A fluorinated dendritic TsDPEN-Ru(ii) catalyst for asymmetric transfer hydrogenation of prochiral ketones in aqueous media

Article abstract of DOI:10.1039/c002168g

The fluorinated dendritic chiral mono-N-tosylated 1,2- diphenylethlenediamine, FTsDPEN, has been synthesized and applied in the ruthenium(ii) complex-catalyzed asymmetric transfer hydrogenation of prochiral ketones in aqueous media.

Full text of DOI:10.1039/c002168g

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A fluorinated dendritic TsDPEN-Ru(II) catalyst for asymmetric transfer
hydrogenation of prochiral ketones in aqueous mediaw
Weiwei Wang and Quanrui Wang*
Received 2nd February 2010, Accepted 4th May 2010
First published as an Advance Article on the web 25th May 2010
DOI: 10.1039/c002168g
The fluorinated dendritic chiral mono-N-tosylated 1,2-diphenyl-
ethlenediamine, FTsDPEN, has been synthesized and applied in
the ruthenium(II) complex-catalyzed asymmetric transfer hydro-
genation of prochiral ketones in aqueous media.
Asymmetric transfer hydrogenation (ATH) has been widely
used as an efficient and practical method for preparation of
optically pure secondary alcohols that are important key
intermediates for the synthesis of a large number of pharma-
ceutical substances. One of the most attractive catalyst system
is based on Ru-TsDPEN (TsDPEN = N-(p-tolylsulfonyl)-1,2-
diphenylethylenediamine) complexes, which was developed by
Noyori in the 1990’s with HCO2H-NEt3 azeotropic mixture as
hydrogen donor.1 In many cases, high activity and enantio-
selectivity can be achieved with this archetypal catalyst.2
A limitation of the methodology is that the Ru-TsDPEN
catalyst cannot be easily separated from products and thus
may erode the practical applicability.
In order to recover and reuse the expensive and sometimes
toxic catalysts, continuous efforts have been devoted to new
catalyst systems for the ATH reactions.3 Among them,
dendritic catalysts have received special attention since they
Fig. 1 Structures of compounds 1–3.
have the potential to combine both the advantages of homo-
geneous and heterogeneous catalysts in just one system.4,5
acetophenone using Ru-(S,S)-3 as catalyst was employed as
the model reaction. Three conditions, i.e. a 5 : 2 formic acid
triethylamine azeotrope (mole ratio),1b HCOOH–NEt3
(1.2 : 1 initial mole ratio) in water2b and aqueous HCO2Na2a
were investigated. As shown in Table 1, faster rates were
obtained in water with HCO2Na as reductant than with the
other two conditions (Table 1, entries 3 vs. 1 and 2). The
stereoselectivity can be further increased with addition of
However, in terms of catalyst activity and reusability,
dendritic catalysts cannot outperform other types of immobi-
lized catalysts, such as catalysts immobilized on silica3b,d or
polymer.3c,h Herein we report a highly efficient fluorinated
dendritic chiral mono-N-tosylated 1,2-diphenylethylenediamine-
ruthenium complex, Ru-FTsDPEN, for the asymmetric
transfer hydrogenation of prochiral ketones in aqueous
medium. This new catalyst has exhibited unprecedented
recycling ability up to twenty-six times.
The required fluorinated dendrimer 1 was prepared by a
six-step protocol starting from 3,5-dihydroxybenzoic acid and
bromopentafluorobenzene (see ESI for details).w Condensation
of 1 with the p-hydroxyphenylsulfonamido modified chiral
ligand (S,S)-2 and consecutive deprotection of the Boc-group
provided successively the fluorinated dendritic chiral ligand
(S,S)-3, FTsDPEN, in 65% overall yield (Fig. 1).
Table 1 Asymmetric Transfer Hydrogenation of Acetophenone 4
Catalyzed by Ru-(S,S)-3a
Entry
Conditions
S CÀ1
T/h
%Conv.b
%eeb
The pre-catalyst was generated by reaction of the ligand
FTsDPEN 3 with [RuCl2(p-cymene)]2 in CH2Cl2 at 35 1C for
10 h with Et3N as a base. The transfer hydrogenation of
1
2
3
4
5
azeotrope
100
100
100
100
27
5
4
4
15
>99
>99
>99
>99
99
87
93
90
97
94
water, azeotrope
water, formate
water, formatec
water, formatec
1000
Department of Chemistry, Fudan University, Shanghai 200433,
PR China. E-mail: qrwang@fudan.edu.cn; Fax: (+86)(21)65641740
w Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data for catalyst intermediates and
reduction products. See DOI: 10.1039/c002168g
a
The reactions were carried out at 40 1C, see ESI for details.
Determined by chiral HPLC. The configuration of the alcohol was S.
TBAI (tetrabutylammonium iodide, 0.5 equiv.) was added.
b
c
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Table 2 Asymmetric Transfer Hydrogenation of ketones Catalyzed
by Ru-(S,S)-3a
and 11 (Table 2, entries 3, 6 and 7). In comparison to the
unmodified Ru-TsDPEN catalyst, the enantiomeric excess for
7, 10, and 11 was evidently inferior. Although the reason is still
a blur at present, we tentatively attribute it to the disturbance
of a chirality-determining diastereomeric transition state by
the o-substituents.7 The situation might be reinforced by the
fluorinated dendrimer scaffold.
One of the most important objectives of designing Ru-(S,S)-3
was to facilitate catalyst/product separation via the solvent
precipitation method. To this end, we chose the catalyst at
1 mol% loading to investigate the reusability. After completion
of the reaction, hexane was added to precipitate the catalyst
and the surfactant TBAI. For the next run to be conducted,
1 equiv. of HCO2H was added to adjust the pH.
Entry
Ketone
t/h
%Conv.b
%eeb
To our delight, the recycling of the Ru-(S,S)-3 was quite
successful. As can be seen from Fig. 2, the catalyst can be
reused more than twenty-six times with no significant decline
both in selectivity and activity. Nearly no appreciable ruthenium
leaching into the hydrocarbon phase (hexane) was observed as
indicated by an ICP analysis.8 During the initial recycling
period (runs 1–9), excellent conversion and enantioselectivity
were obtained with no extension of the reaction time. Even in
the 24th run, the reaction also afforded 93% conversion and
91% ee in 18 h. The ee’s remained almost unchanged until the
26th run (93% conversion and 88% ee, in 24 h).
1
2
3
4
5
6
7
5
6
7
8
9
10
11
2
4
6
3
2
3.5
4
>99
99
98
>99
>99
>99
98
94
97
66
90
92
55
78
a
The reactions were carried out in aqueous HCO2Na with TBAI
b
(0.5 equiv.) at 40 1C, see ESI for details. Determined by chiral
HPLC. The configuration of the alcohol was S.
To the best of our awareness, the literature precedents of
dendritic catalysts could be reused for no more than six times,4
and the recyclability of the most efficient immobilized catalyst
reached to 14 times.3 The catalyst Ru-(S,S)-3 represents a new
type that offers excellent recyclability and activity in ATH
reactions.
0.5 equivalents of TBAI (tetrabutylammonium iodide) as a
surfactant.6 Under the latter conditions, the reaction
proceeded smoothly at a substrate/catalyst (S CÀ1) ratio of
100 and 40 1C with complete conversion and 97% ee in 4 h
(Table 1, entry 4). This result is quite promising, since it is
comparable to or tops those based on the homogeneous
transfer hydrogenation using other recyclable catalysts or
unmodified TsDPEN as ligand.2,3 The reaction was also
feasible at a lower catalyst dosage of S CÀ1 = 1000 with only
a slight erosion on enantioselectivity, yet the reaction time has
to be lengthened to 15 h for complete conversion (Table 1,
entry 5).
It is well known that fluorine, being the most electronegative
atom, plays a profound role in pharmaceuticals, agro-
chemicals and materials. Incorporation of fluorine-containing
groups into an organic molecule can dramatically alter its
chemical stability, lipophilicity and bioavailability.9
The fluorinated dendrimer with well-defined nanostructures
has been proved to be an outstanding carrier, which can be
easily prepared and connected to catalysts. We disclosed that
the catalyst Ru-(S,S)-3 was extremely stable which allows it to
work well for more than 200 h in water (Fig. 2). We assume
that the introduction of fluorine atoms confer certain scaffold
rigidity and chemical resistance on the ligand. In turn, the
To probe the applicability scope of the catalyst Ru-(S,S)-3,
the reaction was extended to different types of aromatic
ketones 5–11. As demonstrated in Table 2, all of the tested
ketones were successfully reduced within a couple of hours.
The enantioselectivities were high except for substrates 7, 10,
Fig. 2 Graph of conversion, ee and reaction time vs. run numbers for the reduction of acetophenone with Ru-(S,S)-3 in water at 40 1C (the 30th
run was performed at 60 1C).
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fluorinated dendritic catalyst is amenable to exhibit special
stability and recyclability. Further studies on the use for other
substrates and to unravel the mechanistic issues are in
progress.
S.-H. Wang, Chem. Commun., 2004, 2070; (e) Y.-Z. Li, Z.-M. Li,
F. Li, Q.-R. Wang and F.-G. Tao, Org. Biomol. Chem., 2005, 3,
2513; (f) X.-H. Huang and J. Y. Ying, Chem. Commun., 2007, 1825;
(g) Y. Arakawa, A. Chiba, N. Haraguchi and S. Itsuno, Adv. Synth.
Catal., 2008, 350, 2295; (h) J.-T. Liu, Y.-G. Zhou, Y.-N. Wu,
X.-S. Lia and A. S. C. Chan, Tetrahedron: Asymmetry, 2008, 19,
832; (i) J. Li, Y.-M. Zhang, D.-F. Han, Q. Gao and C. Li, J. Mol.
Catal. A: Chem., 2009, 298, 31; (j) Z.-Q. Zhou and Y. Sun, Catal.
Commun., 2009, 10, 1685; (k) A. M. Hayes, D. J. Morris,
G. J. Clarkson and M. Wills, J. Am. Chem. Soc., 2005, 127, 7318.
4 (a) Y.-C. Chen, T.-F. Wu, J.-G. Deng, H. Liu, Y.-Z. Jiang,
M. C. K. Choib and A. S. C. Chan, Chem. Commun., 2001, 1488;
(b) P.-N. Liu, Y.-C. Chen, X.-Q. Li, Y.-Q. Tu and J.-G. Deng,
Tetrahedron: Asymmetry, 2003, 14, 2481; (c) Y.-C. Chen, T.-F. Wu,
L. Jiang, J.-G. Deng, H. Liu, J.-Z. and Y.-Z. Jiang, J. Org. Chem.,
2005, 70, 1006; (d) W.-G. Liu, X. Cui, L.-F. Cun, J. Zhua and
J.-G. Deng, Tetrahedron: Asymmetry, 2005, 16, 2525; (e) L. Jiang,
T.-F. Wu, Y.-C. Chen, J. Zhu and J.-G. Deng, Org. Biomol. Chem.,
2006, 4, 3319.
In summary, we have demonstrated that the Ru(II)-complex
from the fluorinated dendritic ligand FTsDPEN is a viable
alternative for the asymmetric transfer hydrogenation of
ketones with excellent enantioselectivity, and unprecedented
recovery and recyclability.
Notes and references
1 (a) S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya and R. Noyori,
J. Am. Chem. Soc., 1995, 117, 7562; (b) A. Fujii, S. Hashiguchi,
N. Uemastu, T. Ikariya and R. Noyori, J. Am. Chem. Soc., 1996,
118, 2521; (c) N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya and
R. Noyori, J. Am. Chem. Soc., 1996, 118, 4916; (d) R. Noyori and
S. Hashiguchi, Acc. Chem. Res., 1997, 30, 97.
2 (a) X.-F. Wu, X.-G. Li, W. Hems, F. King and J.-L. Xiao, Org.
Biomol. Chem., 2004, 2, 1818; (b) X.-F. Wu, X.-G. Li, F. King and
J.-L. Xiao, Angew. Chem., Int. Ed., 2005, 44, 3407; (c) X.-F. Wu,
J. Liu, D. D. Tommaso, J. A Iggo, C. R. A. Catlow, J. Bacsa and
J.-L. Xiao, Chem.–Eur. J., 2008, 14, 7699.
5 S. M. Grayson and J. M. J. Frechet, Chem. Rev., 2001, 101, 3819.
´
6 (a) F. Wang, H. Liu, L.-F. Cun, J. Zhu, J.-G. Deng and Y.-Z. Jiang,
J. Org. Chem., 2005, 70, 9424; (b) H.-F. Zhou, Q.-H. Fan,
Y.-Y. Huang, L. Wu, Y.-M. He, W.-J. Tang, L.-Q. Gu and
A. S. C. Chan, J. Mol. Catal. A: Chem., 2007, 275, 47.
7 R. Noyori, M. Yamakawa and S. Hashiguchi, J. Org. Chem., 2001,
66, 7931.
3 (a) D. J. Bayston, C. B. Travers and M. E. C. Polywka,
Tetrahedron: Asymmetry, 1998, 9, 2105; (b) P.-N. Liu, P.-M. Gu,
F. Wang and Y.-Q. Tu, Org. Lett., 2004, 6, 169; (c) X.-G. Li,
X.-F. Wu, W.-P. Chen, F. E. Hancock, F. King and J.-L. Xiao, Org.
Lett., 2004, 6, 3321; (d) P.-N. Liu, J.-G. Deng, Y.-Q. Tu and
8 The residual ruthenium (in 10 ml 10% liquor of HNO3) was
determined by ICP (P-4010). No leaching of Ru could be found
until the limit of detection (0.02 ppm).
9 (a) M. Schlosser, Angew. Chem., Int. Ed., 1998, 37, 1496;
(b) D. O’Hagan, Chem. Soc. Rev., 2008, 37, 308.
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This journal is The Royal Society of Chemistry 2010
4618 | Chem. Commun., 2010, 46, 4616–4618