N-Benzyl-norephedrine derivatives as new, efficient ligands for ruthenium-catalyzed asymmetric transfer hydrogenation of functionalized ketones

Article abstract of DOI:10.1016/S0957-4166(99)00465-6

Significant catalytic activities (up to 600 h^-1 at 20°C) and enantiomeric excesses ranging from 56 to 89% for the asymmetric transfer hydrogenation of β-ketoesters, methoxyacetone and 2-acetylpyridine to the corresponding alcohols are achieved in the presence of catalytic combinations of [RuCl₂(η⁶-arene)]₂ and N-substituted derivatives of (1S,2R)- norephedrine such as N-benzyl-norephedrine and N-(4-biphenyl)methyl- norephedrine.

Full text of DOI:10.1016/S0957-4166(99)00465-6

Pergamon
Tetrahedron: Asymmetry 10 (1999) 4083–4086
N-Benzyl-norephedrine derivatives as new, efficient ligands for
ruthenium-catalyzed asymmetric transfer hydrogenation of
functionalized ketones
Kathelyne Everaere,a Jean-François Carpentier,a,∗ André Mortreux a and Michel Bulliard b
aLaboratoire de Catalyse de Lille associé au CNRS, ENSCL, B.P. 108, 59652 Villeneuve d’Ascq Cedex, France
bPPG-SIPSY, Z.I. La Croix Cadeau, B.P. 79, 49242 Avrillé Cedex, France
Received 24 September 1999; accepted 22 October 1999
Abstract
Significant catalytic activities (up to 600 h−1 at 20°C) and enantiomeric excesses ranging from 56 to 89% for
the asymmetric transfer hydrogenation of β-ketoesters, methoxyacetone and 2-acetylpyridine to the corresponding
alcohols are achieved in the presence of catalytic combinations of [RuCl2(η6-arene)]2 and N-substituted derivatives
of (1S,2R)-norephedrinesuch as N-benzyl-norephedrineand N-(4-biphenyl)methyl-norephedrine. © 1999 Elsevier
Science Ltd. All rights reserved.
Much effort has been devoted in recent years to the development of asymmetric transfer hydrogena-
tions of ketones. As a result, several excellent chiral catalytic systems, combining a ruthenium or a rho-
dium precursor with chiral bidentate N,X ligands (X=N, O), have been reported for the enantioselective
reduction of simple aryl alkyl ketones and α,β-acetylenic ketones.1–7 Noteworthy among these top li-
gands are (1S,2S)-N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine (TsDPEN 1, Scheme 1) and (1S,2R)-
ephedrine 2.2 However, the few results available from the literature8 and our studies9 clearly demonstrate
that the existing catalytic systems are unsatisfactory for the reduction of functionalized ketones bearing
heteroatoms such as the important β-ketoesters (sluggish activity and/or poor enantioselectivities).10 In
this regard, we have recently reported that chemoselective transfer hydrogenation of alkyl β-ketoesters to
the corresponding alcohols is achieved in the presence of catalytic combinations of ephedrine and a suit-
able [RuCl2(η6-arene)]2 precursor with activities up to 190 h−1 at 20°C but only moderate enantiomeric
excesses ranging from 36 to 44%.9 We here report that N-benzyl substituted derivatives of norephedrine
are promising chiral ligands for the ruthenium-catalyzed transfer hydrogenation of various functionalized
ketones.
(1S,2R)-Norephedrine 3 was N-alkylated via a one-pot two-step procedure11 as described in Scheme 1
using a variety of aldehydes. Among the numerous derivatives thus prepared, it turned out that N-
∗
Corresponding author. E-mail: carpentier@ensc-lille.fr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00465-6

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K. Everaere et al. / Tetrahedron: Asymmetry 10 (1999) 4083–4086
Scheme 1.
CH2Ar-type compounds, of which 4–6 are representative examples, led to the most interesting catalytic
properties. The effectiveness of these ligands was assessed in the reduction of ketones 7a–d (Scheme 2).
The chiral Ru catalyst precursors were prepared in situ by heating a mixture of [RuCl2(η6-arene)]2 and a
chiral ligand (2 equiv. versus Ru) in 2-propanol, and transfer hydrogenation was carried out under usual
reactions conditions as previously described.9
Scheme 2.
The results reported in Table 1 emphasize the main features of these reactions:
(i) The new N-benzyl-norephedrine type ligands 4–6 lead to significantly more enantioselective
catalytic species than reference systems based on 1 and 2. This trend proved to be general for
the different ketones investigated. More particularly, ethyl acetoacetate 7a (entries 1–4) and tert-
butyl acetoacetate 7b (entries 5–11) are reduced in up to 56 and 68% ee, respectively; these values,
although still modest, are so far the best reported for transfer hydrogenation of simple alkyl β-
ketoesters. The level of enantioselectivity is comparable for the reduction of methoxyacetone 7c
(entries 12–14) and reaches nearly 90% ee in the case of 2-acetylpyridine 7d (entries 15–21).
(ii) For a given ruthenium precursor, the activity of the catalytic systems, as judged from the half-
reaction time, follows the order 2>5≈6>4ꢀ1. As aforementioned, TsDPEN 1 systems proved to
always be extremely sluggish in the case of functionalized ketones, and are thus almost inoperative.
A neat illustration of this limitation is the reduction of methoxyacetone 7c for which only 39%
conversion is achieved with 1 in 16 h, while both ligands 2 and 4 allow complete conversion within

K. Everaere et al. / Tetrahedron: Asymmetry 10 (1999) 4083–4086
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Table 1
Asymmetric transfer hydrogenation of functionalized ketones 7a–da
20 min (TOF50=600 h−1) (entries 12–14). Derivatives 4–6 lead to somewhat less active species than
their ephedrine (2) equivalents for the reduction of 7b and 7d. For these ketones, further substitution
of the N-benzyl group of derivative 4, i.e. introduction of a para-phenyl group (5) or a para-methoxy
group (6), significantly enhances the catalytic activity with minimal effects on the enantioselectivity
(compare entries 6–9 and 16–18).
(iii) For a given catalytic system, transfer hydrogenation of the tBu ester 7b always proceeds much faster
than that of 7a. This allows the reduction of 7b to be completed at room temperature within a short
reaction time with a substrate/catalyst ratio of 100. This dramatic increase in the reduction rate

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going from ethyl to tert-butyl acetoacetate is assumed to be related to the bulkiness of the alkoxy
group, which possibly prevents the formation of less reactive chelated species.
(iv) For a given chiral ligand, the catalytic performance is also strongly affected by the nature of the
arene ligand in the Ru precursor.9 This effect is emphasized here for the reduction of ketones 7b and
7d. The comparison of series of results, such as entries 6/10, 7/11, and 17/19/20/21, suggests that
the bulkier the arene, the lower the catalytic activity. However, these effects are undoubtedly more
complex, and the major influence of the arene ligand on enantioselectivity could not be rationalized
so far. Efforts in this direction are under progress.
Acknowledgements
This work was supported by a grant (K.E.) from PPG-SIPSY SA and the CNRS.
References
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