Synthesis and application of chiral N,N'-dialkylated cyclohexanediamine for asymmetric hydrogenation of aryl ketones

Article abstract of DOI:10.1016/j.cclet.2010.09.025

Chiral N,N′-dialkylated cyclohexanediamine derived ligands have been synthesized and used in the asymmetric hydrogenation of aryl ketones. Optically active alcohols with up to 90% enantiomeric excess were obtained in high yields.

Full text of DOI:10.1016/j.cclet.2010.09.025

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 155–158
www.elsevier.com/locate/cclet
Synthesis and application of chiral N,N0-dialkylated
cyclohexanediamine for asymmetric hydrogenation of aryl ketones
a
a
b
Meng Lin Ma a,b, , Chuan Hong Ren , Ya Jing Lv , Hua Chen
, Xian Jun Li
*
b,**
a Department of Chemistry, Xihua University, Chengdu 610039, China
b Key Lab of Green Chemistry and Technology, Ministry of Education, The Institute of Homogeneous Catalysis,
Faculty of Chemistry, Sichuan University, Chengdu 610064, China
Received 12 May 2010
Abstract
Chiral N,N0-dialkylated cyclohexanediamine derived ligands have been synthesized and used in the asymmetric hydrogenation
of aryl ketones. Optically active alcohols with up to 90% enantiomeric excess were obtained in high yields.
# 2010 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
Keywords: Chiral diamine; Aryl ketone; Asymmetric hydrogenation; Ruthenium complex
Asymmetric hydrogenation has become increasingly popular for producing enantiomerically pure compounds in
pharmaceutical and chemical industries [1]. In 1995 Noyori reported that ketones with no secondary binding
functionality could be effectively hydrogenated in the presence of ruthenium catalysts [2]. These are based on a
ruthenium metal centre bearing a chiral diphosphine and such as 1–4 and chiral diamine such as 5a, 7–9 in the presence
of a base (such as t-BuOK or KOH) (Fig. 1). The asymmetric hydrogenation of a wide range of unfunctionalised
ketones now became possible, without the previous need to have a secondary binding group on the substrate.
A series of C2-symmetric diphosphines such as BINAP 1 [3], HexaPHEMP 2 [4] and MeO-BIPHEP 3 [5], which
gave high enantioselectivities in asymmetric hydrogenation, have been used in earlier studies. However, in contrast
with chiral diphosphines, the chiral diamine has not been extensively studied as ligands to date [6]. In a quest to
develop an accessible chiral diamine that forms catalytically active complexes with transition metals, having equal or
improved activity and selectivity to equivalent complexes of known ones, we prepared a series of chiral diamine based
on the (R,R)-1,2-diaminocyclohexane 5a backbone (Fig. 2). Herein, we outline the synthesis and preliminary catalytic
results associated with these ligands.
The route used to synthesise (R,R)-N,N0-dialkyl-1,2-diaminocyclohexane 5b–5e is shown in Scheme 1.
Enantiomerically pure (R,R)-1,2-diaminocyclohexane 5a was converted into its (R,R)-N,N0-dimethyl analogs 5b by
reaction with ethyl chloroformate in the presence of sodium hydroxide, followed by reduction used LAH for 16 h in
THF [7]. The (R,R)-N,N0-diethyl analog 5c was prepared from the corresponding N,N0-diacetyl compound by
* Corresponding author at: Department of Chemistry, Xihua University, Chengdu 610039, China.
** Corresponding author.
E-mail address: mmlchem@163.com (M.L. Ma).
1001-8417/$ – see front matter # 2010 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
doi:10.1016/j.cclet.2010.09.025

1[()TD$FIG] 56
M.L. Ma et al. / Chinese Chemical Letters 22 (2011) 155–158
Fig. 1. Complexes used for ketone hydrogenation catalysts.
[()TD$FIG]
Fig. 2. Our chiral diamine.
[()TD$FIG]
Scheme 1. Reagents and conditions: (a) (1) ClCOOEt, NaOH, toluene 25 8C; (2) LAH in THF 0 8C then Rf. 14 h, 72% yield. (b) (1) AcO2, MeOH;
(2) LAH in THF 0 8C then Rf. 14 h, 82% yield. (c) (1) PhCHO or (CH3)2CO, (2) NaBH4, MeOH, 5d 98 yield%, 5e 90 yield%.
reduction with LAH in THF also [7]. The (R,R)-N,N0-dibenzyl and (R,R)-N,N0-diisopropyl analogs 5d, 5e was
prepared through reductive amination with benzaldehyde and acetone [8].
A series of corresponding new ruthenium complexes were prepared according to literature methods [9], the
precatalysts were readily prepared under inert conditions by reaction of [RuCl2C6H6]2 with a diphosphine in hot DMF
followed by treatment with a diamine at room temperature yielding air stable, easily handled solids (Scheme 2). The
corresponding ruthenium complexes of the DACH 5a were also prepared for comparison.
Parallel experiments were performed to make direct comparison between our catalysts and the reported ones under
identical conditions with the same substrates. We first undertook comparative catalyst testing with each of these
diamines and chose acetophenone as the model substrate and trans-[RuCl2(BINAP)(diamine)] as the precatalyst. The
catalytic activities of these ruthenium complexes in the hydrogenation of acetophenone were tested in i-Pr-OH, with a
substrate/catalyst/base ratio (S/C/B) of 3000/1/100, at 20 8C and under 30 bar of hydrogen (Table 1).
As is evident from Table 1, comparison of different diamines revealed that the N,N0-dimethyl-DACH 5b and N,N0-
diethyl-DACH 5c showed similar activity but higher enantiomerical selectivity. The N,N0-dimethyl-DACH 5b and
N,N0-diethyl-DACH 5c affords the product with 91% and 90% ee (Table 1, entries 2 and 3) and the DACH 5a get 81%
[()TD$FIG]
Scheme 2. Reagents and conditions: (a) DMF and [Ru(benzene)Cl2]2 100 8C, 25 min, (b) (R,R)-5a–5e, 25 8C, 5 h. The solvent DMF was removed
by evaporation at 30 8C under reduced pressure.

M.L. Ma et al. / Chinese Chemical Letters 22 (2011) 155–158
157
Table 1
Asymmetric hydrogenation of acetophenone use different diamines
Entry
Complexes
R
Time (h)
Conc. (%)
ee (%)a
1
2
6a
6b
6c
6d
6e
6a
6b
6c
6d
6e
H
H
H
H
H
H
H
H
H
H
3
3
85
83
83
69
55
99
99
99
99
95
81b
91
90
78
77
82
91
90
79
78
3
3
4
3
5
3
6
12
12
12
12
12
7
8
9
10
a
Reactions were run under 3 MPa H2 and 20 8C in 50 mL magnetically stirred Parr pressure vessels and S/C/B 3000/1/100. Conversion and ees
were determined by GC analysis (Chirasil DEX-CB column), used (S)-1-phenylethanol as refer to determine the absolute configuration of product.
b
Doherty et al. reported 84% ee [10]; J.P. Henschke reported 82% ee [4].
ee (Table 1, entry 1). The results showed that the DACH substituted by alkyl provided a slight improvement in
selectivity over DACH 5a themselves. It appears that the N,N0-dimethylated diamine derivatives 5b that are sterically
less hindered at the nitrogen gave slightly better results in enantioselectivity than those of N,N0-dibenzylated diamine
derivatives 5d and N,N0-diisopropyl derivatives 5e. The N,N0-dimethylated diamine 5b and N,N0-diethylated diamine
5c get 91% and 90% ee (Table 1, entries 2 and 3), whereas the complexes obtained from N,N0-dibenzyldiamine 5d and
N,N0-diisopropyldiamine 5e affords 77% and 78% ee, respectively (Table 1, entries 4 and 5).
Different complexes were synthesized by using different diphosphine ligands and N,N0-dimethyl-DACH 5b. The
catalytic activities of these ruthenium complexes in the hydrogenation of acetophenone were tested too. The results
showed almost no difference in the enantiomerical selectivity (Table 2).
With the optimal reaction conditions in hand, complexes 6b were used in the hydrogenation of a series of
acetophenones derivatives (Table 3, entries 1–9). A range of alkyl phenyl ketones was reduced to secondary alcohols
with a high yield and a satisfactory ee%. The excellent enantioselectivities ee were observed. The best result was
hydrogenation of o-bromoacetophenone (Table 3, entry 6), in which the conversion to products was >99% with 99%
ee. The o-chloroacetophenone (Table 2, entry 7) and o-trifluromethylacetophenone (Table 2, entry 5) could get better
ee at 96%.
In summary, a series of chiral N,N0-dialkylated cyclohexanediamine derivatives were synthesized and used to
produce the corresponding new ruthenium complexes, which were applied in catalysts hydrogenation of aryl ketones.
Table 2
Asymmetric hydrogenation of acetophenone use different diphosphines
Entry
Complexes
R
Time (h)
12
Conc. (%)
ee (%)a
1
2
3
4
6b
6f
6i
H
H
H
H
99
99
99
99
91
89
87
92
6j
a
Reactions were run under 3 MPa H2 and 20 8C in 50 mL magnetically stirred Parr pressure vessels and 12 h. S/C/B 3000/1/100. Conversion and
ees were determined by GC analysis (Chirasil DEX-CB column). Used (S)-1-phenylethanol as refer to determine the absolute configuration of
product.

158
M.L. Ma et al. / Chinese Chemical Letters 22 (2011) 155–158
Table 3
The results of hydrogenation of different acetophenones derivatives
Entry
Complexes
R
Conc. (%)
ee (%)
1
2
3
4
5
6
7
8
9
6b
H
99
99
99
99
99
99
99
99
30
91
91
90
92
97
99
96
94
87
p-CH3O
p-CF3
o-CH3O
o-CF3
o-Br
o-Cl
o-F
o-OH
Reactions were run under 3 MPa H2, 20 8C in 50 mL magnetically stirred Parr pressure vessels and in 12 h. S/C/B 3000/1/100. Conversion and ees
were determined by GC analysis (Chirasil DEX-CB column).
In all cases studied, N,N0-dialkyl-DACH performed as well as or better than the DACH complexes. Further synthesis of
chiral imidazolidines and their application to asymmetric catalysis are underway in our laboratory.
Acknowledgments
We thank the NSFC (No. 20272037), the NSF of Sichuan (No. 07ZA109), the foundation of Xihua University (No.
R0723315) and (No. XZD0912-09) for the financial support of this work.
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