A stereochemically well-defined rhodium(III) catalyst for asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1021/ol052559f

(Chemical Equation Presented) A rhodium(III) catalyst for asymmetric transfer hydrogenation of ketones has been designed. The incorporation of a tethering group between the diamino group and the cyclopentadienyl unit provides extra stereochemical rigidity. The catalyst is capable of enantioselective reduction of a range of ketones in excellent ee using formic acid/triethylamine as both the solvent and the reducing agent.

Full text of DOI:10.1021/ol052559f

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5489-5491
A Stereochemically Well-Defined
Rhodium(III) Catalyst for Asymmetric
Transfer Hydrogenation of Ketones
Daljit S. Matharu,† David J. Morris,† Aparecida M. Kawamoto,†
Guy J. Clarkson,‡ and Martin Wills*,†
Asymmetric Catalysis Group, Department of Chemistry, UniVersity of Warwick,
CoVentry CV4 7AL, U.K., and X-ray Crystallography Unit, Department of Chemistry,
UniVersity of Warwick, CoVentry CV4 7AL, U.K.
m.wills@warwick.ac.uk
Received October 21, 2005
ABSTRACT
A rhodium(III) catalyst for asymmetric transfer hydrogenation of ketones has been designed. The incorporation of a tethering group between
the diamino group and the cyclopentadienyl unit provides extra stereochemical rigidity. The catalyst is capable of enantioselective reduction
of a range of ketones in excellent ee using formic acid/triethylamine as both the solvent and the reducing agent.
The use of asymmetric transfer hydrogenation (ATH) for
the synthesis of enantiomerically enriched alcohols has
recently been developed into a practical and versatile tool
for synthetic chemistry.1 The majority of the developments
in this area have been concerned with the use of catalysts
such as 1, based on Ru(II), which give excellent enantiose-
lectivities. This class of catalyst, which contains the mono-
tosylated diamine ligand TsDPEN 2, was first introduced
by Noyori2 and has enjoyed extensive synthetic application.3
In contrast, the corresponding Rh(III) catalysts such as 3 have
a lower profile. These have been applied to ketone4-6 and
imine7 reductions and are marketed as CATHy catalysts by
Avecia.8 Although less widely reported, they have some
advantages over the Ru(II) catalysts, for example, improved
selectivity in the reduction of R-chloro ketones.
In recent years, we have reported upon the synthesis and
applications of a number of modified Ru(II) catalysts for
(3) (a) Okano, K.; Murata, K.; Ikariya, T. Tetrahedron Lett. 2000, 41,
9277. (b) Li, M.; Scott, J.; O’Doherty, G. A. Tetrahedron Lett. 2004, 45,
1005. (c) Marshall, J. A.; Ellis, K. Tetrahedron Lett. 2004, 45, 1351. (d)
Lennon, I. C.; Ramsden, J. A. Org. Proc. Res. DeV. 2005, 9, 110. (e)
Watanabe, M.; Murata, K.; Lkariya, T. J. Org. Chem. 2002, 67, 1712. (f)
Yamashita, H.; Ohtani, T.; Morita, S.; Otsubo, K.; Kan, K.; Matsubara, J.;
Kitano, K.; Kawano, Y.; Uchida, M.; Tabusa, F. Heterocycles 2002, 56,
123.
(4) (a) Mashima, K.; Abe, T.; Tani, K. Chem. Lett. 1998, 1199. (b)
Murata, K.; Ikariya, T.; Noyori, R. J. Org. Chem. 1999, 64, 2186. (c)
Mashima, K.; Abe, T.; Tani, K. Chem. Lett. 1998, 1201.
(5) (a) Cross, D. J.; Kenny, J. A.; Houson, I.; Campbell, L.; Walsgrove,
T.; Wills, M. Tetrahedron: Asymmetry 2001, 12, 1801. (b) Hamada, T.;
Torii, T.; Izawa, K.; Noyori, R.; Ikariya, T. Org. Lett. 2002, 4, 4373. (c)
Hamada, T.; Torii, T.; Izawa, K.; Ikariya, T. Tetrahedron 2004, 60, 7411.
(d) Hamada, T.; Torii, T.; Onishi, T.; Izawa, K.; Ikariya, T. J. Org. Chem.
2004, 69, 7391.
† Asymmetric Catalysis Group.
‡ X-ray Crystallography Unit.
(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.
(2) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 2521. (b) 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.
(6) (a) Polborn, K.; Severin, K. Eur. J. Org. Chem. 2000, 1687. (b)
Thorpe, T.; Blacker, J.; Brown, S, M.; Bubert, C.; Crosby, J.; Fitzjohn, S.;
Muxworthy, J. P.; Williams, J. M. J. Tetrahedron Lett. 2001, 42, 4041. (c)
Sterk, D.; Stephan, M. S.; Mohar, B. Tetrahedron: Asymmetry 2002, 13,
2605. (d) Wu, X.; Vinci, D.; Ikariya, T.; Xiao, J. Chem. Commun. 2005,
4447.
10.1021/ol052559f CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/02/2005

Scheme 1
ATH which contain a tethering group between the chiral
ligand component and the η6-arene ring.9 Tethered complex
4, for example, reduces ketones more rapidly than the
untethered 1. In addition, certain substrates can be reduced
in much improved yield and enantioselectivity.5
In view of the promising results obtained using complex
4, we thought that a tethered version of the Rh(III) catalyst
3 would be a valuable material for study. We have already
reported the synthesis and use of the tethered amino alcohol/
Rh(III) catalyst 5; however, this proved to be unstable under
the reduction conditions used.10 In contrast, catalysts contain-
ing TsDPEN 2 have generally proved to be significantly more
stable than those containing amino alcohols, and are therefore
much more useful catalysts. Furthermore, and in contrast to
Ru(II) and Rh(III) complexes of amino alcohol ligands, the
TsDPEN 2 complexes are stable to the preferred formic acid/
triethylamine (FA/TEA) solvent system. The use of FA/TEA
significantly reduces the possibility of any significant erosion
in ee due to reversibility, which is often a problem in the
2-propanol/KOH (IPA) solvent system. Our target catalyst
in this project was 6, which represents a Rh(III) analogue
of 4.
formation of one isomer, the relative configuration of which
was confirmed by X-ray crystallography (Figure 1). The
Figure 1. X-ray crystallographic structure of RR-6.
After some investigations, we were able to establish a
successful approach to the synthesis of 6 through the route
illustrated in Scheme 1. Pivotal to this approach was the
lithium/bromine exchange reaction of 7 followed by addition
of cyclopentenone 8 to give the tertiary alcohol 9.10 Depro-
tection of the acetal in 9 was followed by reductive amination
with TsDPEN 2 to furnish 10 in 40% yield.
major diastereoisomer matches that reported for closely
related (i.e., untethered) complexes containing TsDPEN 2
as a ligand.4,6a
Catalyst 6 proved to be a very effective catalyst for ATH
of ketones and demonstrated improved activity over 3
(Scheme 2, Table 1). In our investigations, we chose to focus
1
Intermediate 10 had a very complex H NMR spectrum,
due to the mixture of isomers of the cyclopentadiene
component. Upon treatment of 10 with 1 equiv of RhCl3
and base, the stable complex 6 was formed which, after
purification by flash chromatography and recrystallization,
was isolated as a single diastereisomer. In contrast to 10,
Scheme 2
1
the H NMR of 6 was very clean and clearly indicated the
(7) (a) Mao, J.; Baker, D. C. Org. Lett. 1999, 1, 841.
(8) (a) Blacker, J.; Martin, J. Scale-up studies in Asymmetric Transfer
Hydrogenation. In Asymmetric Catalysis on an Industrial Scale: Challenges,
Approaches and Solutions; Blaser, H. U., Schmidt, E., Eds.; Wiley: New
York, 2004; pp 201-216. (b) Sun, X.; Manos, G.; Blacker, J.; Martin, J.;
Gavriilidis, A. Org. Proc. Res. DeV. 2004, 8, 909.
our studies on the use of the FA/TEA solvent system. In the
reduction of acetophenone, for example, it was possible to
achieve full reduction in this medium at room temperature
to give a product in 98% ee (R). Although the reaction time
was long, this represents the first report, to our knowledge,
of the reduction of acetophenone using a Rh(III)/TsDPEN-
type catalyst in FA/TEA; most literature reports describe the
use of the IPA system.4,6,8 In contrast, more reactive ketones,
(9) (a) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am.
Chem. Soc. 2005, 127, 7318. (b) Hannedouche, J.; Clarkson, G. J.; Wills,
M. J. Am. Chem. Soc. 2004, 126, 986.
(10) Cross, D. J.; Houson, I.; Kawamoto, A. M.; Wills, M. Tetrahedron
Lett. 2004, 45, 843.
5490
Org. Lett., Vol. 7, No. 24, 2005

reduce R-chloro ketones with both high activity and in high
ee. For example, complex 3 gives a product of R-chloro-
acetophenone reduction in 99% yield and 97% ee after 1 h,
whereas the Ru(II) complex 1 completes this reduction in
only 36% yield and 91% ee after 24 h (FA/TEA system).5b,c
Complex 6 was highly competent at this reduction and
furnished the reduction product in 99.6% ee (as determined
by chiral HPLC) after 2 h at room temperature. The addition
of some ethyl acetate cosolvent proved beneficial to this
application (see the Supporting Information). The reductions
of R-hydroxy- and R-phenoxyacetophenones also proved
highly enantioselective; products of 99% and 98% ee were
formed in quantitative yield.
The reduction of acetophenone was also carried out in the
IPA system (0.5 mol % catalyst loading). After 2 h at room
temperature, the reaction was 30% complete and the ee 98%.
After an 18 h reaction time, the conversion had reached 74%
and the ee was 97%. Although the ee was competitive with
the result from the FA/TEA system, the conversions were
not, and there was some evidence of deterioration in the ee
due to the reversibility of the reaction.
In conclusion, it has been demonstrated that the introduc-
tion of a tether into an ATH catalyst brings significant
benefits to its performance in reduction reactions. The reasons
for the dramatic improvement in catalyst performance and
enantioselectivity are not clear. One possibility is that the
tether introduces a further element of stereochemical rigidity
to the catalysts. Alternatively, the preorganized structures
may benefit from a steric or electronic modification which
optimizes the selectivity. We are currently investigating the
scope and mechanism of this catalyst.
Table 1. Asymmetric Transfer Hydrogenation of Aromatic
Ketones Catalyzed by Rhodium Catalyst 6a
ketone
t (h)
% conv
ee (%) (R/S)
X
Y
H
p-Cl
m-Cl
o-Cl
p-CF3
m-CF3
o-CF3
p-(MeO)
m-(MeO)
o-(MeO)
1-naphthyl
2-naphthyl
H
H
H
H
H
H
H
H
H
H
H
H
10
9
8
28
7
8
24
30
30
48
8
10
9
2
100
99
98 R
95 R
96 R
77 R
96 R
96 R
17 R
97 R
97 R
90 R
80 R
95 R
99.9 R
99.6 S
99 S
98 S
100
100
100
100
33
96
93
93
35
100
100
100
100
100
tetralone
H
H
H
Clb,c
OH
OPh
5c
3
a Reaction at 25 °C in a 2 M solution of ketone in a formic acid/
triethylamine (5:2) azeotrope mixture and S/C ) 200 unless otherwise
specified. b EtOAc cosolvent added. c 0.1 mol % of catalyst used.
such as R-chloroacetophenone5 and p-fluoroacetophenone,8
have been reduced by 3 in the FA/TEA system.
A further series of ketones were reduced to the alcohols
using catalyst 6 (Table 1). In most cases, the products were
obtained in high conversions and excellent ee. R-Tetralone
proved to be an excellent substrate and gave a product in
99.9% ee, as measured by chiral HPLC against a racemic
sample. This represents one of the highest reported enan-
tioselectivities for this substrate using any reduction method,
and an improvement upon nontethered systems. In two
reports involving the use of the Rh(III) complexes of
N-tosylated cyclohexyl-1,2-diamine, tetralone reduction prod-
ucts of 95% ee (53% conversion after 24 h) and 97% ee
(79% yield after 48 h) have been reported to be formed, both
with the IPA system.4 Tetralone can be reduced in an ee of
97% (95% yield) using a Rh(III) catalyst related to 3 but
containing cis-aminoindanol as ligand, again in the IPA
solvent system. 8a
Acknowledgment. We thank the EPSRC (Doctoral
Training Account funding to D.S.M. and postdoctoral support
to D.J.M.) for financial support of this project. We acknowl-
edge the generous loan of rhodium salts by Johnson-Matthey
Ltd. and the use of the EPSRC Chemical Database Service
at Daresbury.11
Supporting Information Available: Experimental pro-
cedures, characterization data, NMR spectra, chiral chroma-
tography analysis of reduction products, and data of single-
crystal X-ray analysis of 6. This material is available free
of charge via the Internet at http://pubs.acs.org.
Substitution of the aromatic ring in the ketones did not
have a detrimental effect on the selectivity of the reduction
unless the substituent was in the ortho position, in which
case the enantioselectivity dropped sharply. It is assumed
that this is due to an undesirable steric clash.
OL052559F
One of the strengths of the Rh(III)/TsDPEN complexes
over the corresponding Ru(II) versions is their ability to
(11) Fletcher, D. A.; McMeeking; R. F.; Parkin, D. J. Chem. Inf. Comput.
Sci. 1996, 36, 746.
Org. Lett., Vol. 7, No. 24, 2005
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