Rapid racemization of chiral non-racemic sec-alcohols catalyzed by (η5-C5(CH3)5)Ru complexes bearing tertiary phosphine-primary amine chelate ligands

Article abstract of DOI:10.1016/j.tetlet.2003.08.005

A ternary catalyst system of Cp* RuCl(cod)-2-diphenylphosphinoethylamine-KOt-Bu (Cp=η ⁵-C₅(CH₃)₅, cod=1,5-cyclooctadiene) causes rapid racemization of chiral non-racemic sec-alcohols, which results from the reversible hydrogen transfer between sec-alcohols and ketones. Both tertiary phosphine and primary amine functionalities in the ligand are responsible for the high rate.

Full text of DOI:10.1016/j.tetlet.2003.08.005

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7521–7523
Rapid racemization of chiral non-racemic sec-alcohols catalyzed
5
by (h -C (CH ) )Ru complexes bearing tertiary
5
3 5
ꢀ
phosphine–primary amine chelate ligands
Masato Ito, Akihide Osaku, Sachiko Kitahara, Makoto Hirakawa and Takao Ikariya*
Department of Applied Chemistry, Graduate School of Science and Engineering and Frontier Collaborative Research Center,
Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan
Received 25 June 2003; revised 30 July 2003; accepted 1 August 2003
5
Abstract—A ternary catalyst system of Cp*RuCl(cod)–2-diphenylphosphinoethylamine–KOt-Bu (Cp*=h -C (CH ) , cod=1,5-
5
3 5
cyclooctadiene) causes rapid racemization of chiral non-racemic sec-alcohols, which results from the reversible hydrogen transfer
between sec-alcohols and ketones. Both tertiary phosphine and primary amine functionalities in the ligand are responsible for the
high rate.
©
2003 Elsevier Ltd. All rights reserved.
Recently we have developed ternary catalyst systems
hydrogen transfer between alcohols and ketones. We
now describe the rapid racemization of chiral non-
racemic sec-alcohols based on the redox properties of
based on Cp*RuCl(cod)/amine/base for highly effective
1
2,3
reductive transformation. The outcome of the reac-
tions are strongly influenced by the amine ligands and
the solvents used. N,N-Dimethylaminoethylamine (1a)
serves as an excellent ligand for hydrogenation of
this newly developed catalyst system.
Our initial experiments focused on the change in ee
values of optically active 2-phenylethanol ((R)-2a,
>99% ee) in the presence of Cp*Ru(II)-based catalyst
system with several ligands ((R)-2a:Cp*RuCl-
(cod):ligand:KOt-Bu=100:1:1:1, [(R)-2a]=0.1 M in
toluene, 30°C) (Scheme 1) and results are summarized
1
a
ketones, while 2-diphenylphosphinoethylamine (1b)
ligand is effective not only for hydrogenation of
1b
ketones but also for hydrogenolysis of epoxides (Fig.
).
1
4
Noticeably, 2-propanol is the best solvent in both reac-
tions, but its roles in each reaction differ significantly.
We found that in the Cp*RuCl(cod)/1a/base catalyst-
promoted hydrogenation, 2-propanol only facilitates
in Table 1. The rate of the reaction was found to be
affected by the structure of amine ligands. When 1b was
employed, the starting alcohol was completely racem-
ized within 1 h (entry 2). The turnover frequency (TOF,
−
1
the heterolytic cleavage of H and does not participate
2
h ) of the catalyst, which is defined here by the follow-
TOF×T −2
1
in any redox process. On the other hand, 2-propanol
ing equation: 0.99
=10 f(T) ( f(T): the ee value
does participate in the redox process in which
Cp*RuCl(cod)/1b/base catalyst system may effect a
of the alcohol after a reaction time of T h), is estimated
−1
to be 479 h for 1b. Changing the primary amino
group in 1b to secondary amino group (1c) slightly
lowered the catalytic activity and it required 2.4 h for
the complete racemization (entry 3). In contrast, the ee
value of 2a remains unchanged with 1d, 1,2-bis-
(
diphenylphophino)ethane (dppe), or P(C H ) over 24
6 5 3
h (entries 4, 8, and 9). These results indicated that NH
group in the ligand is crucial for the present racemiza-
tion. In fact, other tertiary phosphine–primary amine
hybrid ligands such as 1f and 1g also cause the decrease
in the ee values, albeit with much slower rate; 13 h and
12 h, respectively for the complete racemization (entries
6 and 7). It is also noted that little decrease of the ee
Figure 1. Amine ligands for Cp*Ru(II)-catalyzed reactions.
5,6
ꢀ
Supplementary data associated with this article can be found at
doi:10.1016/j.tetlet.2003.08.005
*
Corresponding author. Tel.: +81-3-5734-2636; fax: +81-3-5734-2637;
e-mail: tikariya@apc.titech.ac.jp
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.005

7
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M. Ito et al. / Tetrahedron Letters 44 (2003) 7521–7523
A variety of chiral sec-alcohols are rapidly epimerized
7
at 30°C in the presence of the Ru catalyst with 1b. As
shown in Table 2, both benzylic alcohols (2a–c, 2g–h)
and aliphatic alcohols (2d–f) are equally susceptible to
this rapid racemization. trans-4-t-Butylcyclohexanol
(
trans-2i), which is the thermodynamically more stable
isomer than cis-2i, is epimerized into the equilibrium
mixture (trans:cis=4:1) within 24 h. Furthermore, (±)-
exo-norborneol (2j) also give a mixture containing (±)-
endo-norborneol (2k) (2j:2k=85:15) after 42 h of
reaction.
Scheme 1.
Table 1. Reaction of (R)-2a in the presence of
a
Cp*RuCl(cod)/ligand/KOt-Bu catalyst system
TOF,b h−1
T
rac c
, (h)
Entry
Ligand
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
dppe
P(C H )
21
479
191
<1
6
36
40
<1
<1
22d
<1
2.4
–
77
13
12
–
d
The racemization of optically pure (R)-2a with 1b
proceeded rapidly in diethyl ether, CH Cl , or toluene,
2
2
while the use of methanol, ethanol, or 2-propanol con-
8
siderably reduced the rate, presumably because these
–
6
5 3
primary or secondary alcoholic solvents serve as hydro-
gen sources for the hydrogen transfer and therefore
they compete with the substrate in the catalysis. This
was further confirmed by the isotope-labeling experi-
ment using 2-propan-2-d-ol (99.6% atom D). Dissolving
2-propan-2-d-ol, Cp*RuCl(cod), 1b, and KOt-Bu in
a
Reaction conditions: 2a:Ru:1b:KOt-Bu=100:1:1:1, [2a]=0.1–0.5 M
in toluene.
See text.
b
c
Reaction time required for complete racemization, i.e. f(T)<1.
Calculated values.
d
benzene-d6
(alcohol:Ru:1b:KOt-Bu=100:1:1.5:1.5)
caused a rapid H–D scrambling between the 2-position
and the hydroxyl proton in the alcohol, to afford an 1:1
mixture of (CH ) CHOH(D) and (CH ) CDOH(D)
Table 2. Reaction of sec-alcohols in the presence of
a
Cp*RuCl(cod)/1b/KOt-Bu catalyst system
3
2
3 2
Entry
Alcohol
Time (h)
Products
within 1 h at 30°C.
1
2
3
4
5
6
7
8
9
(R)-2a (>99% ee)
(R)-2b (>99% ee)
(R)-2c (>99% ee)
(R)-2d (>99% ee)
(R)-2e (>99% ee)
(R)-2f (98% ee)
(R)-2g (97% ee)
(R)-2h (>99% ee)
trans-2i
1
2
8
1
3
1
2
1
24
42
2a (<1% ee)
2b (<1% ee)
2c (<1% ee)
2d (<1% ee)
2e (2% ee)
2f (<1% ee)
2g (<1% ee)
2h (<1% ee)
2i (trans:cis=4:1)
2j:2k=85:15
The racemization as well as the H–D scrambling
strongly suggest a possible formation of the intermedi-
ary ketones. In fact, the reaction of (R)-2a with the
Cp*RuCl(cod)/1b/KOt-Bu catalyst system in acetone
resulted in the formation of acetophenone and 2-
propanol, instead of racemization (Scheme 2).
1
0
2j
a
Reaction conditions: alcohol:Ru:1b:KOt-Bu=100:1:1:1, [alcohol]=
.1–0.5 M in toluene, 30°C.
0
was observed with structurally analogous NN ligand 1a
or SN ligand 1e (entries 1 and 5). These results clearly
indicated that the aminophosphine ligands bearing NH
group are responsible for the rapid racemization of 2a.
Scheme 2.

M. Ito et al. / Tetrahedron Letters 44 (2003) 7521–7523
7523
References
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7
4
. A typical experimental procedure: A degassed solution of
(
R)-2a (452 mg, 3.7 mmol) in anhydrous toluene (37 mL)
was transferred to a mixture of Cp*RuCl(cod) (14.1 mg,
0
0
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2
-propanol employed as the substrates. We believe that
mixing Cp*RuCl(cod), 1b, and KOt-Bu may generate
Cp*Ru(amido) complex (3) in situ and the interconver-
sion between 3 and Cp*RuH(amine) complex (4)
should be responsible for this rapid racemization via
1b
5,6
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(
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6
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In conclusion, we have found that Cp*RuCl(cod)/1b/
KOt-Bu catalyst system effects extremely rapid racem-
ization of chiral non-racemic sec-alcohols. In view of
recent advances in dynamic kinetic resolution (DKR) of
rac-secondary alcohols in which the transition metal-
catalyzed racemization is coupled with enzymatic trans-
3
7
. The ternary system of Cp*RuCl(cod)/1b/KOt-Bu was used
here as a catalyst for experimental convenience, although the
1
b
preformed complex Cp*RuCl(1b), which is obtainable
from Cp*RuCl(isoprene) and 1a, epimerized sec-alcohols in
toluene containing KOt-Bu at a comparable rate in compari-
son to the ternary system.
. For instance, the ee of optically pure (R)-2a only dropped
to 53% after 1 h and 25% ee after 2 h, respectively, in
3
b,d,9
formation of alcohols,
our racemization catalyst
may also contribute to the DKR since it exhibits high
catalyst performance under conditions favorable for the
enzymatic reactions. Further studies on the DKR using
our catalyst system are in progress.
8
2-propanol (0.1 M) under otherwise identical conditions.
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Supplementary material
4
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Acknowledgements
We appreciate financial support from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan (No. 12305057 and 14078209 ‘Reaction Control
of Dynamic Complexes’) and from Taisho Pharmaceu-
tical Co. Ltd (M.I.). This work is partly supported by
The 21 Century COE Program.