Asymmetric ketone and imine reductions using
ruthenium catalysts
Jonathan Hopewell, José E. D. Martins and Martin Wills*
Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK
J.P.Hopewell@Warwick.ac.uk
Introduction
• This poster is concerned with the asymmetric reduction of ketones and imines
• Previous work in group has led to success with ruthenium based catalysts 1 and 2 1-5
• It has previously been demonstrated that the Shvo catalyst 3 is an efficient transfer
hydrogenation catalyst 6,7
• It would be of great interest to synthesise and test asymmetric derivatives of the Shvo
catalyst in asymmetric transfer hydrogenation
Ruthenium catalyst synthesis
Hydride synthesis
Complex
R
R’
R’’
7
Ph
TBS
TMS
8
Ph
TBS
TIPS
9
Ph
TBS
Ph
10
Ph
TIPS
TMS
11
Ph
TIPS
Ph
12
Ph
TIPS
TBS
• In order to screen in hydrogenation catalysis, activated
hydride species of complexes 4-11 were synthesised
• The ruthenium hydrides complexes were generated
using NaOH followed by phosphonic acid quench9
• The precatalyst hydrides were observed by the
characteristic signal in their 1H NMR spectrum at between
-9 to -11 ppm9
Crystal structure of symmetric complex 5
Synthesis of complexes 7 - 12 affords a mixture of two products in varying ratios (3:1 to
10:1) depending on the R’ and R’’ groups present. The major product is assumed to be the
isomer with the R group on the furan backbone pointing away from the Ru metal centre.
Hydrogenation of ketones
Hydrogenation of imines
Hydrogenation results
• Catalysts 4 – 11 were screened in asymmetric transfer hydrogenation as well as pressure
hydrogenation of acetophenone
• ATH was achieved using either iPrOH or formic acid/triethylamine azeotrope as the hydrogen
source and solvent at 60°C with 0.5 mol% catalyst loading
• The pressure hydrogenation reductions were carried out using 35 bar H2 gas at 30°C in
toluene over 24 h 5 mol% catalyst loading9
• Conversions and, in the case of the asymmetric catalysts, ees were determined by chiral GC
Hydrogen
source
Catalyst
4
5
6
7
8
9
10
11
iPrOH
Conv. % ee %
7
N/A
72
N/A
26
N/A
31
<2 (R)
14
21 (S)
93
4 (R)
15
10 (R)
76
6 (R)
FA/TEA
Conv.%
53
78
14
11
18
72
12
44
Conclusions
• Designed and tested a range of asymmetric Shvo-type
catalysts
• Good conversions in pressure hydrogenation of
acetophenone
• Variable conversions under transfer hydrogenation
conditions
• The metal hydide of complex 6 showed unusually highfield
signal compared to all the other hydride complexes at -17
ppm
• This is indicative of a bridging hydride complex as observed
in the Shvo catalyst6
• Integration of the hydride signal also indicates a 1:2 ratio of
hydride to ligand as further evidence of a bridging hydride
formation
• Modest ees achieved in both pressure and transfer
hydrogenation
• Complexes also indicate good activities for reductions of imines
• Good general route to the synthesis of a library of a new class
of asymmetric ruthenium complexes
ee %
N/A
N/A
N/A
<2 (R)
20 (S)
6 (R)
12 (R)
8 (R)
H2
Conv. %
92
11
97
10
96
27
94
ee %
N/A
N/A
N/A
17 (S)
5 (R)
10 (R)
8 (R)
• In transfer hydrogenation catalysts 7, 9 and
11 exhibited the highest activities both
systems
• For pressure hydrogenations catalysts 5, 7,
9 and 11 proved the most active.
• For the asymmetric catalysts only 7
exhibited no selectivity with modest ees
being observed for all the other catalysts in
all three hydrogenation methods
• ATH reactions took upwards of 100 h to
near completion
28°C, 22 h, 0.5 mol% catalyst in 5:2 FA/TEA and acetonitrile
Using catalysts 8 and 9 successful asymmetric
reduction of the above cyclic imine was achieved
with moderate yields of >60% and ees similar to
those observed for the reductions of acetophenone
References
1) M. Wills, D. S. Matharu and J. E. D. Martins, Chemistry; An Asian Journal, 2008, 3, 1374-1383
2) J. E. D. Martins, D. J. Morris, B. Tripathi and M. Wills, J. Organomet. Chem., 2008, 693, 3527-3532
3) J. E. D. Martins, G. J. Clarkson and M. Wills, Org. Lett. 2009, 11, 847-850
4) A. M. Hayes, D. J. Morris, G. J. Clarkson and M. Wills, J. Am. Chem. Soc. 2005, 127, 7318-9
5) D. J. Morris, A. M. Hayes and M. Wills, J. Org. Chem., 2006, 71, 7035-7044
6) N. Menashe, E. Salant and Y. Shvo, J. Organomet. Chem., 1996, 514, 97-102
7) B. L. Conley, M. K. Pennington-Boggio, E. Boz and T. J. Williams, Chem. Rev., 2010, 110, 2294–2312
8) Y. Yamamoto, Y. Miyabe and K. Itoh, Eur. J. Inorg. Chem, 2004, 3651-3661
9) Y. Yamamoto, K. Yamashita and M. Nakamura, Organometallics, 2010, 29, 1472-1478
Acknowledgements
I would like to thank EPSRC for their generous
financial support for this project, the University
of Warwick for their excellent facilities, Martin
Wills for excellent guidance and supervision
throughout and, Guy Clarkson for x-ray
crystallography.