Chiral β-aminophosphine oxides as ligands for ruthenium assisted enantioselective transfer hydrogenation of ketones

Article abstract of DOI:10.1016/S0957-4166(99)00063-4

Enantiopure β-aminophosphine oxide ligands have been synthesized and used in asymmetric transfer hydrogenation of ketones. Optically active alcohols are obtained in high yields and with up to 84% enantiomeric excess.

Full text of DOI:10.1016/S0957-4166(99)00063-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 831–835
Chiral β-aminophosphine oxides as ligands for ruthenium
assisted enantioselective transfer hydrogenation of ketones
a
a,∗
b,∗
b
Anna M. Maj, K. Michal Pietrusiewicz, Isabelle Suisse, Francine Agbossou and
b,∗
André Mortreux
a
Maria Curie-Sklodowska University, Department of Organic Chemistry, ul. Gliniana, 20614 Lublin, Poland
b
Laboratoire de Catalyse Hétérogène et Homogène, UPRESA 8010, ENSCL, BP 108, 59652 Villeneuve d’Ascq, Cedex, France
Received 26 January 1999; accepted 19 February 1999
Abstract
Enantiopure β-aminophosphine oxide ligands have been synthesized and used in asymmetric transfer hydroge-
nation of ketones. Optically active alcohols are obtained in high yields and with up to 84% enantiomeric excess.
1999 Elsevier Science Ltd. All rights reserved.
©
1. Introduction
There has recently been much interest in asymmetric catalytic transfer hydrogenation of ketones
using 2-propanol as the hydrogen donor for preparation of enantiomerically pure secondary alcohols.1
,2
Catalytic systems with various levels of efficiency have emerged which involve ruthenium complexes
3
4
5
6
modified by various di- or tridentate ligands, i.e., diamines, amino alcohols, diureas, amidates,
7
8
oxazoline/amines and phosphine/amines. It is worth noting that among the most efficient catalysts
developed so far, the presence of a primary or secondary amine moiety is crucial for a catalytic activity.2,9
We have had an ongoing interest in the synthesis and use of optically active ligands in asymmetric
catalysis, especially diphosphines and related chiral modifiers.10 To date, all our studies have featured
one or two phosphorus(III)-end groups for the ligands which are quite sensitive towards oxygen when not
coordinated to a metallic center. On the other hand, some of us are making efforts towards the synthesis
11
of functionalized P-chiral phosphine oxide derivatives. Although the synthetic aspect to P-chiral
12
phosphine oxides has been investigated, to the best of our knowledge the use of such derivatives as
ligands in asymmetric catalysis has not so far been reported. Moreover, even the use of achiral phosphine
oxide based ligands has scarcely been reported.13 We have been attracted by hybrid ligands where one
∗
Corresponding authors. E-mail: michal@hermes.umcs.lublin.pl, isabelle.suisse@ensc-lille.fr and andre.mortreux@ensc-
lille.fr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00063-4

832
A. M. Maj et al. / Tetrahedron: Asymmetry 10 (1999) 831–835
end would be a chiral phosphine oxide and the other an amine, both connected by an appropriate spacer.
In fact, such ligands are expected to exhibit potential activity for asymmetric catalysis as they should
have the combined properties of their components.13 Thus, we sought to develop the chemistry of these
optically active phosphine oxides including the construction of mixed chiral β-aminophosphine oxide
ligands.
In this communication, we present our preliminary results on the synthesis and use of P-chiral β-
amino phosphine oxides in asymmetric catalysis and report the first example of ruthenium-catalyzed
enantioselective transfer hydrogenation of aryl ketones involving such ligands.
2. Results and discussion
As shown in Scheme 1, diphenylvinylphosphine oxide and (R)-tert-butylphenylvinylphosphine
14
oxide were reacted with a 5–10 molar excess of the pertinent enantiomer of 1-phenylethylamine in
water (closed ampule, 110°C, 7 days) and yielded the desired β-aminophosphine oxides 1–3 practically
15
quantitatively. After the extractive workup (CHCl ), and removal of the excess of amines under
3
reduced pressure, the crude oxides 1–3 were finally purified by column chromatography (silica gel,
16
chloroform:acetone, 3:1).
Scheme 1.
These ligands were then examined in the asymmetric transfer hydrogenation of arylketones 4–6 to
the corresponding alcohols (Scheme 2). The catalysts were generated in situ prior to hydrogen transfer
17
by heating a mixture of either [RuCl (p-cymene)] A or [RuCl (hexamethylbenzene)] B with the
2
2
2
2
appropriate ligand (2 equiv. vs Ru) at 80°C for 20 min in dry 2-propanol. During this period, the color
changed from orange to deep red. A 2-propanol solution of the substrate followed by KOH was then
added to the mixture. The results are summarized in Table 1.
Scheme 2.

A. M. Maj et al. / Tetrahedron: Asymmetry 10 (1999) 831–835
833
Table 1
a
Transfer hydrogenation of arylketones in the presence of ruthenium catalysts
The first catalytic system investigated was composed of a combination of the precursor A and the
aryl-substituted ligand 1, presenting a single carbon centered chirality. At room temperature, transfer
hydrogenation to acetophenone 4 occurred slowly with a modest enantioselectivity (34% ee, entry 1) and
stopped at 22% conversion. At 60°C, the rate remained low (31% after 1 h) and the enantiomeric excess
dropped (entry 2 vs 1). In the same way, transfer hydrogenation with ligand 1 to ketones 5 and 6 occurred
with poor conversions and a decrease of the ee along with the time is also observed (entries 3 and 4).
The results obtained with ligand 1 suggest a decomposition of the enantioselective active species during
the catalysis at 60°C. Interestingly, the reaction rate could be enhanced by changing the nature of the
substituents on the phosphorus atom. Thus, replacing a phenyl moiety by a tert-butyl group induced an
increase of the conversion and the reaction could be carried out at room temperature (entries 5, 7 and
8). An increase of the enantioselectivity was observed as well (at room temperature from 34 to 50% ee,
entry 1 vs 5, at 60°C, from 15 to 36 ee%, entry 2 vs 6). However, it has to be noted that in addition to the
substituent change, a second chiral element, phosphorus centered, was present in 2 when compared to 1.
As observed, the reaction rate is also dependent on the steric properties of the substrates. This
point is illustrated by the results obtained upon variation of the alkyl group of the ketone, the iso-
propylphenylketone leading to sluggish catalysis (entries 4, 8 and 14). This trend was further confirmed
when a similar catalysis was performed with PhCOtBu (4.5 h, 35% conversion, 22% ee). Enantioselec-
tivities also relied upon the nature of this alkyl group. For example, lower ees were always observed for
the iso-propyl substituted substrate 6 (entries 4 and 8).
The general trend given above for p-cymene based catalysts was not followed by the complex bearing

834
A. M. Maj et al. / Tetrahedron: Asymmetry 10 (1999) 831–835
the hexamethylbenzene unit. Indeed, a surprisingly higher enantioselectivity was reached for the most
hindered substrate 6 (entry 11). Moreover, even in the presence of the diastereomeric ligand 3, the
induction remained quite good for that substrate as 60% ee were observed with a 62% conversion
over 1 h. That specific trend has not been rationalized so far. Nevertheless, we may attribute the major
contribution to both the activity and the enantioselectivity to the phosphine oxide moiety. The presence
of an alkyl group on the phosphorus atom is essential in two respects. First, an enhancement of the
coordination ability of the oxygen atom of the P_O is expected. Second, the stereogenicity at the
phosphorus atom induced a consequent increase in the level of enantioselection. These features strongly
support the participation, eventually through coordination, of phosphine oxide during the catalytic cycle
of the ruthenium complexes.
We therefore sought to spectroscopically identify the behaviour of the chiral phosphine oxide ligands in
the presence of ruthenium complexes as coordinated P_O exhibit distinctive 31P NMR and IR features
possibly under catalytic conditions. Thus, ligand 2 and A were combined in 2-propanol in a NMR tube.
18
31
The P NMR spectrum of the mixture provided a single signal at 52.2 ppm which is also the chemical
shift for the free ligand. Consequently, there is no real evidence for a P_O coordination. Hence, the
initial color change, i.e., from clear orange to deep red, attributed to the dimer cleavage most probably
by the amino group of the ligand. A subsequent addition of KOH led to a darkening of the mixture.
31
Nevertheless, the P NMR remained unchanged. Next we carefully examined the IR spectra obtained
from the above mixtures as the P_O moiety is most readily distinguished through the change in frequency
of the P_O stretching vibration. Unfortunately, the above experiments provided no clear evidence for
coordination–chelation of the hemilabile ligands through the P_O end.
Although the contribution of the chiral P_O moiety in these ligands have been shown via this study,
there is no evidence for some coordination of this group on the metal. Further studies are in progress
to explain the improvement of both activity and enantioselectivity related to this P_O end group and to
extend the use of these new ligands in other asymmetric catalytic reactions.
Acknowledgements
This work was supported by a grant (Anna M. Maj) from the ‘Ministère des Affaires Etrangères’. The
authors gratefully thank the ‘Ministère de la Recherche et de la Technologie’ and the CNRS for their
financial support.
References
1. (a) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. Rev. 1992, 92, 1051–1069. (b) de Grauuw, C. F.; Peters, J. A.; van
Bekkum, H.; Huskens, J. Synthesis 1994, 1007–1017.
2. Noyori, R., Hashigushi, S. Acc. Chem. Res. 1997, 30, 97–102.
3
. (a) Fujii, A.; Hashigushi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521–2522. (b) Schwink,
L.; Ireland, T.; Püntener, K.; Knochel, P. Tetrahedron: Asymmetry 1998, 9, 1143–1163.
. (a) Takehara, J.; Hashiguchi, S.; Fuji, A.; Inoue, S.-i.; Noyori, R. J. Chem. Soc., Chem. Commun. 1996, 233–234. (b)
Palmer, M.; Walsgrove, T.; Wills, M. J. Org. Chem. 1997, 62, 5226–5228. (c) Alonso, D. A.; Guijarro, D.; Pinho, P.;
Temme, O.; Andersson, P. G. J. Org. Chem. 1998, 63, 2749–2751.
4
5
6
7
8
. Gamez, P.; Dunjic, B.; Lemaire, M. J. Org. Chem. 1996, 61, 5196–5197.
. Ohta, T.; Nakahara, S.-i.; Shigemura, Y.; Hattoti, K.; Furukawa, I. Chem. Lett. 1998, 491–492.
. Jiang, Y.; Jiang, Q.; Zhang, X. J. Am. Chem. Soc. 1998, 120, 3817–3818.
. (a) Gao, J.-X.; Ikariya, T.; Noyori, R. Organometallics 1996, 15, 1087–1089. (b) Jiang, Y.; Jiang, Q.; Zhu, G.; Zhang, X.
Tetrahedron Lett. 1997, 38, 6565–6568.

A. M. Maj et al. / Tetrahedron: Asymmetry 10 (1999) 831–835
835
9. Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285–288.
10. Agbossou, F.; Carpentier, J.-F., Hapiot, F.; Suisse, I.; Mortreux, A. Coord. Chem. Rev. 1998, 180, 1615–1645.
11. (a) Pietrusiewicz, K. M., Phosphorus, Sulfur, and Silicon 1996, 109/110, 573–576. (b) Kielbasinski, P.; Zurawinski, R;
Pietrusiewicz, K. M.; Zablocka, M.; Mikolajczyk, M. Polish J. Chem. 1998, 72, 564–572.
1
2. (a) Pietrusiewicz, K. M.; Zablocka, M. Chem. Rev. 1994, 9, 1375–1411. (b) Haynes, R. K.; Lam, W. W.-L.; Williams, I.
D.; Yeung, L.-L. Tetrahedron Lett. 1996, 37, 4729–4732. (c) Lam, W. W.-L.; Haynes, R. K.; Yeung, L.-L.; Chan, E. W.-K.
Tetrahedron Lett. 1996, 37, 4733–4736.
1
3. (a) Wegman, R. W.; Abatjoglou, A. G.; Harrison, A. M. J. Chem. Soc., Chem. Commun. 1987, 1891–1892. (b) Le Gall,
I.; Laurent, P.; Toupet, L.; Salaün, J.-Y.; Des Abbayes, H. Organometallics 1997, 16, 3579–3581. (c) Faure, B.; Pardigon,
O.; Buono, G. Tetrahedron 1997, 53, 11577–11594. (d) Burns, B.; Studley, J. R.; Wills, M. Tetrahedron Lett. 1993, 34,
7105–7106. (e) Abu-Gnim, C.; Amer, I. J. Chem. Soc., Chem. Commun. 1994, 115–117. (f) Abu-Gnim, C.; Amer, I.
J. Organomet. Chem. 1996, 516, 235–243. (g) Basoli, C.; Botteggi, C.; Cabras, M. A.; Chelucci, G.; Marchetti, M. J.
Organomet. Chem. 1995, 488, C20–C22.
1
1
1
4. The enantiopure (R)-tert-butylphenylvinylphosphine oxide was available from another project and its synthesis will be
published elsewhere. Pietrusiewicz, K. M.; Salamonczyk, G. M.; Holody, W.; Maj, A. M.; Wieczorek, W., in preparation.
5. This is a modification of the published procedure: Pietrusiewicz, K. M.; Zablocka, M. Tetrahedron Lett. 1988, 29,
1
987–1990. For catalyzed additions, see: Märkl, G.; Merkl, B. Tetrahedron Lett. 1981, 22, 4459–4462.
3
1
6. Selected physical properties: 1: mp: 176–177°C, P NMR (CDCl
9.5–71°C, 31P NMR (CDCl
) δ=49.0 ppm, [α] = −56.6 (c 2.5, CHCl
α] = +30.6 (c 2.5, CHCl ).
7. For the synthesis of the ruthenium complexes see: (a) Bennett, M. A.; Smith, A. K. J. Chem. Soc., Dalton Trans. 1974,
3
) δ=32.0 ppm, [α]
D
= −24.0 (c 2.5, CHCl
3
). 2: mp
31
6
3
D
3
). 3: semisolid, P NMR (CDCl ) δ=49.0 ppm,
3
[
D
3
1
233–241. (b) Bennett, M. A.; Matheson, T. W.; Robertson, G. B.; Smith, A. K.; Tucker, P. A. Inorg. Chem. 1980, 19,
1014–1021.
1
8. For 31P NMR examples see: Blaghorough, T. C.; Davis, R.; Ivison, P. J. Organomet. Chem. 1994, 467, 85–94. For IR data
see: Higgins, S. J.; Taylor, R.; Shaw, B. L. J. Organomet. Chem. 1987, 325, 285–292.