New efficient ruthenium catalysts for racemization of alcohols at room temperature

Article abstract of DOI:10.1016/j.tetlet.2004.07.013

(η⁵-Pentaphenylcyclopentadienyl)RuCl(CO)₂ was found to catalyze efficiently the racemization of chiral alcohols such as (S)-1-phenylethanol, (S)-1-phenylpropan-2-ol, (S)-4-phenylbutan-2-ol and (S)-4-methoxy-1-phenylethanol at room temperature in the presence of a base. The catalytic activity of three other Ru(II) complexes was also investigated. The effects of halide and solvent were studied as well.

Full text of DOI:10.1016/j.tetlet.2004.07.013

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6799–6802
New efficient ruthenium catalysts for racemization of alcohols
at room temperature
G a´ bor Csjernyik, Kriszti a´ n Bog a´ r and Jan-E. B a¨ ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Received 23 March 2004; revised 23 June 2004; accepted 2 July 2004
Available online 30 July 2004
5
Abstract—(g -Pentaphenylcyclopentadienyl)RuCl(CO) was found to catalyze efficiently the racemization of chiral alcohols such as
2
(S)-1-phenylethanol, (S)-1-phenylpropan-2-ol, (S)-4-phenylbutan-2-ol and (S)-4-methoxy-1-phenylethanol at room temperature in
the presence of a base. The catalytic activity of three other Ru(II) complexes was also investigated. The effects of halide and solvent
were studied as well.
Ó 2004 Elsevier Ltd. All rights reserved.
Racemization of organic compounds is an important
process that has attracted considerable attention
recently in connection with the preparation of enantio-
OH
OAc
enzyme
Ph
(R)-1
acyl donor
fast
Ph
1
merically pure compounds. Separation of enantiomers
in racemates via resolution, crystallization or chiral
chromatography is still the most common way of
obtaining enantiomerically pure compounds in the
industry. With this technique, however, the yield of
one enantiomer cannot exceed 50% and the other
enantiomer is not used. However, by racemization the
unwanted enantiomer can be brought back into the
process. An important application of racemization is
in combination with kinetic resolution and this is exem-
MLn
MLn
OH
enzyme
Ph
acyl donor
slow
(
S)-1
Scheme 1. Dynamic kinetic resolution (DKR) of alcohols.
plified for enzymatic resolution of alcohols in Scheme
2
1
. If racemization can be achieved in situ during the en-
zymatic resolution it leads to an asymmetric transforma-
tion of the second kind (Scheme 1). This process has
been termed dynamic kinetic resolution (DKR).
mediates. Another mechanistic dichotomy is that the
hydrogen transfer with monohydrides can occur with
or without coordination of the ketone.
7
A number of Rh, Ir and Ru complexes are known to
racemize alcohols under relatively mild reaction condi-
Although many transition metal complexes are known
to racemize alcohols, only a few of these have been suc-
cessfully employed in chemoenzymatic DKR. For exam-
1
b,3–6
tions.
These racemization reactions proceed via
hydrogen transfer from the chiral alcohol to the corre-
sponding ketone, which is generated in situ in catalytic
amounts. The hydrogen transfer reaction proceeds via
metal hydride intermediates and two principally differ-
ent mechanisms have been proposed for Rh, Ir and
2
,8
ple the dimeric ruthenium complex 2
and more
9
recently the amino analogue 3 have been found to be
compatible with the enzyme and the acyl donor in
DKR (Fig. 1). Also, other ruthenium catalysts have
1
0,11
6
been used to some extent.
Ru catalysis. One mechanism involves monohydride
intermediates and the other proceeds via dihydride inter-
A common feature with catalysts 2 and 3 is that they are
sterically hindered. Both 2 and 3 have four phenyl
groups on the cyclopentadienyl ring. In addition to
causing steric bulk, the phenyl groups may influence
*
Corresponding author. Tel.: +46-8-674-7178; fax: +46-8-154908;
e-mail: jeb@organ.su.se
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.013

6800
G. Csjernyik et al. / Tetrahedron Letters 45 (2004) 6799–6802
a
Table 1. Solvent effect on the racemization with 8a
Ph
Ru
O
O
Ph
Ph
Ph
CO
Ph
Ph
H
H
Entry
Solvent
Ee of 1 (%)
Ph
Ph
OC
NH
Ph
Cl
Ph
Ph
Ru
CO OC
1
2
Cyclohexane
t-BuOMe
Diisopropyl ether
0.2
33
Ph Ru
OC
OC
b
3
61
4
PhCH
3
0.0
2
3
a
0
.5mol% of 8a, 0.5mol% of KOtBu, 5lL of iPrOH, 1mL of solvent,
Figure 1.
1
93lL of decane, at rt, for 30min, under argon.
.5 mL.
b
1
the electronic properties of the complex. Complexes 2
and 3 also have CO ligands, which are electron-with-
drawing ligands. To estimate the effect of the sterically
hindered cyclopentadienyls and the electron-withdraw-
ing effect by the ligands, it was of interest to study ruthe-
nium complexes 4–8 as racemization catalysts for
alcohols.
(>98%). Complete racemization was achieved in 45
and 10min, respectively. The half times of the racemiza-
tions were approximately 2.2min for 7 and <2min for
a.
8
The racemization protocol was performed in different
solvents and the results are summarized in Table 1.
R
R
R
R
R
Apolar solvent such as cyclohexane and toluene (Table
1, entries 1, 4) proved to be ideal for the racemization
process. Complete racemizations were obtained within
30min in these solvents, whereas in tert-butyl-methyl
ether (entry 2) there was still a 33% enantiomeric excess
after 30min and racemization was only complete after
Ru
L
X
L
4
5
6
7
R=H, L=PPh
R=CH , L=PPh
R=H, L=CO, X=Cl
R=CH , L=CO, X=Cl
3
, X=Cl
8a R=Ph, L=CO, X=Cl
8b R=Ph, L=CO, X=Br
8cR=Ph, L=CO, X=I
3
3
, X=Cl
3
1
h. Moreover, in diisopropyl ether (entry 3) the rate
of racemization dropped significantly, and a prolonged
reaction time was required to reach complete racemiza-
tion (4.5h). Due to the low solubility of the active ruthe-
nium catalyst the amount of diisopropyl ether was
increased from 1 to 1.5mL.
1
2
13
Complexes 4–5 and 6–8 were prepared by published
literature methods.
The rate of racemization of (S)-1-phenyl ethanol with
complexes 4–8 as the catalyst in toluene was studied
Scheme 2). The active catalyst from the cyclopentadi-
enyl ruthenium chlorides is the corresponding ruthe-
nium hydride (X = H).
The rate dependence on the halide for the racemization
was studied for catalyst precursors 8 (Fig. 2). The rate of
the racemization was only slightly effected by the differ-
ent catalyst precursors used 8a (X = Cl), 8b (X = Br), 8c
(
(
X = I), and all three catalyst had completely racemized
These hydrides were generated in situ from the reaction
of the appropriate ruthenium complex 4–8 with isopro-
panol and 1equiv of base. Thus, treatment of 1mol% of
phosphine complex 4 with 1mol% of potassium t-butox-
ide in the presence of isopropanol in toluene at room
temperature followed by the addition of (S)-1-phenyl-
ethanol and stirring at room temperature for 6h resulted
in complete racemization. The half time (t1/2) for the
the alcohol after 15min. The chloride gave the best re-
sult and full racemization was obtained within 10min.
Therefore, we decided to use chloride 8a in the racemi-
1
4
racemization was 2h. In an analogous experiment
the pentamethyl substituted ruthenium catalyst 5 race-
mized (S)-1-phenylethanol in 5h with a t1/2 of 2h.
On applying the same reaction conditions to 6 the enan-
tiopurity of (S)-1-phenylethanol did not change even
after prolonged reaction time.
Carbonyl complexes 7 and 8a were also applied to the
racemization of (S)-1-phenylethanol. Rapid racemiza-
tion of (S)-1-phenylethanol occurred with only
0
.5mol% catalyst and with excellent substrate recovery
OH
OH
Ru-cat., KOtBu
i-PrOH, PhCH3
Ph
(
Ph
(rac)-1
S)-1
Figure 2. Racemization of (S)-1 at room temperature in toluene
catalyzed by 8a–c (0.5mol%).
Scheme 2. Racemization of secondary alcohols.

G. Csjernyik et al. / Tetrahedron Letters 45 (2004) 6799–6802
6801
a
Table 2. Racemization of secondary alcohols with 8a
Ph
Ph
Ph
Ru
Entry
Substrate
Timerac (min)
t
1/2 (min)
Ph
Ph
OC
OH
Cl
1
10
<2
13
CO
8a
OH
1
OH
base, Ph
(
S)-1
2
75
Ph
Ph
MeO
Ph
Ph
OC
9
OH
OH
Ph
Ru
CO
O
H
O
Ph
3
4
n.r
––
––
Ph
Ph
rac-1
Cl
Br
14
1
0
OH
Ph
Ph
Ph
OH
n.r.
Ph
Ph
OC
Ph
(
S)-1
Ph
Ph
Ph
1
1
Ru
CO
H
1
Ph
Ph
OC
5
b
5
OH
45
90
7
Ru
CO
6
H
O
Ph
1
2
OH
1
6
18
O
Ph
1
3
a
0.5mol% of 8a, 0.5mol% of KOtBu, 5lL of iPrOH and 1mL of
Scheme 3. The mechanism of the racemization.
PhMe at rt under argon.
2mol% of 8a.
b
in the presence of base generates a ruthenium alkoxide
complex (14), which undergoes a spontaneous b-hydride
elimination to give the active hydride catalyst 15.
Insertion of the ketone into the ruthenium hydride bond
of 15 produces the racemic alkoxide complex 16.
1
9
zation studies of some different alcohols. Some addi-
tional alcohols were subjected to the racemization pro-
tocol with 8a as catalyst. The acquired results are
summarized in Table 2.
Exchange of the racemic alkoxide in 16 with alcohol
6
(
S)-1 releases rac-1 and regenerates 14. Control experi-
The enantiopurity of (S)-4-methoxy-1-phenylethanol (9)
was diminished completely within 75min using 8a as
catalyst and resulted in 50% racemization after 13min
ments revealed the necessity of the added base. Omitting
the base resulted in complete suppression of the racemi-
zation and the enantiopure (S)-1-phenylethanol was
recovered in 100% yield.
(
Table 2, entry 2). Unfortunately, the racemization of
-bromo or 4-chloro substituted (S)-1-phenylethanol
10 and 11) did not occur (entries 3 and 4). It has previ-
ously been demonstrated that ruthenium hydride species
4
(
In conclusion, (S)-1-phenylethanol was successfully
racemized with 8a or 7 as catalyst at room tempera-
ture with half times of about 2min or less. With these
catalysts the catalytic loading was kept low, only
1
5
can readily dehalogenate aryl chlorides. However, (S)-
-phenyl-2-propanol (12) and (S)-4-phenyl-2-butanol
13) were completely racemized within 45 and 90min,
1
(
0
.5mol% being required to achieve complete racemiza-
tion with excellent substrate recovery (>98%). Also,
-methoxy-(S)-1-phenylethanol, (S)-1-phenyl-2-propa-
respectively (entries 5 and 6). The half time of the racemi-
zation were 7min for (S)-1-phenyl-2-propanol and
4
1
8min for (S)-4-phenyl-2-butanol.
nol and (S)-4-phenyl-2-butanol were racemized with
excellent substrate recovery with 8a as catalyst. How-
ever, the extension of the racemization protocol to hal-
ogen substituted secondary alcohols was unsuccessful
probably due to dehalogenation.
Several ruthenium-catalyzed transfer-hydrogenation
protocols have been established over the past dec-
7
,16–18
ade.
The ruthenium-mediated transfer hydrogena-
tion of alcohols consists of two reaction steps:
dehydrogenation of the alcohol followed by the addition
of the hydrogens to a susceptible hydrogen acceptor.
Therefore, the ruthenium-catalyzed racemization of al-
cohols falls into the category of redox racemization. The
racemization is accomplished by the successive oxidation
Acknowledgement
Financial support from the Swedish Foundation for
Strategic Research is gratefully acknowledged.
(
dehydrogenation) to the corresponding ketone, followed
by readdition of the abstracted hydrogens to the ketone
formed yielding the racemic alcohol.
References and notes
The mechanism of the racemization is given in Scheme
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