N,N'-dialkylated 1,2-diamine derivatives as new efficient ligands for RuCl2(PPh3)3 catalyzed asymmetric transfer hydrogenation of aromatic ketones

Article abstract of DOI:10.1016/S0040-4039(02)01962-7

Chiral N,N'-dialkylated cyclohexanediamine derivatives ligands have been synthesized and used in an asymmetric transfer hydrogenation of aryl ketones. Optically active alcohols with up to 93% enantiomeric excess were obtained in high yield.

Full text of DOI:10.1016/S0040-4039(02)01962-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8059–8062
N,N%-Dialkylated 1,2-diamine derivatives as new efficient ligands
for RuCl2(PPh3)3 catalyzed asymmetric transfer hydrogenation
of aromatic ketones
Geon-Joong Kim,* Sang-Han Kim, Pong-Hyun Chong and Mi-Ae Kwon
Department of Chemical Engineering, Inha University, Inchon 402-751, South Korea
Received 17 May 2002; revised 6 September 2002; accepted 12 September 2002
Abstract—Chiral N,N%-dialkylated cyclohexanediamine derivatives ligands have been synthesized and used in an asymmetric
transfer hydrogenation of aryl ketones. Optically active alcohols with up to 93% enantiomeric excess were obtained in high yield.
© 2002 Published by Elsevier Science Ltd.
During the last decade, considerable efforts have been
devoted to the development of highly efficient catalysts
for the hydrogen-transfer (H-transfer). An especially
useful method is the catalytic transfer hydrogenation
using 2-propanol1 or HCOOH/Et3N mixture2 as a
hydride source and a chiral ruthenium catalyst complex
bearing ligands. Among these, H-transfer from boiling
isopropyl alcohol to ketones is particularly useful due
to its simplicity and the many favorable properties of
the reaction. Through the work in this area, many other
chiral ligands3 which are highly selective and extremely
active have been achieved with Ru complexes.
reduction of acetophenone at 82°C. The degree of
optical yield tends to increase with increasing of the size
of alkyl groups in the ketone substrates.
In fact, RuCl2[P(C6H5)3]3 is known as an excellent
catalyst for olefin hydrogenation, but very poor for
carbonyl hydrogenation. Chowdhury and Backvall5
have reported that RuCl2[P(C6H5)3]3 catalyses efficient
transfer hydrogenation of ketones by 2-propanol with
very high turnover frequency, but no hydrogenation
occurs in the absence of bases such as NaOH. Okuma
et al.6 have investigated that the combined effects of
diamine and KOH accelerate the carbonyl
hydrogenation.
Chiral 1,2-diamine based Ru(II) complexes effectively
promoted the reduction of acetophenone to give (S)-1-
phenyl ethanol with excellent yield and very high ee%
using 2-propanol as a hydrogen source.4 The reaction
rates and enantioselectivity are highly dependent on the
electronic properties of substituents in phenyl rings as
well as the bulkiness around the carbonyl moiety.
However, the chiral imidazolidine ligands have never
been applied in the reduction of ketones using 2-
propanol. With the aim of exploiting the imidazolidi-
nes, we synthesized new chiral imidazolidines from
optically active (1R,2R)-(+)-N,N%-dialkylcyclohexane-
1,2-diamines. Herein we report the application of the
imidazolidines as a ligand to the Ru-catalyzed asym-
metric H-transfer of aryl ketones. This communication
also describes the preparation of the new imidazolidines
possessing a five-membered backbone.
Langer and Helmchen3 have reported that Ru com-
plexes with chiral phosphinooxazolines are highly reac-
tive and enantioselective in the H-transfer of aliphatic
as well as aromatic ketones. Preformed RuCl2(3)-
[P(C6H5)3]3 acts as an extremely effective catalyst for
Scheme 1 shows the method to synthesize the phosphi-
noimidazolidines and thioimidazolidines. Enantiomeri-
cally pure (R,R)-1,2-diaminocyclohexane was converted
to its N,N%-dialkyl analogs of type (4a–4c). (R,R)-N,N%-
Dimethyl-1,2-diamino cyclohexane (4a) was synthesized
by the reaction of (R,R)-1,2-diamino cyclohexane with
ethyl chloroformate in the presence of NaOH, followed
by lithium aluminum hydride (LAH) reduction in anhy-
* Corresponding author. Tel.: +82-32-860-7472; fax: +82-32-872-0959;
e-mail: kimgj@inha.ac.kr
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01962-7

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G.-J. Kim et al. / Tetrahedron Letters 43 (2002) 8059–8062
Scheme 1.
drous THF. In addition, for the synthesis of (5a),
commercially available (1R,2R)-(+)-N,N%-dimethylcy-
clohexane-1,2-diamine (4a) could be chosen as a start-
ing auxiliary. The N,N%-diethyl analog (4b) was
prepared from the corresponding N,N%-diacetyl com-
pound by reduction with LAH in THF also. (R,R)-
N,N%-Diacetyl-1,2-diaminocyclohexane was synthesized
by the reaction of (R,R)-1,2-diaminocyclohexane with
acetic anhydride in methanol. The N,N%-dibenzyl-1,2-
diamino cyclohexane (4c) was obtained through reduc-
tive amination of (R,R)-1,2-diaminocyclohexane with
benzaldehyde, followed by reduction with NaBH4 at
room temperature for 6 h.
Chiral phosphinoimidazolidine ligands can be readily
synthesized by condensation of N-alkylated diamine
derivatives (4a–4c) and 2-diphenylphosphino benzalde-
hyde in refluxing benzene.

G.-J. Kim et al. / Tetrahedron Letters 43 (2002) 8059–8062
8061
The chiral diazide was obtained from norephedrine and
the reduction of diazide to corresponding diamine was
accomplished by treating the former with LAH in
boiling THF for 16 h. The N,N%-dimethylated diamine
derivative was prepared in the same manner as
described above. A chiral phosphinoimidazolidine (7)
was prepared by condensation of N,N%-dimethylated
diamine with 2-diphenylphosphino benzaldehyde in
refluxing dioxane.
As shown in Table 1, the reactions with RuCl2(PPh3)3,
promoted with NaOH, proceeded remarkably both in
terms of enantioselectivity and reactivity. A range of
alkyl phenyl ketones was reduced to secondary alcohols
with a high yield and a satisfactory ee (%). The enan-
tioselectivity and the reactivity are strongly dependant
on the structure of imidazolidines. New phosphinoimi-
dazolidine ligands 5a–5c and 7 are proved to be very
efficient in terms of enantioselectivity for the transfer
hydrogenation of alkyl aryl ketones. It appears that the
imidazolidines of N-methylated diamine derivatives
that are sterically less hindered at the nitrogen gave
much better results in enantioselectivity than those of
N-benzylated diamine derivatives. In the case of ligand
5a, the product displayed 81% ee with acetophenone
when 99% conversion was reached. The transfer hydro-
genation of propiophenone catalyzed by the imidazo-
lidine 5a–RuCl2(PPh3)3–NaOH system gave the
corresponding alcohol in 89% ee. Enantioselectivities
increased with the bulkiness of the alkyl substituent
adjacent to the carbonyl group in the substrate. It is
known that high-yield H-transfer of a-tetralone, which
has low oxidation potential, is difficult under equi-
librium conditions with 2-propanol as a hydrogen
donor.3,8 In contrast, a-tetralone was reduced to tetra-
lol with 93% ee in the presence of Ru complex of chiral
phosphino-imidazolidine (5a).
Treatment of o-bromobenzaldehyde with chiral dialkyl
cyclohexane-1,2-diamine derivatives yielded the bromo-
imidazolines and these compounds were treated with
tert-butyllithium at −78°C in THF under argon and
allowed to react with diphenyl disulfide furnishing the
chiral thioimidazolidine (8). The ligand (9b) was pre-
pared in the same manner as the procedure reported in
literature.7
To examine the catalytic efficiency of 4a–9b as chiral
ligands for the ruthenium-catalyzed transfer hydrogena-
tion, the chiral Ru catalyst precursors were prepared in
situ by heating a mixture of RuCl2(PPh3)3 and ligands
4a–9b in dry 2-propanol to reflux. For a given ruthe-
nium precursor, RuCl2(PPh3)3 is very air-sensitive and
readily spoiled by moisture, so all H-transfer proce-
dures were proceeded under N2. Transfer hydrogena-
tion started by addition of a substrate and a base
(NaOH, KOH or sodium isopropoxide) in dry 2-
propanol.
The phosphinoimidazolidine (5b) synthesized from
N,N%-diethyl-1,2-diaminocyclohexane (4b) affords the
Table 1. Asymmetric transfer hydrogenation of ketones catalyzed by a chiral RuCl2(PPh3)3 complex in 2-propanol
Entry
Ligand
Substrate
S/Ru/L mole ratio
Time (h)
Conv.a (%)
% eea
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
5a
5a
5a
5b
5b
5c
6
6
7
8
8
9a
9a
9b
9b
Acetophenone
Propiophenone
Acetophenone
Propiophenone
Tetralone
Propiophenone
Acetophenone
Propiophenone
Tetralone
50/1/1.5
50/1/1.5
500/1/1.5
500/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
50/1/1.5
3
3
6
6
3
3
3
3
3
3
3
3
5
5
3
3
3
3
3
3
3
\99
\99
81
90
\99
92
\99
\99
\99
\99
\99
\99
90
56
67
44
53
71
30
81
89
93
86
88
75
48
54
85
77
74
81
86
71
73
9
10
11
12
13
14
15
16
17
18
19
20
21
Propiophenone
Tetralone
Propiophenone
Acetophenone
Propiophenone
Propiophenone
Propiophenone
Tetralone
Propiophenone
Tetralone
Propiophenone
Tetralone
85
98
\99
\99
\99
\99
91
87
a Determined by GC analysis. S: substrate, Ru: RuCl2(PPh)3, L: ligand. Reaction temperature: 82°C (bp of 2-propanol).

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G.-J. Kim et al. / Tetrahedron Letters 43 (2002) 8059–8062
Table 2. Effects of base and ruthenium source on asymmetric transfer hydrogenation of propiophenone with 2-propanol
Entry
Ligand
Base
Ru(II)
Temp. (°C)
Time (h)
Conv.a (%)
% eea
1
2
3
4
5
6
7
4a
4a
4a
4a
4a
9a
9b
KOH
Na–isopropoxide
NaOH
NaOH
NaOH
A
A
A
A
B
B
B
82
82
25
82
82
82
82
3
1
6
3
3
3
3
\98
\98
No reaction
\98
\98
67
66
–
67
53
74
67
NaOH
NaOH
\98
85
a Ruthenium source; A=RuCl2(PPh3)3, B=[RuCl2(p-cymene)]2, S/Ru/L mole ratio=50/1/1.5.
nes and their application to asymmetric catalysis are
underway in our laboratory.
hydrogenated product of propiophenone with 86% ee
(entry 10), whereas that obtained from N,N%-dibenzyldi-
amine compound (4c) affords 75% ee (entry 12). The
phosphino imidazolidine (7) catalyzed the reduction of
propiophenone in 2-propanol to afford the correspond-
ing alcohol in 85% ee.
Acknowledgements
This work was supported by grant No. 2000-1-30700-
002-3 from the Basic Research Program of the Korea
Science & Engineering Foundation.
The reaction rate was relatively slow and the values of
ee% decreased with the prolonged reaction time, when
the substrate/Ru complex ratio was high (entries 3 and
4). As can be seen in Table 1, the higher enantioselec-
tivity was obtained when 2 mol% ruthenium source and
3 mol% ligand were employed. The high enantiomeric
excess of product was maintained consistently through-
out the reaction until completion in our system. The
preformed complex catalyst prepared by the reaction of
RuCl2(PPh3)3 and ligands 5a–9b in dry toluene showed
distinctly improved reactivity. With respect to reaction
rates, the rate obtained on the preformed catalyst was
about 20 times faster than that obtained over the
catalyst prepared in situ.
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