A New Class of "Tethered" Ruthenium(II) Catalyst for Asymmetric Transfer Hydrogenation Reactions

Article abstract of DOI:10.1021/ja0392768

Ruthenium dimer 4 is converted directly to monomeric asymmetric transfer hydrogenation catalyst 2 under the conditions employed for ketone reduction. Using 0.25 mol % of either 4 or 0.5 mol % of 2 in formic acid/triethylamine, it is possible to achieve ketone reduction in quantitative conversion and with ee's as high as 98%. Complex 2 is a robust "single-reagent" catalyst which offers significant scope for modification toward specific substrates. The synthesis and applications of an analogous complex derived from (1R,2S)-norephedrine are also described. Copyright

Full text of DOI:10.1021/ja0392768

Published on Web 01/06/2004
A New Class of “Tethered” Ruthenium(II) Catalyst for Asymmetric Transfer
Hydrogenation Reactions
Je´roˆme Hannedouche,† Guy J. Clarkson,‡ and Martin Wills*,†
Asymmetric Catalysis Group, and X-ray Crystallography Unit, Department of Chemistry, UniVersity of Warwick,
CoVentry, CV4 7AL
Received October 28, 2003; E-mail: m.wills@warwick.ac.uk
Scheme 1 a
The use of organometallic complexes as catalysts for the
asymmetric transfer of hydrogen from a suitable donor (usually
2-propanol or formic acid) has been the subject of ongoing research
for some decades.1 However, it is only in recent years that the level
of interest in this area has risen to the extent which now makes it
one of intense international activity. This has been the result of the
introduction, initially by Noyori,2 and later developed by others,3,4
of highly active and enantioselective ruthenium(II)/arene and
rhodium(III)/pentamethylcyclopentadienyl complexes of â-amino
alcohols and monotosylated 1,2-diamines.
We wished to study ruthenium(II) arene catalysts 1 and 2 in
which the amino alcohol or monotosylated diamine, respectively,
is covalently bound to the η6-arene group.5 Given the correct length
a Conditions: (i) HCl, Et2O, room temperature; (ii) RuCl3 hydrate, EtOH,
of tether, such ligands should allow the chiral ligand component
reflux, 21 h, 66% (two steps) for 4, 55% (two steps) for 3; (iii) in situ
during reaction or Et3N, PrOH, reflux, 1 h (preparation of 2), 57%.
to retain the appropriate conformation for enantiocontrol and benefit
from increased stability resulting from attachment to the metal at
three points.6 Furthermore, the “locking” of the aryl group
(otherwise free to rotate) permits control over the spatial positions
of the substituents on this ring.
i
We envisaged that complexes 1 and 2 could be obtained from
the corresponding ruthenium(II) dimers 3 and 4 by reaction with a
base (such as KOH or HCO2H/Et3N), in an intramolecular variation
upon the process normally employed for the in-situ preparation of
similar transfer hydrogenation catalysts during their application to
ketone reduction.
Figure 1. X-ray crystallographic structure of 2.
%) was employed in the reduction of acetophenone 7a in HCO2H/
Et3N and gave a product in >99% yield and 96% ee (R) after 18
h at 28 °C (Table 1). The product configuration matched that which
would be predicted to be formed from the ligand enantiomer
employed, on the basis that the tethering does not alter its mode of
action.10
Although we were unable to isolate crystals of complex 1 from
treatment of 3 with base, we felt that 1 could be formed in situ
under the reaction conditions employed in transfer hydrogenation
when an amino alcohol is the ligand (iPrOH, KOH). In the event,
the addition of 0.25 mol % of 3 (i.e., 0.5 mol % with respect to 1
and Ru) to a 0.1 M solution of 7a followed by 5 mol % of KOH
resulted in reduction to the corresponding alcohol in 96% yield
and 66% ee after 1 h (Table 1). Although modest, the ee obtained
in this reaction represents an improvement on that of 58% ee (86%
yield) reported for the analogous nontethered catalyst derived from
the combination of (1R,2S)-ephedrine and [Ru(benzene)Cl2]2.3h This
suggests that there is potential for improvement through modifica-
tion of the arene in the catalyst.
The reaction of 5‚HCl or 6‚HCl7 with RuCl3 under reflux in
ethanol8 resulted in the formation of the chloro-bridged η6-arene
ruthenium(II) complexes 3 and 4, respectively (Scheme 1). These
1
complexes were characterized by H and 13C NMR. The amine
groups in 5 and 6 needed to be protonated prior to formation of
the dimers.9 The attempted reaction with the free amines resulted
only in formation of complex product mixtures, possibly because
the chelation of ruthenium(III) by the free amine outpaces arene
oxidation, and the resulting complexes were not electronically
disposed toward reduction of the metal.
Treatment of a quantity of 4 with Et3N in refluxing 2-propanol2d
resulted in successful conversion to 2. An X-ray crystal structure
of this material confirmed its tethered structure (Figure 1). The
diamine ligand is coordinated to the metal in a manner similar to
that observed for the nontethered analogues.2b,d Catalyst 2 (0.5 mol
Complex 3 gave a product of similar enantiopurity when used
at a S/C (with respect to Ru) of 1000. A series of further ketones
7-10 were reduced in similar yields and ee’s (Table 1). As
† Asymmetric Catalysis Group.
‡ X-ray Crystallography Unit.
9
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J. AM. CHEM. SOC. 2004, 126, 986-987
10.1021/ja0392768 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Asymmetric Transfer Hydrogenation of Aromatic Ketones
7-10 Catalyzed by Ruthenium(II) Dimer 3, 4, or Complex 2a
same conditions. This eliminates the possibility that the reaction is
catalyzed by a nontethered component in the reaction.
catalyst
ketone
time/h
% yieldb
%ee(R/S)c
In conclusion, we have developed an effective method for the
synthesis of dimers 3 and 4, which act as precursors of tethered-
ligand complexes 1 and 2, respectively. These “one-component”
catalysts form the basis for controlled and selective modification
toward the development of “fine-tuned” catalysts for the reduction
of an extended range of substrates. Studies are currently underway
to define the scope and mechanisms of these reagents, and further
results will be reported in due course.
2
3
7a
7a
7a
7b
7c
7d
8
18
1
7
1
0.5
1
>99
96
83
88
98
71
44
97
>99
>99
>99
98
>99
>99
>99
96d (R)
66d (R)
67d (R)
57d (R)
54d (R)
52d (R)
66f (R)
58f (R)
96d (R)
93d (R)
92d (R)
90d (R)
84f (R)
90f (R)
98f (R)
3 (S/C 1000)
3
3
3
3
3
4
1
1
9
7a
7a
7c
7d
8
21
45
12
44
14
17
18
4 (S/C 1000)e
Acknowledgment. We thank the EPSRC for financial support
of this project. We also acknowledge the use of the EPSRC
Chemical Database Service at Daresbury.12 We thank J. C.
Bickerton of the Warwick MS service and Prof. D. Games and Dr.
B. Stein of the EPSRC MS service for analyses of certain
compounds.
4
4
4
4
4
9
10
a Reaction at 28 °C in a 0.1 M solution of ketone in propan-2-ol, 5 mol
% KOH, and S/C ) 200 (for 3) or at 28 °C with a 2 M solution of ketone
in a formic acid/triethylamine azeotrope mixture and S/C ) 200 (for 2 and
4) unless otherwise specified. b Determined by GC or 1H NMR. c Assigned
by the sign of optical rotation. d Determined by GC analysis using a Beta
DEX 120 capillary column. e Reaction with a 10 M solution of ketone (12
mmol) in a formic acid/triethylamine (2:1) (1.2 mL) and S/C ) 1000. After
12 h, 0.2 mL of formic acid/triethylamine (2:1) was added. f Determined
by HPLC analysis using a Daicel chiralcel OD column.
Supporting Information Available: Experimental procedures,
characterization data, NMR spectra, chiral chromatography analysis of
reduction products, and data of single-crystal X-ray analysis of 2 (PDF
and CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
References
expected, however, attempts to use 3 in formic acid/triethylamine
resulted in failure; no amino alcohol ligand has, to our knowledge,
been successfully employed in this medium for Ru(II)-catalyzed
transfer hydrogenation reactions.
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We also wished to see if the in-situ strategy could be used for
the generation of 2. This would be desirable as it avoids the
requirement to isolate 2. We were pleased to find that the addition
of 0.25 mol % of 4 (0.5 mol % with respect to ruthenium) to a 5:2
(molar) formic acid/triethylamine solution, followed by acetophe-
none 7a, resulted in reduction to the product 1-phenylethanol in
>99 % yield and 96% ee (R) after a reaction time of 21 h at 28 °C
(Table 1). This result was identical to that obtained with the purified
complex 2. The significantly improved result as compared to that
obtained with 3 may reflect to some extent the lack of reversibility
under the formic acid conditions. As in the case of 3, further tests
demonstrated that 4 could be employed at a S/C of 1000 (Table
1). At the 0.5 mol % level of 2 (0.25 mol % of 4), a further series
of ketones were reduced to alcohols in high yield and enantiose-
lectivity (Table 1).
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(5) Strictly, compounds 1 and 2 are catalyst precursors. The true catalytic
species are formed by HCl elimination.
(6) Related complexes with potential for forming a tether have been reported
since the start of this project: (a) Soleimannejad, J.; Sisson, A.; White,
C. Inorg. Chim. Acta 2003, 352, 121. (b) Wendicke, S. B.; Burri, E.
Scopelliti, R.; Severin, K. Organometallics 2003, 22, 1894.
(7) Compounds 5 and 6 were synthesised respectively via the reductive
coupling of 3-(cyclohexa-1,4-dienyl)propanal with (1R,2S) norephedrine
and the reaction of (R,R)-1,2-diphenylethylenediamine and 2-(cyclohexa-
1,4-dienyl)ethanesulfonyl chloride. See Supporting Information.
We anticipated that the stability of 2 would benefit from the
“three-point” ligand attachment to the metal. Some evidence for
the longevity of 2 was obtained in a preliminary study. Specifically,
following a 24 h acetophenone reduction (400 mg of ketone, S/C
) 200), a further portion of acetophenone (400 mg) and fresh formic
acid/triethylamine (1.5 mL) was added to the reaction. After a
further 73 h, full reduction was again observed, without erosion of
ee. This process was repeated again, and full reduction was once
more observed after 176 h. This suggests that 2 remains intact and
active for some significant time after the initial reduction reaction.
Some important control reactions were also carried out: No
reduction was observed using a combination of RuCl3 (0.5 mol %)
and the oxidized version of either 5 or 6 (0.5 mol %)11 under the
(8) Bennett, M. A.; Smith, A. K. J. Chem. Soc., Dalton Trans. 1974, 233.
(9) Miyaki, Y.; Onishi, T.; Kurosawa, H. Inorg. Chim. Acta 2000, 300-302,
369.
(10) A direct comparison with nontethered ligand performance is hampered
by the fact that the reported work (ref 2b) employed a η6-mesitylene rather
than unsubstituted benzene. In this study, a product of 98% ee was obtained
from acetophenone.
(11) The oxidized versions of 5 and 6 were synthesized in a similar manner
using (3-bromo-propyl)benzene and 2-(phenyl)ethanesulfonyl chloride,
respectively.
(12) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf. Comput. Sci.
1996, 36, 746.
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