3987/COM-08-11563

Highly enantioselective transfer hydrogenation of ketimines to the corresponding chiral amines was achieved with the chiral Ru(II) complex, prepared from the conformationally rigid and sterically bulky "roofed" cis-1,2-diamine.

Full text of DOI:10.3987/COM-08-11563

HETEROCYCLES, Vol. 78, No. 3, 2009
617
HETEROCYCLES, Vol. 78, No. 3, 2009, pp. 617 - 622. © The Japan Institute of Heterocyclic Chemistry
Received, 29th September, 2008, Accepted, 4th November, 2008, Published online, 5th November, 2008
DOI: 10.3987/COM-08-11563
A CHIRAL “ROOFED” cis-DIAMINE-Ru(II) COMPLEX: AN EFFICIENT
CATALYST FOR ASYMMETRIC TRANSFER HYDROGENATION OF
KETIMINES
Hirofumi Matsunaga, a Kyoko Nakanishi,a Makoto Nakajima, a Takehisa
Kunieda,b and Tadao Ishizukaa*
aFaculty of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1
Oe-honmachi, Kumamoto 862-0973, Japan
bFaculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto
860-0082, Japan
Abstract – Highly enantioselective transfer hydrogenation of ketimines to the
corresponding chiral amines was achieved with the chiral Ru(II) complex,
prepared from the conformationally rigid and sterically bulky “roofed”
cis-1,2-diamine.
Optically active amines are very important building blocks for biologically active molecules,
pharmaceuticals, and agrochemicals. Among the numerous methods currently available for the
preparation of enantiomerically pure amines, catalytic enantioselective reduction of ketimines is one of
the most important methods,1 as it is used to accomplish chiral ligand-transition metal complex-catalyzed
high-pressure hydrogenations,2 hydrosilylations3 or transfer hydrogenations4, and chiral organic
compound-catalyzed hydrosilylations.5 However, compared with the reduction of ketones using a similar
procedure, the number of highly effective methods currently available for the reduction of ketimines is
limited. Therefore, the study of versatile and/or highly enantioselective reduction of ketimines remains
challenging.
We previously demonstrated that chiral “roofed” cis-1,2-diamine, which is conformationally rigid and
sterically bulky, was easily derived from chiral “roofed” 2-imidazolidinone. Moreover, cis-1,2-diamine
was an excellent ligand for the Ru(II)-catalyzed asymmetric transfer hydrogenation of a wide variety of
arylketones, including sterically bulky ketones, resulting in high catalytic activity and enantioselectivity

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HETEROCYCLES, Vol. 78, No. 3, 2009
(Scheme 1).6 These positive results encouraged us to apply this system to the catalytic asymmetric
reduction of ketimines.
O
OH
(S)
chiral Ru cat.
(R)
NH2
5HCO2H•2NEt3
(S)
RuClAr
N
1
2
Ts
(Ar = benzene)
>99 % yield, 99 % ee
Scheme 1
In this paper, we describe a highly effective asymmetric transfer hydrogenation of ketimines catalyzed by
the “roofed” cis-1,2-diamine-Ru(II) complex in the presence of 5HCO2H•2NEt3.
Five types of “roofed” cis-1,2-diamines 10a-e were readily prepared by N’-sulfonylation of the optically
pure N-((1S)-2-exo-methoxy-1-apocamphanecarbonyl (abbreviated as MAC))-2-imidazolidinone (7, 8),
obtained from the thermal [4+2] cycloaddition of 1,3-dihydro-2-imidazolone (4), with anthracene (3) and
successive optical resolution, followed by removal of the MAC group and hydrolytic ring cleavage with
Ba(OH)2 (Scheme 2).6,7
i) m-xylene
reflux
i) MAC-Cl, NaH
MAC
O
3
N
+
NH
NH
+
(dl)
ii) Cs2CO3, MeOH
ii) Cs2CO3
MeOH
O
O
N
H
N
N
Ac-N
N-Ac
5
MAC
8
Ac
7
Cl
75%
47%
48%
6
4
O
O OMe
(MAC-Cl)
(R)
NH2
i) RSO2Cl, NaH
ii) PhCH2SLi
Ba(OH)2
EtOH-H2O
[RuCl2(PhH)]2
(R)
NH2
(S)
NH
7
RuClAr
N
71-100%
70-98%
(S)
O
N
NH
SO2R
SO2R
9a-e
10a-e
SO2R
(Ar = benzene)
a : R = Me
b : R = i-Pr
c : R = 4-tolyl
11a-e
d : R = 1-naphthyl
e : R = 2-mesityl
Scheme 2
The “roofed” cis-1,2-diamine-ruthenium(II) complexes (11a-e) were easily prepared by mixing the
1,2-diamines (10a-e) with [RuCl2(benzene)]2 in situ, according to the method of Noyori.8,9
Initially, we examined the catalytic efficiency of the N-tosyl complex 11c toward α-tetralone-derived
ketimine 13 in the presence of an azeotropic mixture of 5HCO2H•2NEt3 as a hydrogen source at 25 °C.
This reaction was completed in 6 hours to give the corresponding chiral amine in 91% yield and 81% ee
(Table 1, entry 1). We also tested the co-solvent effects with ketimine 13. Although the reaction times
were longer and the chemical yields slightly diminished, enantioselectivity was enhanced in the presence
of CH2Cl2.10 Similar reactions were performed in the presence of
a
typical

HETEROCYCLES, Vol. 78, No. 3, 2009
619
1,2-diphenylethylenediamine-Ru(II) (p-cymene) complex (12)4a,8 to give results inferior to those obtained
using catalyst 11c (Table 1, entries 3, 4).
We also tested the substituent effect of a sulfonyl group on the “roofed” cis-1,2-diamine ligand for the
asymmetric reduction of ketimine 13 (Table 1, entries 2, 5-8). Higher enantioselectivities resulted with
catalysts 11b, 11c and 11d (entries 2, 6 and 7). Therefore, additional trials of the asymmetric reduction of
ketimine 14a in the presence of catalysts 11b-d were performed and, intriguingly, the
N-isopropylsulfonylated catalyst 11b showed superior catalytic activity and enantioselectivity (entries
9-11).
Table 1. Asymmetric hydrogen transfer reduction of ketimines catalyzed by chiral Ru(II) complex.
H2
N
(R)
chiral Ru cat. (0.5 mol %)
5HCO2H•2NEt3 (0.5 mL)
Ph
Ph
NBn
NHBn
RuClAr
N
(R)
CH2Cl2 (1.5 mL)
25 °C, 24 h
Ar
R
Ar
R
12
*
Ts
(1 mmol)
(Ar = p-cymene)
Yielda)
(%)
eeb)
(%)
Yielda)
(%)
eeb)
(%)
Imine
Cat.
Imine
NBn
Cat.
Entry
Entry
1c)
2
11c
11c
12
91
83
68
73
81 (S)
88 (S)
77 (R)
76 (R)
5
6
7
8
11a
11b
11d
11e
78
78
71
41
43 (S)
90 (S)
89 (S)
64 (S)
NBn
3c)
13
13
4
12
NBn
9
11b
11c
11d
78
61
56
77 (S)
71 (S)
63 (S)
a) Isolated yields.
b) Determined by chiral HPLC.
For absolute configuration, see ref 11.
c) In the absence of CH2Cl2.
10
11
14a
Table 2 summarizes the results of the transfer hydrogenation reaction with various ketimines 14a-i in the
presence of catalyst 11b and the 5HCO2H•2NEt3 azeotrope in CH2Cl2. Para-substituted
acetophenone-derived ketimines 14a-e showed good to excellent chemical yields and ee values of
74-77%. The electronic nature of the para-substituent did not affect the enantioselectivity.
Propiophenone-derived ketimines 14f showed higher reactivity than acetophenone-derived ketimines with
slightly lower ee values. The greater the bulky of the R2 group of the ketimines (entries 7 and 8), the
lower the observed reactivities and enantioselectivities. Cyclic imine 14i gave inferior enantioselectivity,
but a relatively short reaction time.
1
Apparently, the enantioselectivities were correlated with the E/Z ratios of the imines measured using H
NMR. Thus, higher E-containing ketimines, such as 13 (E only), and acetophenone-derived ketimines
14a-e gave good to excellent enantioselectivities, but higher Z-containing ketimines such as 14g-i showed
poor ee values.
Although the precise structure of the catalyst 11 and the corresponding hydride species are unknown, we
speculate the most likely hydride catalyst 16, depicted in Figure 1. Thus, the re-face of ketimines easily

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HETEROCYCLES, Vol. 78, No. 3, 2009
approach from the less-hindered side, which is opposite the “roof” moiety, of the ruthenium hydride 16 to
create the (S)-amine 17. The clear discrimination between “shielding” and “non-shielding” site by
minimum steric hindrance make the chiral ruthenium complex 16 a highly reactive and selective catalyst.
The “roofed” cis-1,2-diamine structure, which is both conformationally rigid and sterically bulky, creates
an ideal space for asymmetric transfer hydrogenation.
Table 2. Chiral Ru(II) complex 11b -catalyzed asymmetric transfer hydrogenation of various
ketimines 14a-i.
NBn
R2
NHBn
chiral Ru cat. 11b (0.5 mol %)
5HCO2H•2NEt3 (0.5 mL)
R2
*
(R)
NH2
CH2Cl2 (1.5 mL)
25 °C, Time
(S)
R1
R1
14a-i
(1 mmol)
15a-i
RuClAr
N
i
SO2 Pr
Yieldb)
(%)
(Ar = benzene)
Time
(h)
eec)
(%)
R1
R2
Entry Imine
E / Z a)
11b
1
2
3
4
5
14a
14b
14c
14d
14e
H
Me
15 / 1
20 / 1
15 / 1
20 / 1
29 / 1
24
18
24
24
12
78
91
79
71
92
77 (S)
74 (S)
75 (-)d,e)
MeO Me
Me
Cl
Me
Me
Me
a) Measured by 1H NMR (300 or
400 MHz).
b) Isolated yields.
74 (S)
75 (-)d,e)
NO2
c) Determined by chiral HPLC. For
absolute configurations, see ref 11.
d) Absolute configurations were not
determined.
6
7
8
14f
H
H
H
Et
2 / 1
1 / 24
Z only
6
24
48
85
63
13
69 (-)d,e)
51 (S)
1d)
14g
14h
i-Pr
t-Bu
N
e) The signs of optical rotation of
the isolated products are shown.
14i
9
Z only
1.5
83
36 (S)
MeO
OMe
NHR'
5HCO2H•2NEt3
RO2S
N
11
(S)
Ar
R"
Ru
NH
16
17
H
H
R"
R'
N
[Re-face attack]
Figure 1
In conclusion, we demonstrated that the “roofed” cis-1,2-diamine-Ru(II) complex, which is both
conformationally rigid and sterically bulky, is an excellent catalyst for asymmetric transfer hydrogenation
of ketimines. Additional studies are now in progress.
REFERENCES AND NOTES
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HETEROCYCLES, Vol. 78, No. 3, 2009
621
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9. General procedure for asymmetric transfer hydrogenation of ketimines catalyzed by 11: A mixture of
benzeneruthenium (II) chloride dimer (1.25 mg, 0.0025 mmol, 0.25 mol%), N-sulfonylated-“roofed”
diamine 10 (0.005 mmol, 0.5 mol%) and triethylamine (1.4 µL, 0.01 mmol, 1 mol%) in 2-propanol
(1 mL) was refluxed for 1 h under an argon atmosphere (formation of catalyst 11). After removal of
the solvent in vacuo, 5HCO2H•2NEt3 azeotrope (0.5 mL), CH2Cl2 (1.5 mL) and ketimine (1 mmol)
were successively added and the mixture was stirred at 25 °C. The reaction was monitored by TLC
until substantial completion. After the addition of satd. NaHCO3 aq. (5 mL), the product was
extracted (EtOAc, 20 mL × 3), washed (brine, 10 mL × 3), dried (anhyd. Na2SO4) and evaporated in
vacuo, followed by purification using flash column chromatography on silica gel to afford the
corresponding amine. Enantiomeric excess values were determined by chiral HPLC.
10. Other type of co-solvents were also examined (toluene, THF, MeCN, DMF, DMSO and IPA) and
CH2Cl2 gave the optimal result.
11. Absolute configurations of the chiral amines were determined by comparing the sign of optical

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