Ruthenium catalyzed asymmetric transfer hydrogenation of β-ketoesters

Article abstract of DOI:10.1016/S0957-4166(98)00325-5

Chemoselective transfer hydrogenation of β-ketoesters to the corresponding alcohols is achieved in the presence of catalytic combinations of [RuCl₂(η⁶-arene)]₂ and ephedrine or diamino type chiral ligands with activities u

Full text of DOI:10.1016/S0957-4166(98)00325-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2971–2974
Ruthenium catalyzed asymmetric transfer hydrogenation of
β-ketoesters
Kathelyne Everaere,a Jean-François Carpentier,a,∗ André Mortreux a and Michel Bulliard b
aLaboratoire de Catalyse Hétérogène et Homogène 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 23 July 1998; accepted 10 August 1998
Abstract
Chemoselective transfer hydrogenation of β-ketoesters to the corresponding alcohols is achieved in the presence
of catalytic combinations of [RuCl2(η6-arene)]2 and ephedrine or diamino type chiral ligands with activities up to
190 h−1 at 20°C and moderate to good enantiomeric excesses ranging from 36 to 94%. © 1998 Elsevier Science
Ltd. All rights reserved.
Asymmetric catalytic transfer hydrogenation using 2-propanol as a hydrogen source has proved in re-
cent years to be a valuable selective method for reducing simple aryl alkyl ketones1–6 and α,β-acetylenic
ketones.7 Efficient catalytic systems developed by Lemaire, Noyori, Helmchen and others combine a
Rh, an Ir, or better, a Ru1 precursor with a simple chiral bidentate ligand having an NH moiety such as a
diamine or an aminoalcohol. Very few results have been reported on the performance of these systems for
the reduction of β-ketoesters,8,9 although this route to optically active β-hydroxy esters, a valuable class
of chiral intermediates, would afford, if feasible, obvious advantages over the corresponding asymmetric
hydrogenation. Knochel et al. reported recently that the transfer hydrogenation of ethyl acetoacetate 1a,
(Scheme 1) catalyzed by a Ru complex bearing a chiral ferrocenic secondary diamine proceeds much
slower than that of simple ketones (TOF50=ca. 30 h−1 at 80°C)10 and gives the corresponding β-hydroxy
ester 2a in only 20% ee11 This statement prompted us to present our first results in this field, which show
that high catalytic activity together with total chemoselectivity, but still modest enantioselectivity are
attainable.
The chiral Ru complexes were prepared in situ by heating a mixture of [RuCl2(η6-arene)]2 and a
chiral ligand (2 equiv. vs. Ru) in 2-propanol. Screening experiments conducted under typical reaction
conditions11 using iPrOK (6 equiv. vs. Ru) as a co-catalyst and ethyl acetoacetate 1a as a model
substrate indicated that only a limited number of bidentate ligands give significantly active catalysts, of
which (1S,2R)-ephedrine and some derivatives of (1S,2S)-diphenylethylenediamine are notable (Fig. 1).
∗
Corresponding author. E-mail: carpentier@ensc-lille.fr
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00325-5
tetasy 2474 Communication

2972
K. Everaere et al. / Tetrahedron: Asymmetry 9 (1998) 2971–2974
Scheme 1.
Fig. 1.
Quantitative GLC monitoring and NMR spectroscopy revealed that the reaction always proceeds with
total chemoselectivity for β-hydroxyesters, thus showing that reduction of active methylene ketones
under moderately basic conditions does not compete with aldolisation side-processes.
As shown in Table 1, the catalytic performance for the reduction of 1a is also strongly affected by the
nature of the arene ligand in the Ru precursor (entries 1–8). The combination [RuCl2(C6H6)]2/ephedrine
affords the most active system (TOF50=300 h−1 at 50°C, 14 h−1 at 20°C), but 2a is recovered in only
36–39% ee12 On the other hand, the [RuCl2(C6Me6)]2/TsDPEN system affords the best ee so far (56%),
but the activity drops dramatically. A reversal in the configuration of 2a is observed going from the
Ru(benzene) to the Ru(p-cymene) precursor with both chiral ligands (compare entries 2/3 and 5/6).
Most interestingly, the transfer hydrogenation of tBu ester 1b proceeds much faster than for 1a, the
reaction being completed within 1 h at 20°C (TOF50=190 h−1; entry 9), and yields the reduction product,
2b, in a slightly higher ee than 2a. The reaction of iPr ester 1c leads to intermediary results (TOF50=30
h
−1; entry 10). We assume that the dramatic increase in the reduction rate going from R0=Et to R0=tBu in
these acetoacetic esters is related to the bulkiness of the R0 group, which possibly prevents the formation
of less reactive chelated species.
The influence of the substituent R α to the keto function was also examined (entries 11–15). For
β-ketoester 1d, the optimal activity is obtained with the [RuCl2(C6H6)]2/ephedrine system, while the
[RuCl2(p-cymene)]2/ephedrine combination affords a slightly better ee but proved to be extremely
sluggish. Similar trends in the catalytic performance are observed for aromatic β-ketoester 1e, the
[RuCl2(p-cymene)]2/TsDPEN system offering the best compromise activity/enantioselectivity.
If alcohols 2a–d can be recovered in only 36–56% ee so far, ees as high as 94% are observed for
2e; this observation is in direct line with previous studies which have shown the beneficial influence of
an unsaturated α-substituent in the enantiodifferentiation of simple ketones.1–7 However, 1e is reduced
in only 40% ee with the [RuCl2(C6H6)]2/ephedrine catalyst (entry 13). Indeed, the results of this study
clearly demonstrate the dramatic influence of the arene ligand both on the enantioselectivity and the
activity of the catalyst. Efforts in this direction are under progress.

K. Everaere et al. / Tetrahedron: Asymmetry 9 (1998) 2971–2974
2973
Table 1
Asymmetric transfer hydrogenation of β-ketoesters 1a–ea
Acknowledgements
This work was supported by a grant (K.E.) from PPG-SIPSY SA and the CNRS. We gratefully thank
Dr. F. Agbossou for helpful comments.
References
1. Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97–102.
2. Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285–288.
3. Bernard, M.; Guiral, V.; Delbecq, F.; Fache, F.; Sautet, P.; Lemaire, M. J. Am. Chem. Soc. 1998, 120, 1441–1446 and
references therein.
4. Jiang, Y.; Jiang, Q.; Zhang, X. J. Am. Chem. Soc. 1998, 120, 3817–3818.
5. Nishibayashi, Y.; Singh, J. D.; Arikawa, Y.; Uemura, S.; Hidai, M. J. Organomet. Chem. 1997, 531, 13–18.
6. Langer, T.; Helmchen, G. Tetrahedron Lett. 1996, 37, 1381–1384.
7. Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738–8739.
8. Transfer hydrogenation of β-ketoester 1d using HCO2H as the hydrogen source and the catalytic combination
[RuCl2(C6H6)]2/TsDPEN affords 2d in 93% ee; see Ref. 1.

2974
K. Everaere et al. / Tetrahedron: Asymmetry 9 (1998) 2971–2974
9. Note also that the transfer hydrogenation of α-ketoester PhCOCO2Me in iPrOH using Rh/C2-diamine catalysts affords
methyl mandelate in up to 99% ee; Gamez, P.; Fache, F.; Mangeney, P.; Lemaire, M. Tetrahedron Lett. 1993, 34,
6897–6898.
10. TOF50=turnover frequency expressed in mol of produced alcohol/mol of Ru.h and calculated at 50% conversion.
11. Schwink, L.; Ireland, T.; Püntener, K.; Knochel, P. Tetrahedron: Asymmetry 1998, 9, 1143–1163.
12. In every case, ee values were constant (ꢀ4%) throughout the whole reaction course, thus indicating that no significant
racemization occurred with the present catalytic systems.