Transfer Hydrogenation with Ruthenium Complexes of Chiral (Phosphinoferrocenyl)oxazolines

Full text of DOI:10.1021/jo9711044

6104
J . Org. Chem. 1997, 62, 6104-6105
Sch em e 1
Tr a n sfer Hyd r ogen a tion w ith Ru th en iu m
Com p lexes of Ch ir a l
(P h osp h in ofer r ocen yl)oxa zolin es
Tarek Sammakia* and Eric L. Stangeland
Department of Chemistry and Biochemistry, University of
Colorado Boulder, Colorado 80309-0215
Ta ble 1a
Received J une 18, 1997
Transfer hydrogenation using 2-propanol as a source
of hydrogen is an attractive method for the reduction of
ketones to alcohols. The reaction utilizes inexpensive
reagents, is simple to perform, and does not require the
use of reactive metal hydrides or hydrogen. Because the
reaction is governed by mass action, reduction of the
ketone can be driven to high conversion by using iso-
propanol as the solvent. The classical variant of this
reaction, the Meerwein-Pondorff-Verley reduction, typi-
cally utilizes a stoichiometric amount of an aluminum
entry
R
time (h)
% conversionb
%eec
1
2
3
4
5
Me (2)
Bn (3)
i-Pr (4)
Ph (5)
t-Bu (6)
d
8
6
3
6
6
92
93
93
93
51
5
92
90
92
94
94
-
alkoxide as
a promoter. Recently, Backvall and
Chowdhury showed that 0.1% RuCl2(PPh3)3 (1) is an
effective catalyst for this transformation, provided that
about 2% NaOH is present.1 This discovery has lead to
the development of asymmetric processes which utilize
Ru catalysts that are modified with chiral ligands.2,3 Most
notably, Noyori has developed catalysts which will reduce
aryl alkyl ketones to the corresponding alcohols in
excellent yields and enantioselectivities.4 We have previ-
ously described the preparation of chiral ferrocenylox-
azoline complexes which posses complexation induced
chirality (i.e., “planar chirality”).5,6 These complexes are
prepared in high yield and with excellent diastereose-
lectivity via the diastereotopic group selective metalation
of the parent ferrocenyloxazoline using sec-BuLi in ether
containing 1 equiv of TMEDA. We have used this
method for the preparation of chiral (phosphinoferroce-
nyl)oxazolines,7 and describe in this article their use as
6
20
b
a
See text for conditions. The % conversion was determined
by capillary GC using dodecane as an internal standard. c Enan-
tioselectivities were measured by capillary GC using a Supelco
â-dex 120 column (per-methylated â-cyclodextrin chiral phase) and
d
are reproducible to (1%. The reaction was performed without
the ferrocene ligand.
ligands in conjunction with 1 in the enantioselective
transfer hydrogenation of aryl alkyl ketones.
Our initial efforts focused on screening a variety of
ferrocenyloxazolines in which the substituent on the
oxazoline is varied in order to ascertain its effect on the
reaction (Table 1). We chose acetophenone as our test
substrate and performed the reaction at room tempera-
ture in 2-propanol at a concentration of 0.125 M using
0.2% 1, 0.26% of the ferrocene complex, and 6% potas-
sium isopropoxide. The catalysts were prepared in situ
by the addition of our ligand to 1 in 2-propanol followed
by heating the solution to reflux for 1 h. Catalysts
prepared in this fashion are significantly more reactive
than 1 (ligand accelerated catalysis,8 Table 1, compare
entries 1-5 with entry 6). All of the ligands we examined
provide enantioselectivities in excess of 90%, with the
phenyl- and tert-butyl-substituted oxazolines providing
94% ee (Table 1, entries 4 and 5). Furthermore, all of
the reactions containing the ferrocene ligands proceeded
to greater than 90% conversion as shown by GC, with
the exception of the tert-butyl-substituted oxazoline 6
which only proceeded to about 50% conversion (Table 1,
entry 5). Thus, the phenyl-substituted oxazoline was
deemed to provide the optimal combination of conversion
and selectivity.
(1) Chowdhury, R. L.; Backvall, J .-E. J . Chem. Soc., Chem. Commun.
1991, 1063.
(2) For a review, see: Zassinovich, G.; Mestroni, G.; Gladiali, S.
Chem. Rev. 1992, 92, 1051. Gladiali, S.; Pinna, L.; Delogu, G.;
DeMartin, S.; Zassinovich, G.; Mestroni, G. Tetrahedron: Asymmetry
1990, 1, 635. Muller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. Helv. Chim.
Acta 1991, 74, 232. Krasik, P.; Alper, H. Tetrahedron 1994, 50, 4347.
Yang, H.; Alvarez, M.; Lugan, N.; Mathieu, R. J . Chem. Soc. Chem.
Commun. 1995, 1721. Langer, T.; Helmchen, G. Tetrahedron Lett.
1996, 37, 1381. Langer, T.; J anssen, J .; Helmchen, G. Tetrahedron:
Asymmetry 1996, 7, 1599. J iang, Q.; Van Plew, D.; Murtuza, S.; Zhang,
X. Tetrahedron Lett. 1996, 37, 797. J iang, Y.; J iang, Q.; Zhu, G.; Zhang,
X. Tetrahedron Lett. 1997, 38, 215.
(3) For other metal-based systems, see: Evans, D. A.; Nelson, S.
G.; Gagne´, M. R.; Muci, A. R. J . Am. Chem. Soc. 1993, 115, 9800; Genet,
J .-P.; Ratovelomanana-Vidal, V.; Pinel, C. Synlett, 1993, 478. Gamez,
P.; Fache, F.; Mangeney, P.; Lemaire, M. Tetrahedron Lett. 1993, 34,
6897. Gamez, P.; Fache, F.; Lemaire, M. Tetrahedron: Asymmetry
1995, 6, 705. Varghese, J .; Iyers, S. J . Chem. Soc., Chem. Commun.
1995, 465;
(4) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. Haack,
K. J .; Hashiguci, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 285. Hashiguci, S.; Fujii, A.; Haack, K. J .;
Matsumura, K.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl.
1997, 36, 285.
(5) (a) Sammakia, T.; Latham, H. A.; Schaad, D. R. J . Org. Chem.
1995, 60, 10; (b) Sammakia, T.; Latham, H. A. J . Org. Chem. 1995,
60, 6002. (c) Sammakia, T.; Latham, H. A. J . Org. Chem. 1996, 61,
1629.
We have examined the scope of this method for the
reduction of aryl alkyl ketones using ligand 5 as shown
in Table 2. All reactions were initially attempted at room
temperature; however, we found that the reductions of
the more hindered or electron rich substrates did not
proceed to completion. When these substrates were
reduced at elevated temperatures, the reactions pro-
(6) For related work on the metalation of ferrocene oxazolines, see:
Richards, C. J .; Damalidis, T.; Hibbs, D. E.; Hursthouse, M. B. Synlett
1995, 74. Nishibayashi, Y.; Uemura, S. Synlett 1995, 79. Richards, C.
J .; Hibbs, D. E.; Hursthouse, M. B. Tetrahedron Lett. 1995, 36, 3748.
Park, J .; Lee, S.; Ahn, K. H.; Cho, C.-W. Tetrahedron Lett. 1995, 36,
7263. Richards, C. J .; Mulvaney, W. Tetrahedron: Asymmetry 1996,
7, 1419. Zhang, W.; Hirao, I.; Ikeda, I. Tetrahedron Lett. 1996, 37, 4545.
Zhang, W.; Adachi, Y.; Ikeda, I. Tetrahedron: Asymmetry 1996, 7, 451.
Ahn, K. H.; Cho, C.-W.; Baek, H.-H.; Park, J .; Lee, S. J . Org. Chem.
1996, 61, 4937.
(7) For examples of the use of related ligands in asymmetric
catalysis, see: Nishibayashi, Y.; Segawa, K.; Ohe, K.; Uemura, S.
Organometallics 1995, 14, 5486. Richards, C. J .; Hibbs, D. E.; Hurst-
house, M. B. Tetrahedron Lett. 1995, 36, 3745. Zhang, W.; Hirao, T.;
Ikeda, I. Tetrahedron Lett. 1996, 37, 4545; Richards, C. J .; Mulvaney,
A. W. Tetrahedron: Asymmetry 1996, 7, 1419. Zhang, W. B.; Kida, T.;
Nakatsuji, Y.; Ikeda, I. Tetrahedron Lett. 1996, 37, 7995.
(8) Berrisford, D. J .; Bolm, C.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1059.
S0022-3263(97)01104-3 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 18, 1997 6105
Ta ble 2a
Sch em e 3
entry
Ar
R
temp (°C) time (h) %yield %ee
1
2
3
4
5
6
7
8
9b
Ph
Ph
Ph
1-Np
2-Np
o-tolyl
p-Cl-Ph
p-OMe-Ph Me
mesityl Me
Me
Et
28
50
80
50
28
50
28
50
80
7
1
1
3
7
1
6
2
1
80
85
87
92
82
83
83
75
81
94
96
88
91
95
93
93
84
95
i-Pr
Me
Me
Me
Me
We have isolated what we suspect is the catalyst
formed upon treating 1 with 5. Heating a 0.05 M iso-
propanol solution of 1 to reflux in the presence of 1.05
equiv of ligand 5 provides a precipitate (7) which is
soluble in CDCl3 and which provides 1H and 31P NMR
spectra and elemental analysis consistent with RuCl2-
(PPh3)‚5 (see Supporting Information). No free triphen-
ylphosphine is observed in the 31P spectrum. Complex 7
exists as an approximately 5:1 ratio of diastereomers at
24 °C as revealed by NMR and contains two phosphines
in each complex. It was also found to have the same
reactivity as the catalyst prepared in situ from 1 and
ligand 5 and will catalyze the reduction of acetophenone
to the corresponding alcohol in 85% yield and 94% ee
using our standard reaction conditions. Treatment of a
CDCl3 solution of 1 with 5 provides the 31P NMR
spectrum shown in Scheme 3. In this spectrum, 2 equiv
of free triphenylphosphine (δ ) -5.64 ppm) are evident
as well as complex 7, indicating that the in situ prepara-
tion of the catalyst provides complex 7. The diastereo-
meric ratio observed by NMR varies with temperature.
At 24 °C the ratio is about 6:1 (Scheme 3), but at 57 °C,
the ratio is about 2:1, indicating that the diastereomeric
complexes are equilibrating on the NMR timescale and
on the timescale of the reaction. Unfortunately, we have
not been successful in obtaining crystals suitable for
X-ray diffraction.
a
With the exception of the temperature, which is as noted in
b
the table, conditions are the same as for Table 1. This reaction
was conducted at a concentration of 0.0725 M.
Sch em e 2
ceeded to high conversions with only a slight loss of
selectivity (Table 2, entries 2, 3, 4, 6, 8, and 9).
We have performed several experiments designed to
elucidate the structure of the active catalytic species in
this reaction. We have prepared a triphenylphosphine-
free catalyst by substituting our ferrocenyl ligand for
triphenylphosphine in the literature preparation of RuCl2-
(PPh3)3.9 This catalyst is much less active than catalyst
prepared from 1, and its use for the reduction of aceto-
phenone provides material of low enantioselectivity
(Scheme 2).10 Interestingly, the selectivity can be largely
restored by the addition of triphenylphosphine as illus-
trated by the following experiment. Reduction of aceto-
phenone using the triphenylphosphine-free catalyst prepa-
ration in 2-propanol at reflux provides the S-enantiomer
of the carbinol (i.e., the opposite of what is observed with
the triphenylphosphine-containing preparation) in 60%
conversion and in 9% ee after 3 h. If triphenylphosphine
and p-methylacetophenone are then added to this solu-
tion, the p-methylacetophenone is reduced to the R-
enantiomer of the carbinol in 80% ee, suggesting that the
triphenylphosphine is bound to the metal in the stereo-
chemistry determining step (Scheme 2).11,12
In conclusion, we have described a new and selective
catalyst for the enantioselective transfer hydrogenation
of aryl alkyl ketones. The system is subject to ligand-
accelerated catalysis, and our mechanistic studies indi-
cate that the triphenylphosphine is bound to the Ru
during the stereochemistry-determining step. This sys-
tem is readily amenable to modification, and experiments
to further optimize and examine the scope and mecha-
nism of this process are currently in progress.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM48498), Novartis Pharmaceuticals
Corporation, and Pfizer for financial support of this
research. T.S. is a recipient of an American Cancer
Society J unior Faculty Research Award and is an Alfred
P. Sloan Research Fellow (1996-1998).
Su p p or tin g In for m a tion Ava ila ble: Characterization of
alcohol products, 31P and 1H NMR spectra of 7 at 24 °C and
57 °C, and experimental details for the preparation and
characterization of ligands 2-6 and for the typical transfer
hydrogenation procedure (6 pages).
J O9711044
(9) RuCl2(PPh3)3 is typically prepared by heating to reflux a solution
consisting of 1 equiv RuCl3‚3H2O and 6 equiv triphenylphosphine in
methanol for 3 h, during which time the product crystallizes (see:
Stephenson, T. A.; Wilkinson, G. J . Inorg. Nucl. Chem. 1966, 28, 945).
(10) Catalysts prepared using dichloro(1,5-cyclooctadiene)ruthe-
nium(II) polymer or dichloro(p-cymene)ruthenium(II) dimer as catalyst
precursors are also less reactive and unselective.
(11) Reduction of acetophenone at 50 °C in i-PrOH using a catalyst
prepared by refluxing RuCl3‚3H2O (0.4%) with Ph3P (0.4%) and ligand
5 (0.4%) in i-PrOH for 1 h provides the expected (R)-carbinol in 90%
ee and 76% conversion.
(12) When tributylphosphine is substituted for triphenylphosphine,
racemic material is produced at a greatly diminished rate.