Alkoxy substituted MeO-BIPHEP-type diphosphines ligands for asymmetric hydrogenation of aryl ketones

Article abstract of DOI:10.1016/j.cclet.2010.01.030

In this paper, a series of optically active MeO-BIPHEP-type ligands, (S)-6,6′-dimethoxy-2,2′-bis(di-p-alkoxyphenylphosphine)-1,1 ′-biphenyl were synthesized and used to prepare the ruthenium complex. The effects of para-substituted were observed, the results showed that the ruthenium catalysts [diphosphine RuCl₂ diamine] containing both t-Bu and i-Pr substitutions have better activities and enantioselectivities than the non-substituted ruthenium catalysts in the asymmetric hydrogenation of acetophenone.

Full text of DOI:10.1016/j.cclet.2010.01.030

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 576–579
www.elsevier.com/locate/cclet
Alkoxy substituted MeO-BIPHEP-type diphosphines ligands for
asymmetric hydrogenation of aryl ketones
a,b
b
b
b
Meng Lin Ma , Zong Hai Peng , Yu Guo , Li Chen , Hua Chen , Xian Jun Li
b,*
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 9 October 2009
Abstract
0
0
In this paper, a series of optically active MeO-BIPHEP-type ligands, (S)-6,6 -dimethoxy-2,2 -bis(di-p-alkoxyphenylphosphine)-
0
1
,1 -biphenyl were synthesized and used to prepare the ruthenium complex. The effects of para-substituted were observed, the
results showed that the ruthenium catalysts [diphosphine RuCl diamine] containing both t-Bu and i-Pr substitutions have better
activities and enantioselectivities than the non-substituted ruthenium catalysts in the asymmetric hydrogenation of acetophenone.
2010 Hua Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
2
#
Keywords: Aryl ketone; Asymmetric hydrogenation; Biaryl phosphines ligands; Ruthenium complex
Asymmetric hydrogenation has become increasingly popular for producing enantiomerically pure compounds in
pharmaceutical and chemical industries. Chiral diphosphine ligands such as BINAP 1a, BIPHEMP 2a, P-Phos 3a and
MeO-BIPHEP 4a (Fig. 1) have demonstrated their high efficiencies and high enantioselectivities in Rh(I) and Ru(II)
catalyzed homogeneous asymmetric hydrogenation of olefins, ketones and imines [1].
In 1995 Noyori reported that ketones with no secondary binding functionality could be effectively hydrogenated in
the presence of ruthenium catalysts. These are based on a ruthenium metal centre bearing a chiral diphosphine and a
chiral diamine ligand in the presence of a base (such as t-BuOK or KOH). 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 [2].
Ruthenium precatalysts [diphosphine RuCl diamine] formed by the non-substituted biaryl diphosphines ligands
2
MeO-BIPHEP 4a or BINAP 1a and the diamine DPEN 5 (Fig. 1) showed better activities and moderate steric
selectivities for the asymmetric hydrogenation of acetophenone. This seminal discovery has led to the development of
the first highly practical and selective methodology for homogeneous asymmetric ketone hydrogenation in the past
few years. It has been reported that 3,5-disubstituted arene groups generally impart higher activities and selectivities to
the catalyst [3]. The 3,5-disubstituted biaryl diphosphines ligands, such as xyl-BINAP 1b [4], xyl-P-Phos 3b [5], xyl-
*
Corresponding author.
E-mail address: mmlchem@163.com (H. Chen).
1001-8417/$ – see front matter # 2010 Hua Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.01.030

M.L. Ma et al. / Chinese Chemical Letters 21 (2010) 576–579
577
Fig. 1. Ligands used for ketone hydrogenation catalysts.
Fig. 2. Our biaryl diphosphine ligands.
MeO-BIPHEP 4b [6] and xyl-TetraPHEMP 2b [7] (Fig. 1), were used in asymmetric hydrogenation of ketones and get
good results, in which the steric influence of the 3,5-disubstituted was investigated.
Due to the importance of the nature of substituents on the phosphorus atoms, we investigated the influence of newly
designed MeO-BIPHEP-type atropisomeric diphosphines with para-alkoxy phenyl group at each of the phosphorus
atom (Fig. 2). The different structures of the alkoxy are expected to provide an opportunity to investigate the influence
of the para-substituent in the asymmetric hydrogenation of ketones.
0
0
0
In this paper, a series of chiral diphosphines 6,6 -dimethoxy-2, 2 -bis(di-p-alkoxyphenylphosphine)-1, 1 -biphenyl
were synthesized by an improvement way (Scheme 1) based on the Schmid method [8] and our improve way [9].
In order to evaluate alkoxy substituted ligands, their corresponding ruthenium complexes were prepared according
to literature methods [10] (Scheme 2) and tested on the hydrogenation of acetophenone. Parallel experiments were
performed to make direct comparison between our catalysts and reported ones. Basic reaction conditions were first
optimized using acetophenone as substrate and p-methoxy-MeO-BIPHEP 4c phosphine ligand complex as a catalyst.
Scheme 1. Reagents and conditions: (a) P(OEt)
78 8C, (2) anhydrous FeCl
in THF, ꢀ78 8C to rt., 16 h, 49% yield or (1) LTMP (BuLi + 2,2,6,6-tetramethylpiperidine) in THF, ꢀ78 8C, (2)
anhydrous FeCl Cl /Et O, (2) 10% NaOH/CH Cl , >99% ee, (d) SOCl , DMF,
in THF, ꢀ78 8C to rt., 16 h, 58% yield, (c) (1) (ꢀ)-DBTA in CH
9% yield, (e) ArMgBr in THF, ꢀ78 8C to rt., 3 h, 95–68% yield or ArLi in THF, ꢀ78 8C to rt., 0.5 h, 46–35% yield, (f) HSiCl , Et N in toluene,
reflux, 98% yield, >99% ee.
3 2
, anhydrous NiCl , 140 8C, 1 h, 87% yield or microwave, 5 min, 94% yield, (b) (1) LDA in THF,
ꢀ
3
3
2
2
2
2
2
2
9
3
3

578
M.L. Ma et al. / Chinese Chemical Letters 21 (2010) 576–579
2 2
Scheme 2. Reagents and conditions: (a) DMF and [Ru(benzene)Cl ] 100 8C, 25 min and (b) (S,S)-DPEN, 25 8C, 5 h. The solvent DMF was
removed by evaporated at 30 8C under reduced pressure.
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 50 8C and under 40 bar of hydrogen (Table 1). The
same ruthenium complexes were prepared with the MeO-BIPHEP in order to compare the activity and selectivity of
ligands.
As we have already observed with ligands 4c, 4d and 4e, these alkoxy substituted almost have no influence either on
the activity or on the selectivity (Table 1, entry 2, 3 and 4). Moreover some other para-substituent of the diphosphine
ligands has the influence in the asymmetric hydrogenation of ketones. In our reaction conditions, the non-substituted
MeO-BIPHEP ligands 4a provided 99% conversion to products and gave 81% ee at 20 8C (Table 1, entry 1). Different
results were obtained because of their different chemical structures. The ligands substituted by para-t-Bu 4h and para-
i-Pr 4f both gave good ee than non-substituted one, particularly the t-Bu-MeO-BIPHEP 4h could get 99% conversion
with 97% ee (Table 1, entry 7). These results clearly indicated the strong influence of para-substituent with steric
hindrance on the enantioselectivity of the reaction.
With the optimal reaction conditions in hand, ligand 4h was used in the hydrogenation of a series of acetophenones
derivatives (Table 2, entries 1–10). Excellent enantioselectivities ee were observed. The best result was hydrogenation
of o-bromoacetophenone (Table 2, entry 7), in which the conversion to products was >99% with 99% ee. The o-
chloroacetophenone (Table 2, entry 8) and o-trifluoromethylacetophenone (Table 2, entry 6) could get better ee at
9
7%. These results are comparable to the best results reported to date.
In summary, we have investigated the influence of the para-substituent in the asymmetric hydrogenation of ketones,
the results showed that new ruthenium catalysts [diphosphine RuCl diamine] containing the p-t-Bu- or p-i-Pr-
2
substituted MeO-BIPHEP ligand were better than non-substituted ones in both activities and enantioselectivities.
Further study will be focused on the synthesis and applications of other ortho-substituted MeO-BIPHEP ligands.
Table 1
The effect of the para-alkoxy chain in the hydrogenation of acetophenone.
.
1
2
a
Entry
Phosphine
R
R
Con. (%)
ee (%)
b
1
2
3
4
5
6
7
8
4a
4c
4d
4e
4f
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
H
H
H
H
H
H
H
H
99
99
81
82
84
84
92
87
97
77
>99
>99
>99
>99
>99
29
4g
4h
4i
a
2
Reactions were run under 3 Mp H and 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).
b
2
Henschke et al. reported 84% ee using RuCl [(S)-MeO-BIPHEP][(S,S)-DPEN] precatalyst and t-BuOK as base [7].

M.L. Ma et al. / Chinese Chemical Letters 21 (2010) 576–579
579
Table 2
The results of hydrogenation different acetophenones derivatives.
1
2
Entry
Phosphine
R
R
Con. (%)
ee (%)
1
2
3
4
5
6
7
8
9
t-Bu-MeO-BIPHEP (4h)
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
3
3
3
3
3
3
3
3
CH
(CH
3
H
>99
19
82
78
74
84
47
98
99
97
64
0
3
)
2
H
p-CH
3
O
O
89
p-CF
o-CH
3
>99
53
3
o-CF
o-Br
o-Cl
o-F
3
>99
>99
>99
98
1
0
o-OH
0
2
Reactions were run under 3 Mp H , 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).
Acknowledgments
We thank the NSFC (No. 20272037), the Doctor’s Foundation of Education Ministry of China (No. 20030610022)
and Foundation of Xihua University (No. R0723315) and (No. 07ZA109) for the financial support of this work.
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