A class of ruthenium(II) catalyst for asymmetric transfer hydrogenations of ketones

Article abstract of DOI:10.1021/ja051486s

Ruthenium dimer 6 (readily available in two steps from TsDPEN) is converted directly to monomeric asymmetric transfer hydrogenation catalyst 3 in situ under the conditions employed for ketone reduction. Catalyst 3 is a significantly more active catalyst f

Full text of DOI:10.1021/ja051486s

Published on Web 05/03/2005
A Class of Ruthenium(II) Catalyst for Asymmetric Transfer Hydrogenations of
Ketones
Aidan M. Hayes,† David J. Morris,† Guy J. Clarkson,‡ and Martin Wills*,†
Asymmetric Catalysis Group and X-ray Crystallography Unit, Department of Chemistry,
UniVersity of Warwick, CoVentry CV4 7AL, U.K.
Received March 8, 2005; E-mail: m.wills@warwick.ac.uk
Scheme 1 a
Asymmetric transfer hydrogenation (ATH) has recently been the
subject of intense study by a number of groups worldwide.1 The
initial impetus for this was provided by Noyori et al., who reported
highly active and robust Ru(II) catalysts based on complexes of
monotosylated diamines2-4 and amino alcohols5 in the mid-1990s.
Although many new catalysts have been reported for this applica-
tion,6,7 TsDPEN/Ru(II) complexes, such as 1, have proved to be
the catalysts of choice, as reflected by their applications to date.8
The best results with TsDPEN/Ru(II) catalysts have been achieved
in formic acid/triethylamine,2 rather than 2-propanol.3 The former
solvent has the advantage that reactions more readily go to
completion, whereas in 2-propanol, there is an element of revers-
a Conditions: (i) 4A MS, DCM, o/n; (ii) LiAlH4, THF, 2 h, 47%; (iii)
HCl, Et2O, rt, then RuCl3 hydrate, EtOH, reflux, o/n, 89%; (iv) PrOH,
ibility. A limitation of the methodology is that the reactions are
i
not particularly rapid; overnight reaction times are typically
Et3N, 56% or in situ.
required, although reactions in water are reported to be faster.9
As a part of our own program of studies, we recently reported
the synthesis and use of catalyst 2 in which the η6-arene ring and
the diamine ligand are connected through a three-atom tether.7e As
well as increasing the stability of the complex, the tether serves to
prevent the rotation of the arene ring, thus offering the potential
for the addition of functional groups at various positions in a
predictable manner. The opportunity to exploit this for the “fine-
tuning” of the catalyst toward specific substrates remains the subject
of continuing investigations.
Figure 1. X-ray crystallographic structure of (S,S)-3.
in less than 3 h at 28 °C, and the alcohol was formed in 96% ee.
This was a pleasing result since the untethered equivalent complex
requires overnight reaction times for this transformation. The rate
of the reaction could be increased by raising the temperature to 40
°C without any loss of enantiocontrol, while the time for completion
of the reaction was reduced to ca. 100 min. A kinetic plot, obtained
During the course our studies, we found that complex 2, while
1
by following a reduction by H NMR, revealed that the tethered
highly effective at the reduction of acetophenone and other aryl/
compound was significantly more active than the untethered
alkyl ketones, was no faster or no more enantioselective than the
complex formed in situ through the combination of TsDPEN and
untethered system. For example, cyclohexylmethyl ketone was
[Ru(cymene)Cl2]2 (see Supporting Information).
reduced in only 19% ee. In this paper, we report the synthesis and
It was found that it was not necessary to isolate monomer 3; the
applications of the “reverse-tethered” complex 3, which has proven
direct use of 6 at 40 °C resulted in full acetophenone reduction
to be significantly more active and versatile.
Complex 3 was prepared by reductive amination of TsDPEN 4
within 3 h in 96% ee. In this experiment, 6 was heated in the formic
acid/triethylamine for 30 min prior to addition of ketone. However,
with the known aldehyde 77e to furnish 5, which was reacted, as
if 6 was treated for 3.5 h at 40 °C before the addition of ketone,
the hydrochloride salt, with ruthenium trichloride to give dimer 6
(Scheme 1). Upon treatment with triethylamine in IPA,4 6 was
converted to 3, which was characterized by X-ray crystallography
then the reduction took place as rapidly as with 3 alone, reflecting
the complete prior conversion of dimer to monomer. In view of
these results, dimer 6 was used as catalyst in most subsequent
(Figure 1) after purification by chromatography on silica gel.
investigations (Table 1).
Although both antipodes of 6 were prepared, only (S,S)-6 was
converted to 3 for isolation and characterization.
Complex 3 proved to be a very active catalyst for ATH. The
Decreasing the catalyst loading to 0.1 mol % increased the time
for complete reaction using 3 (40 °C) to 5 h but with no loss of
enantioselectivity. At 80 °C, the reaction time was reduced to 20
reduction of acetophenone 8 was completed using 0.5 mol % of 3
min with a loss of enantiomeric excess of only 2%. Catalyst 3 was
active and equally enantioselective at a loading as low as 0.01 mol
%, which is unprecedented for this class of ATH catalyst. The
† Asymmetric Catalysis Group.
‡ X-ray Crystallography Unit.
9
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J. AM. CHEM. SOC. 2005, 127, 7318-7319
10.1021/ja051486s CCC: $30.25 © 2005 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
8-13 Catalyzed by Ruthenium(II) Dimer 6 or Monomer 3a
loading
(mol %)
T
t
%ee
catalyst
(
°
C)
ketone
(h)
% conv.
(R/S)
(S,S)-3
(S,S)-3
(R,R)-6
(R,R)-6
(S,S)-3
(S,S)-3
(S,S)-3
(R,R)-6
(R,R)-6
(R,R)-6
(R,R)-6
(R,R)-6
(R,R)-6
0.5
0.5
0.5
0.5
0.1
0.01
0.1
0.1
0.5
0.5
0.5
0.5
0.5
28
40
40
40
40
40
80
40
40
40
40
40
28
8
8
8
8
8
8
8
8
9
10
11
12
13
3
2
3
2
5
100
100
100
100
100
98
96 (S)
96 (S)
96 (R)
96 (R)
96 (S)
96 (S)
94 (S)
96 (R)
94 (R)
95 (R)
77 (R)
94 (R)
69 (S)
added to a triethylamine/formic acid mixture prior to addition of
ketone. The ligand/metal stoichiometry is effectively “built-in” to
the catalyst design. The reduction rates exceed those reported for
the untethered complexes, and the catalyst is effective at loadings
of as low as 0.01 mol %. The reduction enantioselectivity is, in
most cases, superior to that in other ATH catalysts.
79
0.33
99
12
3
24
32
24
24
100
100
92
95
90
Acknowledgment. We thank the EPSRC and Warwick Uni-
versity (research fellowship to A.M.H.) for financial support of this
project.
100
a Reaction at 28 °C in a 2 M solution of ketone in a formic acid/
triethylamine (5:2) azeotrope mixture, and S/C ) 200 unless otherwise
specified.
Supporting Information Available: Experimental procedures,
characterization data, NMR spectra, chiral chromatography analysis of
reduction products, and data of single-crystal X-ray analysis of 3. This
material is free of charge via the Internet at http://pubs.acs.org.
longevity of catalyst 3 was also demonstrated by an experiment in
which further portions of acetophenone were repeatedly added to the
reaction mixture (together with additional formic acid) after the
reduction had gone to completion. After each addition, the catalyst
continued to be effective in achieving full reduction without loss of
enantioselectivity, over seven cycles (see Supporting Information).
A further series of ketones were reduced using 3 and 6 (Table
1). Studies focused on the variation of the alkyl group in the series
8-12, while the alkyl/alkyl ketone 13 represents a substrate which
does not usually work very well with this class of catalyst. In the
event, all ketones proved to be compatible substrates, although the
best results were at 40 °C. At this temperature, ketones 9, 10, and
12 were reduced in excellent enantioselectivity, while the enantio-
meric excess for 11 was lower. These results compare favorably
with other ATH catalysts employed for these substrates.1b,6b,c Using
the untethered 1, 10 is reported to be reduced in just 41% yield
(83% ee), and 11 is not reduced to any measurable extent.2b
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Ketone 13 was reduced in 69% ee, which is the best result for
any TsDPEN-related transfer hydrogenation catalyst.5,10 Ketones
8-12 were all reduced to the R enantiomer using R,R-catalyst,
which represents the same configuration with respect to the position
of the aromatic ring, while 13 gave the S product using the R,R-
catalyst, indicating hydride delivery from the opposite face. These
results suggest that 3 reduces aryl/alkyl ketones through a transition
state in which a stabilizing π-aryl-arene interaction ensures a high
enantiomeric excess.2,3 The reversed selectivity for 13 suggests that
when this interaction is not available, the transition state has the
larger ketone substituent facing away from the arene ring. We have
obtained direct evidence (1H NMR) for the formation of both the
16-electron Ru(II) and the Ru-H intermediates involved in this
reaction mechanism (see Supporting Information).
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tether is not fully clear. However, it is not merely the effect of a
secondary amine over a primary; a nontethered complex formed
from N-benzyl-N′-tosyl-DPEN 14 was totally ineffective as a
catalyst.11 This confirms that the fixed positioning of the tether is
important to its activity.
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The catalyst is exceptionally practical and easy to prepare and
use as it is a single-component catalyst which merely has to be
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