Direct formation of tethered Ru(II) catalysts using arene exchange

Article abstract of DOI:10.1021/ol4024979

An 'arene exchange' approach has been successfully applied for the first time to the synthesis of Ru(II)-based 'tethered' reduction catalysts directly from their ligands in one step. This provides an alternative method for the formation of known complexes, and a route to a series of novel complexes. The novel complexes are highly active in both asymmetric transfer and pressure hydrogenation of ketones.

Full text of DOI:10.1021/ol4024979

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Direct Formation of Tethered Ru(II)
Catalysts Using Arene Exchange
Rina Soni, Katherine E. Jolley, Guy J. Clarkson, and Martin Wills*
Department of Chemistry, The University of Warwick, Coventry, CV4 7AL, U.K.
m.wills@warwick.ac.uk
Received August 30, 2013
ABSTRACT
An ‘arene exchange’ approach has been successfully applied for the first time to the synthesis of Ru(II)-based ‘tethered’ reduc-
tion catalysts directly from their ligands in one step. This provides an alternative method for the formation of known complexes, and a
route to a series of novel complexes. The novel complexes are highly active in both asymmetric transfer and pressure hydrogenation of
ketones.
Complexes of type 1ꢀ3 have been widely adopted in
academic and industrial research as enantioselective
catalysts for the reduction of CdO and CdN bonds.
Noyori et al. first reported the synthesis and use of com-
plexes of type 1,1ꢀ3 which catalyze the asymmetric reduc-
tion of ketones1 and imines2 in high ee using either hydrogen
gas4 (asymmetric pressure hydrogenation, APH) or a re-
agent such as formic acid, sodium acetate, or isopropanol
(asymmetric transfer hydrogenation, ATH).1ꢀ3
(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) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738–8739. (d) Haack, K. J.; Hashiguchi, S.; Fujii,
A.; Ikariya, T.; Noyori, R. Angew. Chem. 1997, 109, 297–300. Angew.
Chem., Int. Ed. Engl. 1997, 36, 285–288. (e) Alonso, D. A.; Brandt, P.;
Nordin, S. J. M.; Andersson, P. G. J. Am. Chem. Soc. 1999, 121, 9580–
9588.
(2) (a) Wills, M. In Modern Reduction Methods; Andersson, P. G.,
Munslow, I. J., Eds.; Wiley-VCH: Weinheim, 2008; Chapter 11, pp 271ꢀ296.
(b) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1996, 118, 4916–4917. (c) Williams, G. D.; Wade, C. E.;
Wills, M. Chem. Commun. 2005, 4735–4737. (d) Sun, X.; Manos, G.;
We reported5ꢀ7 the synthesis and applications of
‘tethered’ complexes of type 2 which exhibit increased
reactivity relative to 1. First Ikariya, and later this group,
(4) (a) Ohkuma, T.; Utsumi, N.; Tsutsumi, K.; Murata, K.;
Sandoval, C.; Noyori, R. J. Am. Chem. Soc. 2006, 128, 8724–8725. (b)
Sandoval, C. A.; Ohkuma, T.; Utsumi, N.; Tsutsumi, K.; Murara, K.;
Noyori, R. Chem.;Asian. J. 2006, 1ꢀ2, 102–110. (c) Ohkuma, T.;
Tsutsumi, K.; Utsumi, N.; Arai, N.; Noyori, R.; Murata, K. Org. Lett.
2007, 9, 255–257. (d) Ohkuma, T.; Utsumi, N.; Watanabe, M.; Tsutsumi,
K.; Arai, N.; K. Murata, K. Org. Lett. 2007, 9, 2565–2567. (e) Ito, M.;
Endo, Y.; Ikariya, T. Organometallics 2008, 27, 6053–6055. (f) Li, C. Q.;
Wang, C.; Villa-Marcos, B.; Xiao, J. L. J. Am. Chem. Soc. 2008, 130,
14450–14451.
Blacker, J.; Martin, J.; Gavriilidis, A. Org. Process Res. Dev. 2004, 8,
˚
909–914. (e) Aberg, J. B.; Samec, A. M.; Backvall, J.-E. Chem. Commun.
€
2006, 2771–2773. (h) Casey, C. P.; Clark, T. B.; Guzei, I. A. J. Am. Chem.
Soc. 2007, 129, 11821–11827.
(5) (a) Soni, R.; Cheung, F. K.; Clarkson, G. C.; Martins, J. E. D.;
Graham, M. A.; Wills, M. Org. Biomol. Chem. 2011, 9, 3290–3294. (b)
Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc.
2005, 127, 7318–7319.
(3) (a) Takamura, H.; Ando, J.; Abe, T.; Murata, T.; Kadota, I.;
Uemura, D. Tetrahedron Lett. 2008, 49, 4626–4629. (b) Fu, R.; Chen, J.;
Guo, L.-C.; Ye, J.-L.; Ruan, Y.-P.; Huang, P.-Q. Org. Lett. 2009, 11,
5242–5245. (c) Kumarasway, G.; Ramakrishna, G.; Naresh, P.;
Jagadeesh, B.; Sridhar, B. J. Org. Chem. 2009, 74, 8468–8471. (d) Zhang,
B.; Xu, M.-H.; Lin, G. Q. Org. Lett. 2009, 11, 4712–4715. (e) Bradley,
P. A.; Carroll, R. L.; Lecouturier, Y. C.; Moore, R.; Noeureuil, P.; Patel,
B.; Snow, J.; Wheeler, S. Org. Process Res. Dev. 2010, 14, 1326–1336.
(f) Ding, Z.; Yang, J.; Wang, T.; Shen, Z.; Zhang, Y. Chem. Commun.
2009, 571–573. (g) Carpenter, I.; Clarke, M. L. Synlett 2011, 65–68.
(h) Kumaraswamy, G.; Ramakrishna, G.; Sridhar, B. Tetrahedron Lett.
2011, 52, 1778–1782.
(6) (a) Soni, R.; Collinson, J.-M.; Clarkson, G. C.; Wills, M. Org.
Lett. 2011, 13, 4304–4307. (b) Cheung, F. K.; Lin, C.; Minissi, F.;
ꢀ
Lorente Criville, A.; Graham, M. A.; Fox, D. J.; Wills, M. Org. Lett.
2007, 9, 4659–4662.
(7) 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.
r
10.1021/ol4024979
XXXX American Chemical Society

independently reported the synthesis and applications of
‘ether-tethered’ complex 3.8
substitutions of complexes initially complexed through
a nitrogen atom.10b,c
Given the precedents we attempted to form tethered
Ru(II)/TsDPEN complexes using an intramolecular arene
displacement. When an electron-rich ring was used to
displace an electron-poor one,10ꢀ12 i.e. biasing the system
toward the tethered product, less than 15% of the required
complex (R,R)-4 was formed from 5 upon heating in
DCM at 90 °C after 49 h (Scheme 1, product observed
by NMR and not isolated) accompanied by extensive
decomposition.
Although complexes 2 and 3 are excellent catalysts, their
syntheses require multistep processes; our original route
to 2 (n = 0ꢀ2)5a,b required (i) Birch reduction of an
alcohol, (ii) oxidation to an aldehyde, (iii) reductive cou-
pling with a diamine, (iv) complexation with RuCl3, and
(v) conversion of the dimer to a monomer. Improved
synthetic approaches to 2 (n = 1)7,8a require conversion
of the alcohol from step (i) to the tosylate, triflate, or
mesylate and coupling with the diamine component, and
also combine the last two stages into one. In alternative
approaches, a [4 þ 2] cycloaddition may be employed to
form the required diene.8,9 Hence, although efficient, the
majority of current synthetic approaches (one exception
being the synthesis of 3 by Ikariya et al.8a) require the
intermediacy of a 1,4-cyclohexadiene intermediate con-
taining a TsDPEN unit.
An appealing alternative approach to the synthesis of
tetheredcomplexes would be a direct‘arene substitution’ in
which the arene on the tether displaces another η6-arene
from Ru(II).10 This may have an advantage in certain
cases for example when the Birch reduction is difficult to
achieve.10d or in cases where a large excess of diene is
required for efficient complexation. The majority of re-
lated literature examples of this process involve ligands
attached to a metal through a phosphine, typically conducted
at ca. 120ꢀ130 °C, in a solvent such as chlorobenzene.
η6-Arenes containing an electron-withdrawing function
are generally favored as leaving groups. However there
appear to be only two reported examples of η6-arene
Scheme 1. Attempted Approach to Catalyst 4
The formation of complexes such as 5 from the
Ru(II) dimer precursor (e.g., [Ru(C6H5CO2Et)Cl2]2) and
a TsDPEN-derived ligand generally requires the addition
of a base such as triethylamine and temperatures in the
range of 80 °C in iPrOH, which are below those typically
required for η6-arene displacement.
Scheme 2. Direct Complexation Approach to Tethered Catalyst
2 (n = 1)
(8) (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.
(9) Cheung, F. K.; Hayes, A. M.; Morris, D. J.; Wills, M. Org.
Biomol. Chem. 2007, 5, 1093–1103.
(10) (a) Adams, J. R.; Bennett, M. A. Adv. Organomet. Chem. 2006,
54, 293–331. (b) Melchart, M.; Habtemariam, A.; Novakova, O.;
Moggach, S. A.; Fabbiani, F. P. A.; Parsons, S.; Brabec, V.; Sadler,
P. J. Inorg. Chem. 2007, 46, 8950–8962. (c) Ito, M.; Komatso, H.; Endo,
Y.; Ikariya, T. Chem. Lett. 2009, 38, 98–99. (d) Bennett, M. A.; Huang,
T.-N.; Matheson, T. W.; Smith, A. K.; Ittell, S.; Nickerson, W. Inorg.
Synth. 1982, 21, 74–78.
(11) Naphthalene has also been reported to be an efficient ‘leaving
€
group’ for arene substitution in Ru(II) complexes. Kundig, E. P.;
Monnier, F. R. Adv. Synth. Catal. 2004, 346, 901–905.
We proposed that through omission of the base and
by rapid heating of ligand 6a and precursor complex,
the η6-arene ring substitution could outpace diamine
complexation, i.e via formation of intermediates 7
and 8 rather than 5, and hence lead to direct formation
of tethered complexes (Scheme 2). In the event these
conditions worked well and provided a new route to
both 2 (n = 1) and the new complexes (R,R)-4 and
(R,R)-9 (Scheme 3) through direct combination of the
(12) For the synthesis of [Ru(C6H5CO2Et)Cl2]2) and its precursor
diene, see: (a) Emerman, S. I.; Meinwald, J. J. Org. Chem. 1956, 21, 375.
(b) Rigby, J. H.; Balasubramanian, N. J. Org. Chem. 1989, 54, 224–228.
(c) Agudo, R.; Roiban, G.-D.; Reetz, M. T. ChemBioChem 2012, 13,
1465–1473. (d) Mashima, K.; Kusano, K.-H.; Sato, N.; Matsumura,
Y.-I.; Nozaki, K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; T. Ishizaki, T.;
Akutagawa, S. Takaya, H. J. Org. Chem. 1994, 59, 3064–3076. (e)
Therrien, B.; Ward, T. R.; Pilkinton, M.; Hoffmann, C.; Gilardoni,
F.; Weber, J. Organometallics 1998, 17, 330–337. (f) Bennett, M. A.;
Smith, A. K. J. Chem. Soc., Dalton Trans. 1974, 233–241.
B
Org. Lett., Vol. XX, No. XX, XXXX

precursor dimer with ligands 6aꢀc in DCM or chloro-
benzene at 90ꢀ140 °C for 2ꢀ54 h. The use of an
electron-rich ring in the substituting ligand appears
to be advantageous and may lead to the formation
of a more stable complex as a result of the increased
electron density in the new η6-arene ring.10d,13
formation of tethered catalysts containing electron-rich
arene rings.
The importance of the higher temperature at an early
stage of the complexation was highlighted by stirring 6b
and [Ru(C6H5CO2Et)Cl2]2 in DCM at RT. This was found
to form only the unproductive complex 5 (see SI) and none
of the tethered complex (R,R)-4. In further tests we found
that [RuCl2(1,4-(EtO2C)2C6H4)]2 worked well in the sub-
stitution; however, [RuCl2(1,4-(EtO2C)(CH3)C6H4)]2 and
[RuCl2(p-cymene)]2 did not, highlighting the importance
of the use of an electron-withdrawing group on the initial
η6-arene ring.10
Scheme 3. Synthesis of 2 (n = 1) and Electron-Rich Tethered
Catalysts (R,R)-4 and (R,R)-9 via Direct η6-Arene Substitution
(isolated yields)
The novel electron-rich complexes (R,R)-4 and (R,R)-9
are highly active in the ATH and APH of ketones.5ꢀ8
Selected results for reduction of ketones 13ꢀ32 (Figure 1)
are given in Tables 1 (ATH) and 2 (APH), and further
details are in the SI. In the ATH tests shorter reaction times
were observed at 60 °C compared to 28 °C (SI) with only
marginal loss of enantioselectivity; therefore, the substrate
screen was conducted at the higher temperature. Most of
the substrates containing aromatic rings adjacent to the
ketone, other than ortho-substituted rings, were reduced
in consistently high ee using (R,R)-4. Fused-ring and
R-substituted ketones were particularly good substrates. In
most cases (R,R)-9 gave products in lower ee than (R,R)-4;
however, in several cases it was comparable and in the case
of acetylcyclohexane, superior. The latter result may arise
from an increased steric hindrance in the transition state as
has previously been documented.6b
The X-ray crystallographic structures of both (R,R)-4
and (R,R)-9 were obtained (see Supporting Information
(SI)).14 These served to confirm both that their structures
were correct and also that the relative stereochemistry
of the Ru(II) center relative to the diamine backbone
matched that previously observed for complexes of this
type.1,5 The arene substitution reaction is slower at lower
temperatures, but additional impurities are formed at
higher temperatures; therefore, careful control of the con-
ditions is required (see SI for full details). In DCM at
90 °C a reaction time of 40ꢀ50 h is typically required. In
chlorobenzene (following initial combination of reagents
in DCM) the reaction at 90 °C is faster than that in DCM.
The reaction can be carried out in the presence of a mild
inorganic base; however a stronger base is unfavorable and
leads to lower yields of product, as predicted (see SI).
Complexes 10ꢀ12 were also prepared by this route, each as
mixtures of diastereoisomers as has been observed pre-
viously for related complexes.5b,7 For the novel electron-
rich examples (R,R)-4 and (R,R)-9, this method represents
a highly efficient approach which appears well suited to the
Figure 1. Ketone substrates used in ATH and APH reactions.
(13) (a) Soleimannejad, J.; White, C. Organometallics 2005, 24, 2538–
2541. (b) Soleimannejad, J.; Sisson, A.; White, C. Inorg. Chim. Acta
2003, 352, 121–128.
(14) The full structural data for ((R,R)-4; CCDC913682,
(R,R)-8; CCDC 923077) can be obtained free of charge from the
Cambridge Crystallographic Centre via www.ccdc.cam.ac.uk/da-
ta_request/cif.
Although not listed, an imine was reduced in moderate
ee (up to 76% ee) but full conversion using catalyst (R,R)-9
(see SI). In the case of the APH reductions a similar pattern
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 1. ATH Reductions of Ketones
Table 2. APH Reductions of Ketonesa
temp/
t/
substrate
catalyst
t/h
conv %
ee %
substrate catalyst
s/c
°C
h
conv %a
ee %a
13
13
14
17
17
22
22
23
23
26
26
27
27
28
28
29
29
30
31
32
4
9
4
4
9
4
9
4
9
4
9
4
9
4
9
4
9
4
4
4
16
16
16
24
24
24
24
48
48
48
48
48
48
16
16
16
16
24
48
24
100
100
70
94 (R)
84 (R)
84 (R)
91 (S)
88 (S)
>99 (R)
99 (R)
99 (R)
99 (R)
37 (S)
81 (S)
98 (R)
95 (R)
94 (R)
80 (R)
92 (R)
74 (R)
82 (R)
80 (R)
95 (S)
13
13
13
13
14
14
15
16
16
17
17
18
18
19
19
20
21
22
22
23
23
24
25
25
26
26
26
4
4
9
9
4
9
4
4
9
4
9
4
9
4
9
4
4
4
9
4
9
4
4
9
4
9
9
1000
100
60
28
60
28
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
28
2
100
99
96 (R)
97 (R)
89 (R)
91 (R)
97 (R)
88 (R)
96 (R)
98 (R)
96 (R)
98 (S)
95 (S)
97 (S)
94 (S)
98 (R)
93 (R)
99 (R)
94 (R)
99 (R)b
>99 (R)b
99 (R)
99 (R)
88 (R)
99 (R)
96 (R)
37 (S)c
73 (S)c
74 (S)
4.5
4
1000
100
100
99
100
94
8
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
100
3.5
5
100
100
100
100
99
98
100
100
60
1.5
2
3
99
2
100
100
99
40
2
95
1
72
2
99
100
100
98
1
100
99
2
3
100
100
100
100
99
99
2
100
32
3
3
100
5
a Conv % and ee % calculated as for Table 1.
5
100
99
1.5
3
100
100
100
100
99
complexes prepared by this route are effective for the
asymmetrictransferandpressurehydrogenation ofarange
of ketones. We are continuing to establish the potential of
this novel method.
7
5
6
21.5
a Conv % and ee % calculated by chiral GC analysis unless otherwise
indicated. b ee % calculated by chiral HPLC analysis. c ee % calculated
for acetate derivative.
Acknowledgment. We thank the EPSRC (funding of
R.S. and K.E.J.) and the Leverhulme Trust (funding of
R.S.) for financial support. The X-ray diffraction instru-
ment was obtained through the Science City Project with
support from Advantage West Midlands (AWM) and
partly funded by the European Regional Development
Fund (ERDF).
of results was obtained (Table 2). Following initial screen-
ing it was found that an s/c of 500 and a temperature of
60 °C represented convenient reaction conditions.7,8 The
results of the ATH and APH experiments suggest that the
methoxy-substituted complexes catalyze ketone reduction
through a broadly identical mechanism similar to that of
the known tethered and untethered catalysts.1
In summary, a concise route to synthetically valuable
tethered Ru(II)/TsDPEN catalysts for ATH and APH
reactions is described. The direct ‘arene exchange’ process
works efficiently under specific conditions, and the new
Supporting Information Available. Full experimental
details, analytical data, and X-ray crystallographic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX