Asymmetric hydrogenation of ketones using a ruthenium(II) catalyst containing BINOL-derived monodonor phosphorus-donor ligands

Article abstract of DOI:10.1021/ol0481840

(Chemical Equation Presented) A series of ruthenium(II) complexes containing BINOL-based monodonor phosphorus ligands have been prepared and applied to the asymmetric catalysis of the hydrogenation of aryl/alkyl ketones. The best ligands for this application are those which contain an aromatic groups with either a methoxide or bromide on the ortho position. Using these ligands, alcohols with ee's of up to 99% are formed.

Full text of DOI:10.1021/ol0481840

ORGANIC
LETTERS
2004
Vol. 6, No. 22
4105-4107
Asymmetric Hydrogenation of Ketones
Using a Ruthenium(II) Catalyst
Containing BINOL-Derived Monodonor
Phosphorus-Donor Ligands
Yingjian Xu,† Nat W. Alcock,† Guy J. Clarkson,† Gordon Docherty,‡
Gary Woodward,‡ and Martin Wills*,†
Department of Chemistry, UniVersity of Warwick, CoVentry CV4 7AL, U.K.,
Rhodia Consumer Specialities Limited, P.O. Box 80, Trinity Street,
Oldbury, West Midlands B69 4L, U.K.
m.wills@warwick.ac.uk
Received September 8, 2004
ABSTRACT
A series of ruthenium(II) complexes containing BINOL-based monodonor phosphorus ligands have been prepared and applied to the asymmetric
catalysis of the hydrogenation of aryl/alkyl ketones. The best ligands for this application are those which contain an aromatic groups with
either a methoxide or bromide on the ortho position. Using these ligands, alcohols with ee’s of up to 99% are formed.
The asymmetric reduction of ketones remains a pivotal
method for the formation of enantiomerically pure alcohols.1
Catalytic methods include transfer hydrogenation with Ru(II)
and Rh(III) complexes2 and pressure hydrogenation using
organometallic complexes of Ru(II) and other metals.3 Until
recently, the latter process could only be successfully applied
to substrates containing a nearby coordinating group.4 How-
ever, a number of researchers5 have now introduced hydro-
genation systems that are capable of the highly enantio-
selective reduction of unfunctionalized ketones.6,7 Perhaps
the most notable of these is the Ru(II) system 1 reported by
(4) Asymmetric Catalysis in Organic Synthesis; Noyori, R., Ed.; J. Wiley
and Sons: New York, 1993; Chapter 2.
(5) (a) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 41. (b)
Ohkuma, T.; Koizumi, M.; Muniz, K.; Hilt, G.; Kabuto, C.; Noyori, R. J.
Am. Chem. Soc. 2002, 124, 6508. (b) Doucet, H.; Ohkuma, T.; Murata, K.;
Yokozawa, T.; Kozawa, M.; Katayama, E.; England, A. F.; Ikariya, T.;
Noyori, R. Angew. Chem., Int. Ed. 1998, 37, 1703. (c) Ohkuma, T.; Ishii,
D.; Takeno, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 6510.
(6) (a) Chen, C.-Y.; Reamer, R. A.; Chilenski, J. R.; McWilliams, C. J.
Org. Lett. 2003, 5, 5039. (b) Cobley, C. J.; Foucher, E.; Lecouve, J.-P.;
Lennon, I. C.; Ramsden, J. A.; Thominot, G. Tetrahedron: Asymmetry 2003,
14, 3431. (c) Li, X.; Chen, W.; Hems, W.; King, F.; Xiao, J. Org. Lett.
2003, 5, 4559. (d) Xie, J.-H.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Fan, B.-M.;
Duan, H.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2003, 125, 4404. (e) Henschke,
J. P.; Zanotti-Gerosa, A.; Moran, P.; Harrison, P.; Mullen, B.; Casy, G.;
Lennon, I. C. Tetrahedron Lett. 2003, 44, 4379. (f) Hartmann, R.; Chen, P.
Angew. Chem., Int. Ed. 2001, 40, 3581. (g) Hu, A.; Ngo, H. L.; Lin, W. J.
Am. Chem. Soc. 2003, 125, 11490.
† University of Warwick.
‡ Rhodia Consumer Specialities Limited.
(1) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999.
(2) (a) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045.
(b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
(3) (a) Dang, T. P.; Kagan, H. B. Chem. Commun. 1971, 481. (b)
Vineyard, D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.; Weinkauf,
D. J. J. Am. Chem. Soc. 1977, 99, 5946. (c) Miyashita, A.; Yasuda, A.;
Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. J. Am. Chem. Soc.
1980, 102, 7932. (d) Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518.
10.1021/ol0481840 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/06/2004

Noyori, which contains both a diphosphine and a diamine
(typically DPEN) which cooperatively interact in an ex-
tremely active and enantioselective reduction catalyst.5 This
system works successfully for simple aryl/alkyl ketones,
heterocyclic ketones, and enones. Many variants of this
successful Ru(II)/diphosphine/diamine combination have
been reported.6
prepared by the reaction between S-BINOL and the ap-
propriate bis(dimethylamino)phosphine precursors.
Each ligand was converted to the [L2RuCl2(DPEN)]
complex by reaction with [RuCl2(benzene)]2 followed by
(S,S)-DPEN. The complexes were yellow-brown solids and,
in their solid forms, stable to air and moisture. The structures
of the complexes were confirmed by spectroscopic methods
and by high-resolution mass spectrometry. An X-ray crystal
structure of one of the complexes, that derived from S-8,
was also obtained (Figure 1).
A second significant development in asymmetric hydro-
genation has been the introduction of monodonor chiral
ligands, usually based on the BINOL backbone.8 An example
is Feringa’s MONOPHOS 2.8-10 Rhodium complexes of 2,
typically containing two ligands per metal atom, are capable
of the asymmetric reduction of CdC bonds in outstanding
enantioselectivities. Best results are obtained with substrates
containing coordinating functions, such as R-acylamino-
acrylates and unsaturated carboxylic acids.1,4 Given the
excellent results obtained with BINOL-derived monodonor
phosphorus ligands, we wished to establish whether such
ligands could also replace diphosphines such as BINAP in
1. If so, then this would have a significant advantage in terms
of practicality, since the monodonor ligands are less expen-
sive and more readily available than most chiral bidentate
ligands. Toward this end, we prepared a series of BINOL-
derived ligands. In addition to phosphoramidite 2,8 we
prepared the known phosphite 3 and phosphonite 4.9,10 We
also prepared a series of ligands 5-9 containing a substituted
aromatic ring attached to the P atom. Ligands 5 and 7 have
been reported previously;9a,d,e,11 however, ligands 6, 8, and
9 are, to the best of our knowledge, new. The ligands were
Figure 1. X-ray crystallographic structure of the (S,S,SS)-Ru(II)‚
DPEN complex derived from 8.
An investigation into the applications of the new com-
plexes to the asymmetric hydrogenation of simple ketones
was undertaken (Scheme 1). In the first stage of the study,
Scheme 1
the (S,S,SS) complex derived from ligand 8 (‘BrXuPHOS’)12
was selected for a short statistical experimental design study
(MODDE 6).13,14 A total of 17 experiments were carried out
with variation of the substrate concentration, mol % of base,
and the temperature. The substrate was acetophenone, S/C
(7) (a) Jiang, Q.; Jiang, Y.; Xiao, D.; Cao, P.; Zhang, X. Angew. Chem.,
Int. Ed. 1998, 37, 1100.
(8) (a) Pena, D.; Minaard, A. J.; de Vries, A. H. M.; Feringa, B. L. Org.
Lett. 2003, 5, 475. (b) Pena, D.; Minnaard, A. J.; de Vries, J. G.; Feringa,
B. L. J. Am. Chem. Soc. 2002, 124, 14552. (c) Pena, D.; Minnaard, A. J.;
Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Org.
Biomol. Chem. 2003, 1087.
(9) (a) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.;
Martorelli, A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961.
(b) Reetz, M. T.; Goossen, L. J.; Meiswinkel, A.; Paetzold, J.; Feldthusen
Jensen, J. Org. Lett. 2003, 5, 3099. (c) Reetz, M. T.; Mehler, G. Tetrahedron
Lett. 2003, 44, 4593. (d) Reetz, M. T.; Sell, T. Tetrahedron Lett. 2000, 41,
6333.
(10) (a) Jia, X.; Li, X.; Shi, Q.; Yao, X.; Chan, A. S. C. J. Org. Chem.
2003, 68, 539-41. (b) Hannen, P.; Militzer, H.-C.; Vogl, E. M.; Rampf, F.
A. Chem. Commun. 2003, 2210. (c) Zhu, S.-F.; Fu, Y.; Xie, J.-H.; Liu, B.;
Xing, L.; Zhou, Q.-L. Tetrahedron Lett. 2003, 14, 3219. (d) Gergely, I.;
Hegedus, C.; Gulyas, H.; Szollosy, A.; Monsees, A.; Riermeier, T.; Bakos,
J. Tetrahedron: Asymmetry 2003, 14, 1087. (e) Huang, H.; Zheng, Z.; Luo,
H.; Bai, C.; Hu, X.; Chen, H. Org. Lett. 2003, 5, 4137. (f) Reetz, M. T.;
Mehler, G.; Meiswinkel, A.; Sell, T. Tetrahedron Lett. 2002, 43, 7941.
(11) (a) Martorell, A.; Naasz, R.; Feringa, B. L.; Pringle, P. G.
Tetrahedron: Asymmetry 2001, 12, 2497. (b) Tillack, A.; Selke, R.; Fischer,
C.; Bilda, D.; Kortus, K. J. Organomet. Chem. 1996, 518, 79.
(12) The suggested trivial name for this ligand acknowledges the first
researcher in the group to prepare and use it.
(13) The (S,S,SS) complex contains the matched combination of con-
figurations. The corresponding complex of (S,S,RR) configuration gave a
lower, reversed configuration of acetophenone reduction product (ca. 33%
ee S).
(14) The MODDE optimised conditions for 8 may not correspond to
those for other ligands.
(15) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf. Comput.
Sci. 1996, 36, 746.
4106
Org. Lett., Vol. 6, No. 22, 2004

) 5000, solvent 2-propanol, run time ) 20 h, and hydrogen
pressure )10 bar. This, followed by a series of more focused
studies, revealed that the best conditions with respect to ee
were [ketone] ) 0.3 M, 1 mol % base (with respect to
substrate), and a temperature of 20 °C. Under these condi-
tions, a product of 85% ee (R) was formed in 56% conversion
after 40 h. Lowering the S/C to 2000 gave a 72% conversion
in 86% ee after the same time (Table 1, entry 1). At S/C
1000 the conversion was complete in 15 h and the ee was
84% (entry 2).
of 10 000 with the same ee but only 80% conversion over
26 h. A series of further ketones were reduced using the
complex from 8, under standard conditions (Table 1, entries
12-20). In all but two cases the reactions were essentially
complete after 20 h at 10 bar, and the ee’s generally high
and in some cases better than that for acetophenone. The
complex derived from 7 was also applied to three further
ketones, giving enantioselectivities between 88% and 94%
(entries 21-23).
A further improvement could be achieved at 0 °C. A higher
pressure (50 bar) was required to counteract the rate
reduction; however, products were obtained in up to 99%
ee (Table 2).
Table 1. Asymmetric Hydrogenation of Ketones by
Ruthenium(II) Complexes of Ligands 2-9a
[ketone] pressure convb
eec
Table 2. Asymmetric Hydrogenation of Ketones at 0 °C
ligand
Ar
S/C
(M)
(bar)
(%)
(%)
time
(h)
convb
(%)
eec
1e
2h
3d
4
8
8
2
3
4
5
6
7
9
8
8
8
8
8
8
8
8
8
8
8
7
7
7
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2000
1000
1000
1000
1000
1000
1000
1000
1000
2000
10000
2000
2000
2000
2000
2000
2000
2000
2000
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0.15
0.30
0.15
0.15
0.15
0.15
0.15
0.30
0.30
0.15
0.15
0.15
10
10
10
10
10
10
10
10
10
50
50
10
10
10
10
10
10
10
10
10
20
20
20
72 86 (R)
99 84 (R)
100 54 (R)
11 43 (R)
entry
ligand
Ar
C6H5
1′-naphthyl
o-BrC6H4
S/C
(%)
1
2
3
8
8
8
2000
2000
2000
4
8
8
95
92
93
93 (R)
99 (R)
99 (R)
5
2
7
5
17 (R)
37 (R)
35 (R)
6
a Reactions were conducted in 2-propanol, 0.5 mol % t-BuOK, and S/C
) 2000 (autoclave placed in the ice bath) at 50 bar pressure with a 0.15 M
solution of ketone. b Determined by GC or 1H NMR. c ee’s were determined
by chiral GC or HPLC.
7
8e
100 88 (R)
0
9
10f
11g
12
13
14e
15
16
17
18
19
20
21
22
23
100 90 (R)
80 90 (R)
100 75 (R)
100 80 (R)
100 91 (R)
100 86 (R)
97 96 (R)
99 85 (R)
93 94 (R)
98 94 (R)
100 85 (R)
100 94 (R)
100 88 (R)
100 89 (R)
The reason for the high stereocontrol by ligands containing
a modestly sized ortho substitutent is at present unclear.
However, the X-ray structure reveals a tightly packed
conformation of two ligands in a cis position. It is possible
that the ortho substituent, which points away from the
BINOL, is required to provide a “lock” into the structure
which prevents ligand rotation and hence enforces a well-
defined steric environment on the reaction. In conclusion,
we have demonstrated that it is possible to use monodonor,
BINOL-derived, ligands in Ru(II) complexes for asymmetric
ketone hydrogenation. The ligand has an unexpected struc-
tural requirement for optimal results.
p-CF3C6H4
p-BrC6H4
o-BrC6H4
m-CH3C6H4
p-CH3C6H4
2′-naphthyl
1′-naphthyl
p-FC6H4
p-OCH3C6H4 2000
p-CH3C6H4
1′-naphthyl
p-FC6H4
1000
1000
1000
a Reactions were conducted at 20-22 °C in 2-propanol for 20 h, 10
equiv of base wrt catalyst. b Determined by GC or 1H NMR. c The eee’s
were determined by chiral GC or HPLC. The absolute configuration was
determined by comparison of the sign of optical rotation or retention time
with literature data. d Reaction time: 96 h. e Reaction time: 40 h. f Reaction
time: <4 h. g Reaction time: 26 h. h Reaction time: 15 h.
Acknowledgment. We thank Rhodia and ORS for
financial support of this project (to Y.X.) We acknowledge
the use of the EPSRC Chemical Database Service at
Daresbury15 and 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. We also
acknowledge the generous loan of ruthenium salts by
Johnson-Matthey Ltd.
Following these encouraging studies, a series of further
investigations were completed using the other catalysts.
Ligand 2, excellent for CdC hydrogenation, gave a product
in full conversion but only 54% ee. Phosphite ligand 3 and
phosphonite 4 gave products in low conversion and moderate/
low ee. Complexes derived from 5 and 6 were also poor;
however, the result obtained from the complex derived from
7 (entry 8) was comparable to that obtained using 8, while
that using 9 was again poor.
Supporting Information Available: Experimental pro-
cedures, characterization data, NMR spectra, chiral chroma-
tography analysis of reduction products, and results of the
single-crystal X-ray analysis of the catalyst derived from 8.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Using ligand 8 at 50 bar and S/C of 2000, acetophenone
was fully reduced with 90% ee in less than 4 h and at a S/C
OL0481840
Org. Lett., Vol. 6, No. 22, 2004
4107