An alternative route to tethered Ru(II) transfer hydrogenation catalysts

Article abstract of DOI:10.1016/j.tetlet.2018.01.071

A new route towards a series of tethered η⁶-arene/Ru(II) catalysts for use in the transfer and pressure hydrogenation of ketones and aldehydes to alcohols is reported. The route proceeds through the formation of an amide from the diamine precursor, followed by reduction, rather than the direct alkylation of the diamine. This has the advantage that dialkylation of the amine is avoided during the synthesis. Through this new route, both racemic and enantiomerically-pure η⁶-arene/Ru(II) tethered catalysts can be prepared in high yield.

Full text of DOI:10.1016/j.tetlet.2018.01.071

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
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An alternative route to tethered Ru(II) transfer hydrogenation catalysts
a
b
b
b
a,
⇑
ˇ
Roy Hodgkinson , Václav Jurcík , Hans Nedden , Andrew Blackaby , Martin Wills
a Department of Chemistry, Warwick University, Coventry CV4 7AL, UK
b Johnson Matthey, Catalysis and Chiral Technologies, 28 Cambridge Science Park, Cambridge CB4 0FP, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A new route towards a series of tethered
g
6-arene/Ru(II) catalysts for use in the transfer and pressure
Received 12 December 2017
Revised 17 January 2018
Accepted 23 January 2018
Available online xxxx
hydrogenation of ketones and aldehydes to alcohols is reported. The route proceeds through the forma-
tion of an amide from the diamine precursor, followed by reduction, rather than the direct alkylation of
the diamine. This has the advantage that dialkylation of the amine is avoided during the synthesis.
Through this new route, both racemic and enantiomerically-pure
can be prepared in high yield.
g
6-arene/Ru(II) tethered catalysts
Keywords:
Ruthenium
Catalyst
Ó 2018 Elsevier Ltd. All rights reserved.
Tethered
Reduction
Alcohol
Hydrogenation
Introduction
replacing the p-toluenesulfonyl group with a more lipophilic
substituent. In the event, we first attempted to form ligand 7
from the reaction between 3 and TrisEN 86 using the established
alkylation method. Unfortunately, and in contrast to TsDPEN 2,
the reaction was complicated by a competing dialkylation reaction
of TrisEN 8. The use of tosylate and mesylate derivatives of 3 did
not provide a solution as these were either unreactive or also gave
competing dialkylation products. Hence, an alternative approach
was required.
Enantiomerically pure tethered
g
6-arene/Ru(II) complexes of
type 1 have been widely applied to the asymmetric reduction of
ketones and imines to alcohols and amines, respectively.1 This
class of catalyst was first reported by Wills et al. in 20052 and an
improved synthesis by Wills et al./Johnson Matthey was reported
in 2012.3 Several other groups have also reported derivatives of
the original tethered complex 1 and these have also been tested
in a number of synthetic applications.1,4 Complex 1 may be pre-
pared on a large scale through an established reaction sequence
in which a diene is attached to the diamine precursor (TsDPEN)
through an SN2 substitution reaction of monotosylated diamine 2
with triflate 3 to form ligand 4 (Scheme 1).3 In some cases, a tosy-
late or mesylate leaving group may be employed in this step. Com-
plex 1 is subsequently formed via a dimer 4 which may isolated or
converted directly into the monomer without isolation.2,3
Whilst this route works well for complex 1, the synthesis of a
racemic derivative of 1 (i.e. in which the two phenyl groups were
absent from the diamine unit), which is a valuable catalyst for gen-
eral reduction applications,5 has proved to be more challenging,
and low yields were achieved upon cyclisation of the correspond-
ing intermediate dimer to the required product.3a As it was
suspected that this was due to the high polarity of the racemic
complex compared with 1, we sought to compensate for this by
Results and discussion
Towards identifying a solution to this challenge, we considered
the use of an amide intermediate, therefore avoiding issues of
dialkylation. Firstly, amine 8 was coupled with acid 97 to form
amide 10, which was subsequently reduced to amine 7 using
lithium aluminium hydride. Subsequent complexation to the
dimer 11 followed by conversion to 6 upon treatment with base,
following the established protocols for this stage of the tethered
catalyst synthesis, completed the development of the improved
synthetic route (Scheme 2).
Through a similar process but reversing the position of the
amide, amine 7 was also formed through the combination of car-
boxylic acid 12 (prepared from glycine) with amine 13 to give
14, followed by reduction, representing a further amide-based
approach to the required ligands (Fig. 1). The high yields obtained
in each of the final steps reflects the much greater compatibility of
⇑
Corresponding author.
E-mail address: m.wills@warwick.ac.uk (M. Wills).
https://doi.org/10.1016/j.tetlet.2018.01.071
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
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R. Hodgkinson et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Scheme 3. New route to hindered asymmetric tethered complexes via an amide.
Scheme 1. Established route to tethered complexes 1.5
and was applied successfully to the ligand precursor for 1. In this
case, amide 15 was formed from TsDPEN 2 and reduced to 4 in
93% and 66% yields, respectively, for each step. Throughout this
study, EDC/HOBt was found to be an efficient reagent combination
for the amide formation step of the sequence.
In addition, some highly hindered (also known) derivatives
were prepared by this method (Scheme 4). The extra level of steric
hindrance and the variation in tether length can, in some cases,
moderate the level of selectivity and activity of the complexes. In
this synthesis, (S,S)-TrisDPEN 16 was first coupled with either acid
9 or 17 to give the amides 18a and 18b, respectively, in good yields.
Subsequent reduction to the known amines 19a/b proceeded
cleanly; these are known precursors to the hindered tethered cat-
alysts 20a/b following an established method.3b In the synthesis of
4, 19a and 19b by this method, the 1H NMR spectra indicated the
formation of a single diastereoisomer of the product in each case,
suggesting that no epimerisation takes place at either chiral
centre during the reduction reactions.
Scheme 2. Amide route to racemic tethered complex 6 via amide 10.
Fig. 1. Amide intermediate 14 and precursors 12 and 13.
the more lipophilic ligand 7 (compared to the NTs analogue)3a with
the reaction conditions used.
The amide approach was also demonstrated to be effective for
Scheme 4. New route to hindered asymmetric tethered complexes via an amide
intermediate.
the synthesis of several known asymmetric catalysts2,3 (Scheme 3)
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R. Hodgkinson et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
The new racemic complex 6 worked efficiently as a catalyst for
the reduction of acetophenone and several aldehydes (Table 1). In
acetophenone reduction, full conversion could be achieved using as
little as 0.1 mol% catalyst with either hydrogen gas or formic acid/
triethylamine as the reducing agent. In all cases except entry 2, the
reductions worked effectively without the requirement for the
addition of a further reagent, such as a base, to activate the cata-
lyst. In the case of the hydrogenations, ionization takes place in a
methanol solution.3a,8 The reasons for the lower conversion in
entry 2 are not clear, however reactions in isopropanol are
reversible and it may be the case that the reaction had not
proceeded with full conversion even over the extended reaction
time. Aldehyde reduction worked equally well and the loading
could be reduced further but at the cost of a small amount of
formylated side product. A series of aldehydes were reduced in
full within 5 h using 0.2 mol% catalyst and with high selectivity
for reduction of the carbonyl group over other sensitive
functional groups in the molecule. This preference from the
selective reduction of the more reactive and polar C@O bond in
the aldehyde is in common with previous observations using this
class of substrate.3a
reduction catalysts such as 1 using an arene-displacement strategy
recently reported by Wills et al.10
In conclusion, we have developed an alternative route to a ser-
ies of tethered Ru(II) catalysts using an amide intermediate, which
avoids the problems of multiple alkylation which were encoun-
tered using the existing alkylation strategy. Through this approach,
it was possible to prepare a highly effective racemic catalyst (6) for
the reduction of ketones and aldehydes, which may also be
employed with hydrogen gas or with a combination of formic acid
and triethylamine. Using this method, complex 6 was prepared
cleanly and in high yield without the complications of side-product
formation. The clean reductions, using an economical metal source,
provide an advantage over more established stoichiometric meth-
ods. The approach can also employed to form known asymmetric
tethered catalysts in high yield.
The route was further applied to the preparation of catalyst pre-
cursor ligands 219 and 22, which contains an aromatic ring in place
of the diene, i.e. via the amides 23 and 24 respectively in good
yields (Fig. 2). Intermediate 21 has been employed to form
Fig. 2. Precursors to the synthesis of complex 1 and its racemic analogue via an
arene-exchange route.9
Table 1
Application of catalyst 6 to the racemic reduction of acetophenone and aldehydes.
Entry
1
Substrate
PhCOMe
Reagent, Solvent S/C
FA/TEA 400:1
t/[h S]
T/°C
Conv/%
98%
5 h
40
1 M
2
PhCOMe
iPrOH 400:1
29 h
0.1 M
24 h
1 M
24 h
0.5 M
24 h
1 M
40
60
60
60
40
60
60
60
60
40
40
40
40
40
26%
3
PhCOMe
30 bar H2 MeOH 500:1
30 bar H2 MeOH 1000:1
30 bar H2 MeOH 1000:1
FA/TEA 500:1
99%
4
PhCOMe
99%
5
PhCOMe
99%
6
PhCHO
5 h, 7 h
1.5 M
5 h
86, 100
96%, 4%*
89%, 10%*
56%, 18%*
37%, 9%*
100
7
PhCHO
FA/TEA 1000:1
FA/TEA 5000:1
FA/TEA 10,000:1
FA/TEA 20,000:1
FA/TEA 500:1
1.5 M**
5 h
8
PhCHO
1.5 M**
24 h
1.5 M**
24 h
1.5 M**
5 h
9
PhCHO
10
11
12
13
14
15
PhCHO
p-Br C6H4CHO
p-NO2 C6H4CHO
p-iPr C6H4CHO
p-OMe C6H4CHO
PhCH@CHCHO
1.5 M
5 h
1.5 M
5 h
1.5 M
5 h
1.5 M
5 h
FA/TEA 500:1
99
FA/TEA 500:1
99
FA/TEA 500:1
100
FA/TEA 500:1
96
1.5 M
*
Formylated alcohol.
Contains DMF (ca. 0.25 mL).
**
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4
R. Hodgkinson et al. / Tetrahedron Letters xxx (2018) xxx–xxx
(e) Vyas VK, Bhanage BM. Org Lett. 2016;18:6436–6439;
Acknowledgments
(f) Wakeham RJ, Morris JA, Williams JMJ. ChemCatChem. 2015;7:4039–4041;
(g) Mangion IK, Chen C-Y, Li H, et al. Org Lett. 2014;16:2310–2313;
(h) Su Y, Tu Y-Q, Gu P. Org Lett. 2014;16:4204–4207.
2. Hannedouche J, Clarkson GJ, Wills M. J Am Chem Soc. 2004;126:986–987.
3. (a) Jolley KE, Zanotti-Gerosa A, Hancock F, et al. Adv Synth Catal.
2012;354:2545–2555;
The authors thank the Technology Strategy Board (TSB), the
Engineering and Physical Sciences Research Council (EPSRC) and
Johnson Matthey Catalysis and Chiral Technologies for financial
support of this project. Dr Antonio Zanotti-Gerosa is thanked for
his advice and enthusiastic support for the area of transfer hydro-
genation of ketones and our studies.
ˇ
(b) Hodgkinson R, Jurcík V, Zanotti-Gerosa A, et al. Organometallics.
2014;33:5517–5524.
4. (a) Touge T, Hakamata T, Nara H, et al. J Am Chem Soc. 2011;133:14960–14963;
(b) Parekh V, Ramsden JA, Wills M. Catal Sci Technol. 2012;2:406–414;
´
(c) Kišic A, Stephan M, Mohar B. Org Lett. 2013;15:1614–1617;
(d) Kišic´ A, Stephan M, Mohar B. Adv Synth Catal. 2014;356:3193–3198;
A. Supplementary data
´
(e) Kišic A, Stephan M, Mohar B. Adv Synth Catal. 2015;357:2540–2546;
(f) Sun G, Zhou Z, Luo Z, et al. Org Lett. 2017;19:4339–4342;
(g) Touge T, Nara H, Fujiwhara M, Kayaki Y, Ikariya T.
2016;138:10084–10087;
(h) Wang B, Zhou H, Lu G, Liu Q, Jiang X. Org Lett. 2017;19:2094–2097;
(i) Jeran M, Cotman AE, Stephan M, Mohar B. Org Lett. 2017;19:2042–2045.
5. Grainger D, Zanotti-Gerosa A, Cole KP, et al. ChemCatChem. 2013;5:1250–1254.
6. Tan J, Tang W, Sun Y, et al. Tetrahedron. 2011;67:6206–6213.
7. Snider BB, Kirk TC. J Am Chem Soc. 1983;105:2364–2368.
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.01.071.
J Am Chem Soc.
References
1. (a) Nedden HG, Zanotti-Gerosa A, Wills M. Chem Rec. 2016;16:2623–2643;
(b) Liu R, Zhou G, Hall TH, Clarkson GJ, Wills M, Chen W. Adv Synth Catal.
2015;357:3453–3457;
8. Ohkuma T, Utsumi N, Tsutsumi K, Murata K, Sandoval C, Noyori R. J Am Chem
Soc. 2006;128:8724–8725.
9. Martins JED, Morris DJ, Wills M. Tetrahedron Lett. 2009;50:688–692.
10. Soni R, Jolley KE, Wills M. Org Lett. 2013;15:5110–5113.
(c) Forshaw S, Matthews AJ, Brown TJ, Diorazio LJ, Williams L, Wills M. Org Lett.
2017;17:2789–2792;
(d) Soni R, Hall TH, Mitchell BP, Owen MR, Wills M.
2015;80:6784–6793;
J Org Chem.
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