A catalytic deracemisation of alcohols

Article abstract of DOI:10.1039/b704956k

Racemic alcohols have been converted into enantiomerically enriched alcohols with up to 99% ee in a one-pot oxidation/reduction procedure. The Royal Society of Chemistry.

Full text of DOI:10.1039/b704956k

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A catalytic deracemisation of alcohols{
Gareth R. A. Adair and Jonathan M. J. Williams*
Received (in Cambridge, UK) 3rd April 2007, Accepted 16th May 2007
First published as an Advance Article on the web 4th June 2007
DOI: 10.1039/b704956k
Preliminary screening experiments led to the development of
Racemic alcohols have been converted into enantiomerically
the following reaction procedure, as shown in Scheme 2.
[RuCl2(benzene)]2 (1 mol%), (R)-BINAP 1 (2 mol%) and (R,R)-
DPEN 3 (2 mol%) were heated in cyclohexanone at 110 uC for 1 h
in order to effect complexation. The racemic alcohol, solvent
(THF) and potassium tert-butoxide were added and the reaction
mixture was heated at 60 uC for 20 h, resulting in oxidation of the
alcohol into the corresponding ketone by transfer hydrogenation.
Pressurisation of the reaction mixture with hydrogen reduced the
ketone back into the alcohol with a good level of enantioselectivity
for most of the alcohols examined (Table 1). The enantiomeric
excess of products was established by analysis of the chiral HPLC
traces.9
enriched alcohols with up to 99% ee in a one-pot oxidation/
reduction procedure.
Deracemisation is usually thermodynamically disfavoured because
of the entropy cost of converting two enantiomers into a single
enantiomer.1 We have developed a strategy to overcome this
thermodynamic problem for the deracemisation of alcohols. The
process involves the non-selective oxidation of an alcohol into an
achiral ketone by transfer hydrogenation, followed by asymmetric
reduction back into an enantiomerically enriched alcohol by direct
hydrogenation, according to Scheme 1. In some cases, catalysts are
known to be highly selective for direct hydrogenation but to be
poorly selective for transfer hydrogenation.2 In a recent report
from Nishibayashi and co-workers, they achieve a successful
deracemisation by oxidation of the alcohol by acetone using one
ruthenium catalyst and reduction by adding a second catalyst and
a huge excess of isopropanol.3
The alcohol 11 containing a chlorophenyl group was reduced
more slowly and with a lower enantiomeric excess. It has
previously been observed that aryl chlorides can react with
ruthenium complexes, which may explain the lack of success with
this substrate.10 In the case of the formation of the product 5
where the R group is propyl (C3H7), the starting alcohol was the
corresponding alkene (R is CH2CHLCH2). Under the reaction
conditions, the allyl alcohol was isomerised into the saturated
ketone prior to reduction.
[RuCl2(cymene)]2 was treated with (R)-BINAP in d8-toluene at
60 uC in the presence of an additive (DMF, DMSO, THF or
cyclohexanone) to enhance ligand exchange. The 31P {1H} NMR
spectra showed signals at d 24.3 (d, J = 61.8 Hz) and 40.7 (d, J =
61.8 Hz), assigned to [RuCl[(R)-BINAP](p-cymene)]Cl11 along
with minor unidentified species. Addition of (R,R)-DPEN and
further heating provided a new signal at d 46.8 (s) assigned to
RuCl2[(R)-BINAP][(R,R)-DPEN].12 Using cyclohexanone as the
In order to achieve oxidation of an alcohol by transfer
hydrogenation, it is conventional to use a large excess of the
acceptor ketone, such as acetone, in order to drive the equilibrium
towards complete oxidation of the alcohol.4,5 We chose to use
cyclohexanone as the acceptor ketone, since it is known to be a
stronger oxidant than similar acyclic ketones,6 thereby reducing
the need for a large excess.
Our initial studies demonstrated that the use of the preformed
Noyori complex RuCl2[(R)-BINAP][(R,R)-DPEN]7 proved to be
unsatisfactory, since unwanted aldol reactions were found to occur
during the oxidation process. The use of the ruthenium hydride
complex Ru(PPh3)4H2 in the presence of the ligands (R)-BINAP 1
and (R,R)-DPEN 3 led to clean oxidation of the alcohol into
ketone, which was reduced back to alcohol with a reasonable level
of enantioselectivity.8 However, we recognized that the enantios-
electivity was being compromised by the presence of achiral
triphenylphosphine in the reaction mixture and our attention
turned to the use of commercially available, phosphine-free
ruthenium complexes as catalyst precursors.
Scheme 1 Deracemisation by an oxidation/reduction sequence.
Department of Chemistry, University of Bath, Claverton Down, Bath,
UK BA2 7AY. E-mail: j.m.j.williams@bath.ac.uk; Fax: 44 1225 386231;
Tel: 44 1225 323942
{ Electronic supplementary information (ESI) available: Full experimental
details and analysis of enantiomeric excess. See DOI: 10.1039/b704956k
Scheme 2 General procedure for the deracemisation of alcohols.
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2608 | Chem. Commun., 2007, 2608–2609

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Table 1 Results of ruthenium catalysed deracemisation
Alcohol
Ar
R
Yielda (%)
ee (%)
4
C6H5
C6H5
C6H5
2-Naphthyl
m-MeC6H4
p-MeOC6H4
p-MeOC6H4
m-ClC6H4
p-Me2NC6H4
C2H5
C3H7
C4H9
C5H11
C5H11
CH3
C5H11
C5H11
C5H11
87
82
92
95
97
89
94
26
96
83
87
86
82
90
79
88
57
92
b
5b
6
7
8
9
10
11
12
a
Scheme 4 Stereoinversion of enantiomerically enriched alcohols.
Isolated yields after column chromatography or distillation. The
starting alcohol was PhCH(OH)CH2CHLCH2.
non-selective transfer hydrogenation followed by an enantioselec-
tive direct hydrogenation back into the regenerated enantiomeri-
cally enriched alcohol.
We thank the Engineering and Physical Sciences Research
Council for funding a studentship through the Doctoral Training
Account (to G. R. A. A.).
Notes and references
1 C. C. Gruber, I. Lavandera, K. Faber and W. Kroutil, Adv. Synth.
Catal., 2006, 348, 1789.
2 V. Rautenstrauch, X. Hoang-Cong, R. Churland, K. Abdur-Rashid
and R. H. Morris, Chem.–Eur. J., 2003, 9, 4954.
Scheme 3 Higher selectivity obtained using xylyl-BINAP 2.
3 Y. Shimada, Y. Miyake, H. Matsuzawa and Y. Nishibayashi, Chem.–
Asian J., 2007, 2, 393.
4 S. Gladiali and E. Alberico, Chem. Soc. Rev., 2006, 35, 226.
5 M. L. S. Almeida, M. Beller, G.-Z. Wang and J.-E. Ba¨ckvall, Chem.–
Eur. J., 1996, 2, 1533.
6 H. Adkins, R. M. Elofson, A. G. Rossow and C. C. Robinson, J. Am.
Chem. Soc., 1949, 71, 3622.
7 T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya and R. Noyori, J. Am.
Chem. Soc., 1995, 117, 2675.
8 G. R. A. Adair and J. M. J. Williams, Chem. Commun., 2005, 5578.
9 A Chiralcel OD-H1 column was used for alcohol 4 (3 : 97 isopropanol–
hexane, 14.7 min (R), 16.7 min (S), alcohol 5 (3 : 97 isopropanol–
hexane, 14.1 min (R), 15.6 min (S), alcohol 6 (3 : 97 isopropanol–
hexane, 18.8 min (R), 21.0 min (S), alcohol 7 (2 : 98 isopropanol–
hexane, 30.1 min (S), 35.5 min (R), alcohol 8 (2 : 98 isopropanol–
hexane, 11.6 min (R), 13.3 min (S), alcohol 11 (2 : 98 isopropanol–
hexane, 14.4 min (S), 16.4 min (R). A Chiralcel OB-H1 column was
used for alcohol 9 (10 : 90 isopropanol–hexane, 18.0 min (S), 24.4 min
(R), alcohol 10 (5 : 95 isopropanol–hexane, 22.7 min (S), 27.0 min (R),
alcohol 12 (5 : 95 isopropanol–hexane, 25.0 min (R), 31.4 min (S),
alcohol 13 (5 : 95 isopropanol–hexane, 19.6 min (S), 23.2 min (R). The
flow rate was 1 mL min21 in all cases. Further details, including
comparison of specific rotation with literature values are included in the
ESI{.
additive provided a sample without any significant impurities,
whilst the other additives led to spectra which contained signals
suggesting the formation of other RuCl2[(R)-BINAP](L) species.
Essentially the same observations were made using
[RuCl2(benzene)]2 although the exchange reactions were slightly
faster. It is not clear why the catalyst prepared in situ was more
effective than the use of preformed complex. Several other
bidentate phosphine ligands were examined for their ability to
achieve deracemisation. Under the standard reaction conditions,
(S)-Phanephos13 and (S)-xylyl-Phanephos14 reduced catalytic
activity dramatically in the reduction step and were not
investigated further. (R)-Synphos15 was comparable to (R)-
BINAP in terms of selectivity and yield when applied to the
deracemisation of 1-phenylpropanol (78% ee, 100% conversion).
As expected, the use of the other enantiomers of ligands, (S)-
BINAP and (S,S)-DPEN, led to the selective formation of the
other enantiomer of alcohol. Xylyl-BINAP 216 has been shown to
be more selective than BINAP 1 in some reactions,17 and we found
that this ligand provided very high enantioselectivity in the
deracemisation of alcohols 10 and 12, as shown in Scheme 3. The
bulkier ligand required a longer reaction time in order to achieve
the complete reduction back into the alcohol, but provided 99% ee
and 98% ee in the deracemisation process.
10 M. E. Cuculla, S. P. Nolan, T. R. Belderrain and R. H. Grubbs,
Organometallics, 1999, 18, 1299.
11 K. Mashima, K. Kusano, T. Ohta, R. Noyori and H. Takaya, J. Chem.
Soc., Chem. Commun., 1989, 1208.
12 M. Kitamura, M. Tokunaga, T. Ohkuma and R. Noyori, Org. Synth.,
1993, 71, 1.
Since these reactions proceed via an achiral ketone, the
opportunity for stereoinversion exists. Thus, one enantiomer of a
starting alcohol can be converted into the opposite enantiomer by
the same oxidation/reduction sequence employed for deracemisa-
tion reactions. These reactions were performed using xylyl-BINAP
2 as the diphosphine ligand, and led to an overall stereoinversion
of substrates 4 and 13 (Scheme 4). The lower isolated yields in
these cases are a consequence of incomplete reduction.
13 (S)-Phanephos = (S)-(+)-4,12-bis(diphenylphosphino)[2,2]paracyclo-
phane: P. J. Pye, K. Rossen, R. A. Reamer, N. N. Tsou, R. P.
Volante and P. J. Reider, J. Am. Chem. Soc., 1997, 119, 6207.
14 (S)-Xylyl-Phanephos = (S)-(+)-4,12-bis[di(3,5-xylyl)phosphino][2,2]par-
acyclophane: M. J. Burk, W. Hes, D. Herzberg, C. Malan and
A. Zanotti-Gerosa, Org. Lett., 2000, 2, 4173.
15 (R)-Synphos = (R)-(+)-6,69-bis(diphenylphosphino)-2,29,3,39-tetrahydro-
5,59-bi-1,4-benzodioxin: S. Duprat de Paule, S. Jeulin,
V. Ratovelomanana-Vidal, J.-P. Geneˆt, N. Champion and P. Dellis,
Eur. J. Org. Chem., 2003, 1931.
16 (R)-Xylyl-BINAP
= (R)-(+)-2,29-bis[di(3,5-xylyl)phosphino]-
In summary, we have developed a procedure for the derace-
misation of alcohols using a non-biological system that provides
up to 99% enantiomeric excess. The process operates using a
1,19-binaphthyl: K. Mashima, K. Kusano, N. Sato, Y. Matsumura,
K. Nozaki, H. Kumobayashi, N. Sayo, Y. Hori, T. Ishizaki,
S. Akutagawa and H. Takaya, J. Org. Chem., 1994, 59, 3064.
ruthenium catalysed oxidation of
a
racemic alcohol by
17 R. Noyori and T. Ohkuma, Angew. Chem., Int. Ed., 2001, 40, 40.
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