Synthesis and evaluation of a chiral heterogeneous transfer hydrogenation catalyst

Article abstract of DOI:10.1016/S0957-4166(98)00214-6

A polymer bound transfer hydrogenation catalyst has been developed based on Noyori's (1S,2S)- or (1R,2R)-N-(p-tolylsulfonyl)-1,2- diphenylethylenediamine. The ruthenium catalysed reduction of acetophenone was examined and the activity of the catalyst was found to be dependent on the type of polymer used. The catalyst was found to be reusable and retained high ee's when HCO₂H:Et₃N was used as the hydrogen donor.

Full text of DOI:10.1016/S0957-4166(98)00214-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2015–2018
Synthesis and evaluation of a chiral heterogeneous transfer
hydrogenation catalyst
∗
Daniel J. Bayston, Catherine B. Travers and Mario E. C. Polywka
Oxford Asymmetry International Ltd, 151 Milton Park, Abingdon, Oxfordshire OX14 4SD, UK
Received 27 March 1998; accepted 25 May 1998
Abstract
A polymer bound transfer hydrogenation catalyst has been developed based on Noyori’s (1S,2S)- or (1R,2R)-N-
p-tolylsulfonyl)-1,2-diphenylethylenediamine. The ruthenium catalysed reduction of acetophenone was examined
(
and the activity of the catalyst was found to be dependent on the type of polymer used. The catalyst was found to
be reusable and retained high ee’s when HCO2H:Et3N was used as the hydrogen donor. © 1998 Elsevier Science
Ltd. All rights reserved.
Hydrogenation of unsaturated groups remains a fundamental strategy for the preparation of chiral
molecules. Many catalysts are now available which perform this transformation with high degrees of
1
enantiocontrol especially in the case of olefin and ketone reduction. The most common of these catalysts
incorporate chiral diphosphine ligands bound to either ruthenium or rhodium and require high pressure
2
to achieve hydrogenation. More favourable sources of hydrogen other then molecular hydrogen are
found in transfer hydrogenation reactions where isopropyl alcohol or a 5:2 formic acid:triethyl amine
3
azeotrope serve as hydrogen donors. Recently, Noyori has discovered that (1S,2S)- or (1R,2R)-N-(p-
tolylsulfonyl)-1,2-diphenylethylenediamine is an excellent chiral ligand for the ruthenium catalysed
transfer hydrogenation of aryl ketones, alkynyl ketones and imines giving products with up to 99% ee.4
The structures of several intermediate catalytic species have been well characterised and the mechanism
5
elucidated.
We, and others, have recently been interested in the utilisation of solid phase ligands in transition
metal promoted asymmetric reactions thereby providing clean, recoverable and reusable chiral catalysts.6
Indeed, recovery of such a catalyst by filtration provides an exceptional process improvement over
homogeneous catalysis. Not only is it possible to reuse the often expensive ligands but also the potentially
toxic transition metal species may be removed from the reaction mixture. A recent publication concerning
the immobilisation of the Noyori ligand has prompted us to disclose our own results in this area.7
Scheme 1 shows our route to a polymer bound ligand for use in transition metal promoted transfer
hydrogenation reactions. The commercially available (1S,2S) diamine 1 (>99% ee) is first sulfonylated
∗
Corresponding author. E-mail: mpolywka@oai.co.uk
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00214-6

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D. J. Bayston et al. / Tetrahedron: Asymmetry 9 (1998) 2015–2018
with 4-(chlorosulfonyl)benzoic acid 2. Protection of the free amine functionality as its Boc derivative
provides 4 which is ready to be coupled to a solid support. Immobilisation onto both aminomethylated
polystyrene and Novasyn Tentagel amino resin is readily achieved using standard peptide coupling
reagents. Deprotection of the Boc group occurs readily with 95% TFA and provides ligands 6a and 6b.
Ligand 6a contains a standard polystyrene backbone and was found to have a loading of 0.70 mmol/g (by
mass increase). Ligand 6b has a loading of 0.22 mmol/g (by mass increase) and contains a 3000–4000
unit polyethyleneglycol (PEG) spacer unit. The active transfer hydrogenation catalyst was formed in situ
by mixing the ligand with an equimolar amount of [RuCl (p-cymene)] in the reaction solvent giving
2
2
orange/red beads for each polymer.
Scheme 1. Reagents and conditions: (i) Et
3
N, CH
2
Cl
2
, 81%; (ii) (Boc)
2
O, NaOH, THF, H
2
O, 27%; (iii) DIC, DMAP, Pri
Cl
2
NEt,
DMF, CH Cl , aminomethylated polystyrene (for a) or aminomethylated PEG polystyrene (for b); (iv) TFA, CH
2
2
2
2
The effectiveness of these ligands were assessed in the reduction of acetophenone (Fig. 1). Table 1
shows the results for the ruthenium catalysed transfer hydrogenation of acetophenone using isopropyl
alcohol as the hydrogen donor (all reactions were performed with 1 mol% catalyst). The homogeneous
ligand 3 (entry 1) shows good activity and enantioselectivity (93.5% ee at 93% conversion to (S)-1-
phenethanol, the absolute configuration was determined by comparison with a standard using Noyori’s
4
b
ligand ) indicating that the electron withdrawing acid functionality is only slightly detrimental to
catalytic behaviour (c.f. 97% ee at 95% conversion after 15 h with 0.5 mol% catalyst for the Noyori
4
b
ligand ). Ligand 6a gave (S)-1-phenethanol in 90.5% ee at 88% conversion (entry 2). During the transfer
hydrogenation reactions the visual appearance of the polymer is unchanged with the beads remaining
orange/red in colour. The catalyst from this reaction was isolated by filtration under nitrogen. Attempted
reuse under the same reaction conditions failed to give any reaction. The reason for this deactivation is
at this time unclear. Ligand 6b gives a poor ee and only 9% conversion to (S)-1-phenethanol (entry 3).
Swelling measurements indicated that the polymer only swells to 1.5 times its dry volume. Thus, the lack
of activity may be attributed to the active sites being inaccessible.
8
Use of a 5:2 formic acid:triethylamine azeotrope shows more promising results as seen in Table 2.
Whereas ligand 6a is fairly inactive in neat HCO H:Et N giving only 21% conversion after 28 h (entry
2
3

D. J. Bayston et al. / Tetrahedron: Asymmetry 9 (1998) 2015–2018
2017
Fig. 1.
Table 1
Ruthenium catalysed transfer hydrogenation of acetophenone using isopropyl alcohol as the hydrogen
sourcea
Table 2
2 3
Ruthenium catalysed transfer hydrogenation of acetophenone using HCO H:Et N
1
), the PEG containing ligand 6b gave (S)-1-phenethanol in 96.7% ee at 96% conversion (entry 2, c.f.
4
c
98% ee at 99% conversion after 20 h with 0.5 mol% catalyst for the Noyori ligand ). The catalyst can
be reused but shows a drop in activity, taking 72 h to go to 96% conversion with the ee remaining high at
9
1
7.1% (entry 3). A third use shows no further activity. The reaction can be pushed to completion in only
6 h by conducting the reaction at 60°C but gives a product with only 92.0% ee (entry 4).
A cosolvent can also be used in these reactions. When CH Cl or DMF are used as the cosolvents
2
2
then polystyrene ligand 6a (entries 5 to 10) becomes more active than 6b (entries 11 and 12) with
neither solvent being superior. The catalyst can also be reused twice under these conditions giving >50%
conversion in each case although with progressively longer reaction times. After three uses the catalyst
has lost most of its activity. Addition of more [RuCl (p-cymene)] to the polymer bound ligand does
2
2
not regenerate the catalytic activity. The cause of the drop in activity is unknown at the present time. A
reaction was performed to ensure that no monomer of the ligand was held as a salt (arising from less
than 100% active ester formation during the coupling step) in the polymer. In the presence of formic
acid such a salt would be soluble and may have been the ligand involved in catalysis rather than the
polymer bound ligand. In this reaction acetophenone was fully reduced with 10 mol% catalyst (1R,2R)-
6
a in CH Cl and HCO H:Et N (5:2) over 20 h. After the reaction was complete, the polymer bound
2 2 2 3
catalyst was removed by filtration under nitrogen and to the filtrate was added another equivalent of
acetophenone and another portion of HCO H:Et N. Stirring for a further 20 h gave no further conversion
2
3

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D. J. Bayston et al. / Tetrahedron: Asymmetry 9 (1998) 2015–2018
Fig. 2.
to 2-phenethanol indicating that a homogeneous catalyst was not responsible for ketone reduction. This
reaction also confirmed that no leaching of catalyst from the polymer was occurring.
We have also used the polymer bound catalyst to reduce 2-chloroacetophenone (Fig. 2). Our best
conditions for this transformation were found to be ligand (1S,2S)-6b in DMF using HCO H:Et N as the
2
3
9
source of hydrogen. (R)-2-Chloro-1-phenethanol was obtained in 90% yield and 95.3% ee.
In summary, we have developed a practical route to a heterogeneous enantioselective transfer
hydrogenation catalyst. The reduction of acetophenone has been examined and a reusable catalyst has
been identified. The reduction is best performed neat in HCO H:Et N for polymer 6a containing the
2
3
polyethyleneglycol spacer unit. A cosolvent such as DMF or CH Cl is necessary to attain good reactivity
2
2
for the simple polystyrene based catalyst 6b. The reactivity of the polymeric catalyst on reuse decreases
and after three uses the reaction time for good conversion becomes impractically long although the
enantiomeric excesses remain high. Investigation into further reuse of this catalyst and its application
to industrially useful transformations is currently in progress.
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