Novel Tethered Ru(II) arene/TsDPEN complexes using a
novel and concise ‘arene swapping’ method
A new method for the formation of Ru(II) complexes using a
method in which a [Ru(arene)Cl2]2 complex is converted directly to
a tethered Ru(II) complex in one step by Professor Martin Wills
and his team at the University of Warwick, UK. Advantages
include the synthesis of new catalysts and a concise route with no
need for the use of a cyclohexadiene intermediate or a Birchreduction step.
BACKGROUND
Arene/Ru(II) complexes such as 1 are widely used as
catalysts for asymmetric reductions of ketones and
imines.1 The catalysts typically employ hydrogen gas,
formic acid, sodium acetate or isopropanol as the
reducing agent. The ‘tethered’ complexes such as 2 and 3
exhibit increased reactivity and also catalyse reductions
by the same reducing agents.2,3
The original approach (‘diene intermediate’ method)2a to
2 requires a synthesis of a precursor ligand featuring an
early stage Birch reduction. This creates an intermediate
which is complexed with RuCl3. An improved synthesis of
22d replaces the original reductive amination approach to
the precursor ligand with a direct substitution reaction. A
related synthesis of 3 requires a similar sequence but
avoids the Birch reduction through the use of a
cycloaddition reaction of propiolic acid with isoprene,
however this synthesis requires eight synthetic steps.3a
ligand 6 in chlorobenzene at 90 ºC for 5 h. Novel
electron-rich complexes 4 and 5 can be prepared for the
first time by this method. The conditions for the
substitution have been optimised and protected in a
patent application, WO2013GB52869.
Scheme 1. Synthesis of 2 (n=1), 4 and 5 via direct6-arene
substitution (isolated yields).
Complexes 7-10 were also prepared by this route,
directly from the aromatic precursor ligands; of the
seven complexes, five are novel and have been prepared
for the first time using this method. For the known
complexes 2 (n=1) and 10, the direct approach is shorter
compared to the ‘diene intermediate’ method.
INVENTION
Through the appropriate choice of reaction conditions,
the direct formation of tethered complexes can be
achieved using a method in which the arene on the side
chain of a precursor ligand displaces another 6-arene
ring from the Ru(II) atom. We have found that both
known complex 2 (where n=1) and the new complexes 4
and 5 (Scheme 1) can be formed through direct reaction
of a precursor Ru(II) dimer (a known complex) with
ligands 6 in DCM or chlorobenzene at 90-140 oC. Both
new complexes have been purified and their X-ray
crystallographic structures have been obtained. The
arene-substitution reaction can also be carried out by
directly heating a mixture of the ruthenium dimer and
The novel complexes (4, 5, 7-9) formed in this process
have been shown to be highly active in asymmetric
transfer hydrogenation (ATH; Table 1) and asymmetric
pressure hydrogenation (APH; Table 2) of ketones.
Methoxy-substituted catalysts 4 and 5 are highly robust
and stable and gave particularly good results. The
selected results in the table are for acetophenone
reduction, whilst an extended series of ketones have also
been reduced in high enantioselectivity using low
catalyst loadings under mild conditions (Figure 1).
Table 1: Selected ATH reductions of acetophenone (Formic
acid/triethylamine - FA/TEA used as reductant).
Catalyst
Mol%
T/ºC
t/h Conv./% [a] Ee/%
Catalyst
0.1
60
2
99.8
96.3 (R)
4
1
28
4.5 >99
97.4 (R)
4
0.1
60
4
99.9
88.8 (R)
5
1
28
8
99.1
91.2 (R)
5
1
28
22 99.9
97.4 (R)
7
1
28
94 54.8
87.4 (R)
8
1
28
23 99.9
96.1 (R)
9
Table 2: Selected APH reductions of acetophenone (MeOH, 30
bar H2, 60oC, 0.2 mol% catalyst).
Catalyst
t/h
Conv./%
Ee/%
16
99.9
94.0 (R)
4
16
99.8
83.5 (R)
5
Figure 1: Examples of alcohols formed in other APH
(asymmetric pressure hydrogenation using hydrogen gas) and
ATH (asymmetric transfer hydrogenation using formic
aid/triethylamine) reductions:
BENEFITS OF OUR ‘ARENE SWAPPING’ METHOD
Reactions no longer require:
o the use of a cyclohexadiene intermediate which can
become deactivated due to its oxidation to an
aromatic ring.
o the need for the Birch reduction step which is labour
intensive, time consuming and provides a low yield.
Syntheses of novel electron rich catalysts using our
method which are otherwise highly challenging.
Novel catalysts are produced with
o high reproducibility
o higher stability
o high enantiomeric excess.
Novel catalysts such as the –OMe benefit from improved
compatibility with aqueous systems.
REFERENCES
1.
a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1995, 117, 7562-7563. b) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521-2522. c) Haack, K. J.;
Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem. 1997, 109, 297300; Angew. Chem. Int. Ed. 1997, 36, 285-288. d) Sandoval, C. A.; Ohkuma,
T.; Utsumi, N.; Tsutsumi, K.; Murara, K.; Noyori, R. Chem. Asian. J. 2006, 12, 102-110.
2. a) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc.
2005, 127, 7318–7319. b) Soni, R.; Collinson, J.-M.; Clarkson, G. C.; Wills,
M. Org. Lett. 2011, 13, 4304–4307. c) Cheung, F. K.; Lin, C. Minissi, F.;
Lorente Crivillé, A.; Graham, M. A.; Fox, D. J.; Wills, M. Org. Lett. 2007, 9,
4659-4662. d) Jolley, K. E.; Zanotti-Gerosa, A.; Hancock, F.; Dyke, A.;
Grainger, D. M.; Medlock, J. A.; Nedden, H. G.; Le Paih, J. J. M.; Roseblade,
S. J.; Seger, A.; Sivakumar, V.; Morris, D. J.; Wills, M. Adv. Synth. Catal.
2012, 354, 2545-2555
3.. a) Touge, T.; Hakamata, T.; Nara, H.; Kobayashi, T.; Sayo, N.; Saito, T.;
Kayaki, Y.; Ikariya, T. J. Am. Chem. Soc. 2011, 133, 14960-14963. b) Parekh,
V.; Ramsden. J. A.; Wills, M. Catal.: Sci. Technol. 2012, 2, 406-414
TARGET PARTNERS
The technology is expected to be of interest to companies who
are manufacturing and selling hydrogenation catalysts for
asymmetric reduction reactions.
The new catalysts also work well under aqueous conditions
and full details are given in the patent application. The patent
application also contains details of the synthesis of a number
of catalyst derivatives, including racemic catalysts, and their
applications to reductions. We can send you a small sample of
approx. 100 mg of this p-OMe catalyst to evaluate under a
Material Transfer Agreement.
The novel method reported herein for the synthesis of
6
tethered  arene complexes provides a concise route to
synthetically-valuable tethered Ru(II)/TsDPEN catalysts for
ketone reduction reactions. An advantage of the method is
that an intermediate TsDPEN derivative containing a 1,4- diene
is not required. This reduces the number of synthetic steps
required for the synthesis of the tethered catalysts.
PATENT & PUBLICATION
'Direct Formation of Tethered Ru(II) Catalysts Using Arene
Exchange', Rina Soni, Katherine E Jolley, Guy J. Clarkson and
Martin Wills, Org. Lett. 2013, 15, 5110–5113.
http://pubs.acs.org/doi/pdf/10.1021/ol4024979
‘Catalyst and Process for Synthesising the Same’. International
Patent Application No. PCT/GB2013/052869,
WO2013GB52869. Priority date, 2nd Nov 2012.Publication No.
WO 2014/068331. Publication date, 8th May 2014.
CONTACT
Further information is available on request from:
Dr Shum Prakash, Warwick Ventures Ltd, Tel: +44 (0) 24 7657
4145, or via email: s.prakash@warwick.ac.uk Warwick
Ventures Ltd is the commercial arm of the University of
Warwick.