An investigation into the tether length and substitution pattern of arene-substituted complexes for asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1021/ol702226j

(Figure Presented) A series of Ru(II) catalysts were prepared and tested in the asymmetric transfer hydrogenation of ketones. The catalyst containing a "4-carbon" tether gave the fastest rates of ketone reduction. This is due to both increased rate of reg

Full text of DOI:10.1021/ol702226j

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4659-4662
An Investigation into the Tether Length
and Substitution Pattern of
Arene-Substituted Complexes for
Asymmetric Transfer Hydrogenation of
Ketones
Fung K. Cheung,† Changxue Lin,† Franco Minissi,† Adriana Lorente Criville´,†
Mark A. Graham,‡ David J. Fox,*,† and Martin Wills*,†
Asymmetric Catalysis Group, Department of Chemistry, UniVersity of Warwick,
CoVentry, CV4 7AL, U.K., and Cancer & Infection Chemistry, AstraZeneca, Mereside,
Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K.
m.wills@warwick.ac.uk
Received September 11, 2007
ABSTRACT
A series of Ru(II) catalysts were prepared and tested in the asymmetric transfer hydrogenation of ketones. The catalyst containing a “4-
carbon” tether gave the fastest rates of ketone reduction. This is due to both increased rate of regeneration of hydride “Ru H” and increased
−
rate of ketone reduction. Several classes of ketone were reduced in enantiomeric excesses of up to 97%. Substituents on the arene ring of
the catalyst influence the reaction rate and enantioselectivity.
Enantioselective ketone reduction is a pivotal reaction in
asymmetric synthesis and catalysis.1-3 Asymmetric transfer
hydrogenation (ATH) of ketones using monosulfonated
diamine complexes of Ru(II) was first reported by Noyori
in 19952a and has since become one of the most widely
studied and applied enantioselective reduction reactions.
In our studies in this field, we recently reported the
synthesis and applications of “tethered” catalysts 1 and 2 in
which covalent linkages from the diamine to the η6-arene
unit provide extra stability and a significant increase in rate
(with 2) relative to “untethered” catalyst 3.4 Using catalyst
2, acetophenone is fully reduced in 96% ee within 3 h at
S/C ) 200, presumably through the established TS illustrated
in Figure 1.5,6 The high ee for the reduction of acetophenone
derivatives arises from the stabilizing electrostatic interaction
† University of Warwick.
‡ AstraZeneca.
(1) (a) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045.
(b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (c) Clapham,
S. E.; Hadzovic, A.; Morris, R. H. Coord. Chem. ReV. 2004, 248, 2201. (d)
Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. ReV. 1992, 92, 1051.
(2) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1995, 117, 7562. (b) Fujii, A.; Hashiguchi, S.; Uematsu,
N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521. (c)
Matsumura, K.; Hashiguchi, Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997,
119, 8738. (d) Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.;
Ikariya, T. Org. Lett. 1999, 1, 1119. (e) Haack, K. J.; Hashiguchi, S.; Fujii,
A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285.
(3) (a) Gladiali, S.; Alberico, E. Chem. Soc. ReV. 2006, 35, 226. (b)
Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol. Chem. 2006, 4, 393.
(4) (a) Hannedouche, J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc.
2004, 126, 986. (b) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M.
J. Am. Chem. Soc. 2005, 127, 7318. (c) Morris, D. J.; Hayes, A. M.; Wills,
M. J. Org. Chem. 2006, 71, 7035.
10.1021/ol702226j CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/27/2007

acid/triethylamine (FA/TEA) because they are directly
converted to the monomers 4-8, respectively, in situ. Hence,
for synthetic applications, the dimers and monomers can be
used interchangeably.4 However, for purposes of comparison
and analysis, each of the monomers 4-8 were isolated for
use in ATH of acetophenone 11. With the exception of 6,
which has the longest tether, formation of monomers from
dimers took place within a few hours. In the case of 10c,
however, only a small amount of 6 was obtained even after
extended reaction times.
The results from the ATH studies (Table 1) indicated that
the “4C”-tethered complex 5 was the most active, achieving
Figure 1. Relative positions of arene substituents to substrate
during ATH by catalysts 1-3.
Table 1. ATH of Ketones 11-21 Catalyzed by Ruthenium(II)
Catalysts 2 and 4-8a,b
in the hydrogen transfer transition state illustrated in Figure
1.5,6 This interaction is not available for dialkyl ketones of a
similar size; acetylcyclohexane is reduced by 2 in only 69%
ee, arising from weaker steric effects.
loading
(mol %)
temp
(°C)
time
(h)
conv
(%)
ee (%)
(R/S)
catalyst
ketone
In order to increase the activity and versatility of catalyst
2, we wished to examine the effect of tether length and the
η6-arene ring substitution pattern. An examination of the
crystal structure of 2 reveals that the ipso carbon of the η6-
arene lies directly above the nitrogen atom to which it is
tethered. As a result, substituents at positions X and Y (Figure
1) are most likely to produce catalysts with improved
properties. In contrast, position Z might be usefully substi-
tuted with electron-rich or -poor groups.
S,S-2c
R,R-4
R,R-5
R,R-5
R,R-5
R,R-6
R,R-7
R,R-8
R,R-5
R,R-5
R,R-2
R,R-5
R,R-2
R,R-5
R,R-2
R,R-5
R,R-5
R,R-2
R,R-5
R,R-2
R,R-5
R,R-2
R,R-5
R,R-5
R,R-8
0.5
0.5
0.5
0.1
0.01
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
40
40
40
rt
rt
40
40
40
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
11
11
11
11
11
11
11
11
12
13
14
14
15
15
16
16
17
18
18
19
19
20
20
21
21
2
15
1.25
8
70
6
4
5
18
3
3
1
3
1
3
1
2
3
1
100
19
100
100
100
38
96 S
92 R
96 R
96 R
96 R
94 R
96 R
93 R
94 R
91 R
96 S
96 S
95 S
96 S
93 S
94 S
91 R
95 R
96 R
94 R
97 R
94 R
94 R
66 S
90 S
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
We identified complexes 4-8 as a series of systematically
modified catalysts that were worthy of study. These were
prepared in good yield via the route illustrated in Scheme 1.
Scheme 1. Synthesis of Tethered Catalysts
3
1
3
1
o/n
o/n
a Reaction at 28 °C in a 1.62 M solution of ketone in a formic acid/
triethylamine (5:2) azeotrope mixture and S/C ) 200 unless otherwise
specified. b For substrates 12-21, the dimeric precursors were used directly
as sources of catalysts 2 and 5. c From ref 4b.
full reduction within 75 min at S/C ) 200. This is faster
than the previously reported “3C”-tethered complex 2 and
significantly faster than the “5C” and “2C” complexes 4 and
6. However, the latter catalysts still gave products in high
(5) (a) Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem., Int. Ed.
2001, 40, 2818. (b) Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org.
Chem. 2001, 66, 7931. (c) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem.
Soc. 2000, 122, 1466.
(6) (a) Alonso, D. A.; Brandt, P.; Nordin, S. J. M.; Andersson, P. G. J.
Am. Chem. Soc. 1999, 121, 9580. (b) Brandt, P.; Roth, P.; Andersson, P.
G. J. Org. Chem. 2004, 69, 4885.
The precursors, 9a-e, were obtained by Birch reduction of
the corresponding arenes. Dimers 10a-e can be employed
directly in ketone ATH if the reaction is carried out it formic
4660
Org. Lett., Vol. 9, No. 22, 2007

ee, suggesting that they are still operating through the TS
expected for these compounds, although slowly. As a result
of this increased reactivity of 5, the catalyst loading can be
decreased to as low as 10 000:1, matching the level at which
2 has been used.
ring (Figure 3), which may be electrostatic5a in nature or
the result of dispersion effects.6b
A kinetic study was conducted (see Supporting Information
for details) using both 1H NMR and chiral GC to follow the
conversion. These studies were carried out at 40 °C using
1.62 M ketone in FA/TEA, S/C ) 200. Catalysts 2, 4, 6, 7,
and 8 demonstrated essentially zero-order kinetics for the
majority of the reaction. In contrast, catalyst 5 displayed
mixed-order kinetics.
An analysis of these data, assuming second-order kinetics
for the ketone reduction7 by the Ru-H species and first-
order kinetics8 for the regeneration of Ru-H by formic acid,
was carried out (Figure 2). The results indicate that the high
Figure 3. Reduction of acetophenone in 93% ee (R) by com-
plex 8.
Catalysts 2 and 5, supplied to the reaction in their dimeric
precursor forms, were employed in the reduction of a series
of ketones (Table 1); in all cases, the latter catalyst proved
to be more active. Ketones 14-16 produce 2-chloro-1-phene-
thanols, important synthetic intermediates for enantiomeri-
cally pure epoxides and related intermediates.10 Alcohols
derived from cyclic ketopyridines such as 18-20 are useful
precursors of chiral ligands for asymmetric hydrogenation
reactions11 and may be converted into the related amines
which are currently being evaluated as chemokine receptor
binding agents for treatment of HIV12 and are represented
in hydrogenation ligands.13 Using catalyst 5, it was possible
to reduce 18-20 in ees of 94-97%. Catalyst 2 also worked
well in this application but was less active.
Figure 2. Kinetic data for acetophenone reduction.
Catalyst 5 reduced acetylcyclohexane 21 in only 66% ee;
however, catalyst 8 gave a product of 90% ee. Both the sense
(opposite to acetophenone) and the increased ee for this
substrate suggest that the extra methyl groups on the η6-
arene ring in 8 force the larger ketone substituent into the
less hindered region (Figure 4). This represents the first
rate obtained with catalyst 5 is the result of an increased
rate of hydride regeneration coupled with rapid ketone re-
duction. For the other tethered catalysts, the overall reduction
rate is limited by the rate of hydride regeneration, until the
ketone concentration has fallen to low levels. The Noyori
catalyst, 3, takes 20 h to complete the reduction and exhibits
mixed-order kinetics similar to those of 5.9 The results
obtained with catalysts 7 and 8 are also informative. The
reduced reduction rate for the former relative to 2 appears
to result from slightly slower hydride regeneration, rather
than slower reduction.
Figure 4. Increased steric hindrance increases ee of reduction of
acetyl cyclohexanone by complex 8 (left; 90% ee) over 2 (right;
69% ee).
example of a Ru/TsDPEN ATH catalyst designed and
demonstrated to have useful levels of enantioselectivity for
(8) Koike, T.; Ikariya, T. AdV. Synth. Catal. 2004, 346, 37-41.
(9) Noyori has reported a kinetic study of the use of catalyst 3 in the
isopropanol/KOH system (ref 2e) and has found that, at high (>0.4 M)
concn of ketone (acetone), the turnover limiting step was the regeneration
of hydride. However, these studies were carried out under conditions
different than ours.
The rate of reduction using 8 is particularly slow, yet the
ee is not significantly eroded. This indicates that a stabilizing
interaction is operating through the methyl group on the arene
(10) Tanis, S. P.; Evans, B. R.; Nieman, J. A.; Parker, T. T.; Taylor, W.
D.; Heasley, S. E.; Herrinton, P. M.; Perrault, W. R.; Hohler, R. A.; Dolak,
L. A.; Hester, M. R.; Seest, E. P. Tetrahedron 2006, 17, 2154.
(7) Wisman, R. V.; de Vries, J. G.; Deelman, B.-J.; Heeres, H. J. Org.
Proc. Res. DeV. 2006, 10, 423-429.
Org. Lett., Vol. 9, No. 22, 2007
4661

nonaromatic substrates by replacing electronic control ele-
ments with steric ones.14
in the reduction of dialkyl ketones, which are challenging
substrates for this application. At present, the reasons for
the improved activity relative to untethered complexes are
unclear; however, we anticipate that these result from a slight
conformational adjustment to the structure which renders the
complexes more correctly preorganized toward the reduction
reactions. This is the subject of ongoing kinetic studies and
molecular modeling, the results of which will be published
in due course.
In conclusion, we have demonstrated that the tether length
and η6-arene substitution pattern have a significant effect
upon the activity of tether Ru(II) ATH complexes. The most
active of these complexes (2 and 5) can be applied to the
ATH of a range of ketone substrates to give alcohols in high
conversion and ee. Increasing the level of substitution at the
meta position of the arene ring can deliver an improved ee
(11) (a) Kaiser, S.; Smidt, S. P.; Pfaltz, A. Angew. Chem., Int. Ed. 2006,
45, 5194. (b) Bell, S.; Wuestenberg, B.; Kaiser, S.; Menges, F.; Netscher,
T.; Pfaltz, A. Science 2006, 311, 642. (c) Mazet, C.; Roseblade, S.; Kohler,
V.; Pfaltz, A. Org. Lett. 2006, 8, 1879. (d) Kallstrom, K.; Hedberg, C.;
Brandt, P.; Bayer, A.; Andersson, P. G. J. Am. Chem. Soc. 2004, 126, 14308.
(e) Kang, J.; Kim, H. Y.; Kim, J. H. Tetrahedron: Asymmetry 1999, 10,
2523. (f) Liu, Q.-B.; Yu, C.-B.; Zhou, Y.-G. Tetrahedron Lett. 2006, 47,
4733. (g) Okano, K.; Murata, K.; Ikariya, T. Tetrahedron Lett. 2000, 41,
9277.
Acknowledgment. We thank the EPSRC (Project stu-
dentship to F.M., project grant to C.L., ARF to D.J.F.) and
the BBSRC and Astrazeneca (CASE studentship to F.K.C.)
for generous financial support of this project, and the EPSRC
national Mass Spectrometry service (Swansea) for analyses.
(12) Skupinska, K. A.; McEachern, E. J.; Baird, I. R.; Skerlj, R. T.;
Bridger, G. J. J. Am. Chem. Soc. 2003, 68, 3546.
(13) Engman, M.; Diesen, J. S.; Paptchikhine, A.; Andersson, P. G. J.
Am. Chem. Soc. 2007, 129, 4536.
(14) (a) Reetz, M. T.; Li, S. J. Am. Chem. Soc. 2006, 128, 1044. (b)
Hamada, T.; Torii, T.; Onishi, T.; Izawa, K.; Ikariya, T. Org. Lett. 2004,
69, 7391. (c) Schlatter, A.; Kundu, M. K.; Woggon, W.-D. Angew. Chem.,
Int. Ed. 2004, 43, 6731.
Supporting Information Available: Experimental pro-
cedures, characterization data, NMR spectra, and kinetic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL702226J
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Org. Lett., Vol. 9, No. 22, 2007