Efficient ruthenium-catalyzed racemization of secondary alcohols: Application to dynamic kinetic resolution

Article abstract of DOI:10.1016/S0957-4166(02)00187-8

Three new ruthenium-based catalytic systems are described which are capable of catalyzing the racemization of chiral secondary alcohols. In addition, one of these systems, [TosN(CH₂)₂NH₂]RuCl(p-cymene)/TEMPO, was able to catalyze the in situ racemization during enzymatic resolution, i.e. dynamic kinetic resolution.

Full text of DOI:10.1016/S0957-4166(02)00187-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 879–884
Efficient ruthenium-catalyzed racemization of secondary alcohols:
application to dynamic kinetic resolution
Arne´ Dijksman, Jeoffrey M. Elzinga, Yu-Xin Li, Isabel W. C. E. Arends and Roger A. Sheldon*
Biocatalysis and Organic Chemistry, Department of Biotechnology, Delft University of Technology, Julianalaan 136,
2628 BL Delft, The Netherlands
Received 8 April 2002; accepted 18 April 2002
Abstract—Three new ruthenium-based catalytic systems are described which are capable of catalyzing the racemization of chiral
secondary alcohols. In addition, one of these systems, [TosN(CH2)2NH2]RuCl(p-cymene)/TEMPO, was able to catalyze the in situ
racemization during enzymatic resolution, i.e. dynamic kinetic resolution. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
none and 3 equiv. of triethylamine, based on the sub-
strate, to achieve their activity. In addition, at least
three column-extractions are required to purify complex
1.
Enantiomerically pure secondary alcohols are impor-
tant synthetic intermediates and chiral auxiliaries.1
They can be prepared in high enantiomeric purity by
asymmetric hydrogenation2 or transfer hydrogenation3,4
of prochiral ketones using well-designed chiral Ru(II)
complexes as catalysts. Alternatively, chiral Ru(II)
complexes can also be conveniently employed in the
kinetic resolution of a racemic alcohol using either
aerobic oxidation5 or transfer hydrogenation with ace-
tone.6 In both cases, one of the enantiomers is con-
verted to the corresponding ketone.
Herein, we report on the development of readily acces-
sible ruthenium catalysts for the efficient racemization
of chiral secondary alcohols without a requirement for
substantial amounts of additives.
Higher enantiomeric excesses (e.e.s) can be obtained,
however, in the kinetic resolution of alcohols via lipase-
catalyzed7 or aminoacylase-catalyzed8 acylation. One
major limitation with both the ruthenium-catalyzed and
enzymatic resolution method is that the maximum yield
is 50% based on the racemate. As a method to over-
come this limitation, dynamic kinetic resolution pro-
cesses (or second-order asymmetric transformations)
have been introduced for secondary alcohols, in which
the alcohols are continuously racemized with metal
catalysts during an enzymatic resolution.9 For example,
[RuH(CO)2(h5-Ph4C4CO)]2 110 and (h5-indenyl)-
RuCl(PPh3)2 211 have been shown to catalyze in situ
racemization of alcohols. However, the major draw-
back of these systems is the requirement for large
amounts of additives, i.e. up to 1 equiv. of acetophe-
2. Results and discussion
2.1. Combination of RuCl2(PPh3)3 and TEMPO
For our initial experiments, we selected (S)-1-
phenylethanol as the test substrate and a RuCl2(PPh3)3/
TEMPO system as the racemization catalyst.
RuCl2(PPh3)3/TEMPO was previously shown by us to
be an efficient catalyst for the aerobic oxidation of
alcohols.12
As shown in Table 1, RuCl2(PPh3)3 alone is inactive in
the racemization of (S)-1-phenylethanol (entry 1).
* Corresponding author. Tel.: +31 152782675; fax: +31 152781415;
e-mail: r.a.sheldon@tnw.tudelft.nl
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00187-8

880
A. Dijksman et al. / Tetrahedron: Asymmetry 13 (2002) 879–884
Table 1. Ru/TEMPO-catalyzed racemization of (S)-1-
Addition of TEMPO (3 mol%), which itself is also
inactive, to RuCl2(PPh3)3 leads to a substantial increase
in activity (entry 2). The use of tert-butanol as solvent
was found to be quite essential, i.e. racemization in
other solvents resulted in much lower activities (entries
3–7).
phenylethanola
Entry
Solvent
E.e. (%)b
1c
2
3
4
5
6
7
tert-Butanol
tert-Butanol
Chlorobenzene
1,2-Dimethoxyethane
Toluene
99
38 (0)
78
88
82 (74)
73
We propose that the Ru/TEMPO-catalyzed racemiza-
tion involves initial ruthenium-catalyzed oxidation of
the alcohol, to the corresponding ketone, with TEMPO
as the stoichiometric oxidant (Scheme 1). By analogy
with the RuCl2(PPh3)3-catalyzed hydrogen-transfer
reactions14 and the RuCl2(PPh3)3/TEMPO-catalyzed
aerobic oxidation of alcohols,15 we propose that
RuH2(PPh3)3 is the active intermediate in the Ru/
TEMPO-catalyzed racemization (Scheme 2). This
ruthenium hydride subsequently reacts with the in situ
generated acetophenone to form an alkoxyrutheniu-
m(II) complex that consists of a 1:1 mixture of (a) and
(b) in which the alkoxy ligand has (R)- or (S)-configu-
ration, respectively. Reaction of complex (a) with a
molecule of (S)-1-phenylethanol affords (R)-1-
phenylethanol and complex (b). The latter undergoes
b-hydride elimination to afford acetophenone and
RuH2(PPh3)3 to complete the catalytic cycle. The over-
all result is racemization of the alcohol. The observa-
tion that catalytic amounts of RuH2(PPh3)4 and
acetophenone gave the same results, i.e. complete
racemization in 2 days, is consistent with the proposed
mechanism.
Ethyl acetate
d
[bmim]BF4
88
a Reaction conditions: (S)-1-phenylethanol (1 mmol), RuCl2(PPh3)3
(10 mmol), TEMPO (30 mmol), solvent (3 mL), N2 atmosphere,
T=70°C, 24 h.
b E.e.s13 based on HPLC results; numbers in parentheses are e.e.s
after 48 h.
c No TEMPO.
d (1-Butyl-3-methylimidazolium)tetrafluoroborate.
The use of RuCl2(PPh3)3/TEMPO as racemization cata-
lyst was then applied to some other chiral secondary
(benzylic) alcohols. Using a substrate/ruthenium ratio
of 100, alcohols 3, 4 and 5 were moderately active and
e.e.s of 45, 51 and 25%, respectively, could be obtained
within 48 h. Fortunately, extended reaction time (3–5
days) led to full racemization in all cases,16 indicating
that the catalyst was not deactivated with time.
Scheme 1. Ru-catalyzed oxidation of benzyl alcohol with
TEMPO as oxidant.
Scheme 2. Proposed mechanism for the Ru/TEMPO catalyzed racemization of (S)-1-phenylethanol.

A. Dijksman et al. / Tetrahedron: Asymmetry 13 (2002) 879–884
881
Table 2. Racemization of (S)-1-phenylethanol with 8 as
catalysta
Entry
Co-catalystb
Solvent
E.e. (%)c
1
2
3
4
–
tert-Butanol
tert-Butanol
tert-Butanol
tert-Amyl alcohol
Toluene
99
22 (0)
0
3 (0)
84
13 (10)
96
55
80
75
98
KOH (10)
KOH (20)
KOH (10)
KOH (10)
5
6d
7
KOH (30)
Toluene
K2CO3 (10)
DBU (10)e
DABCO (10)f
Triethylamine (10)
Pyridine (10)
TEMPO (45)
TEMPO (45)
TEMPO (45)
tert-Butanol
tert-Butanol
tert-Butanol
tert-Butanol
tert-Butanol
tert-Butanol
8
9
Although the Ru/TEMPO-catalyzed racemization of
chiral secondary (benzylic) alcohols is potentially inter-
esting, it is still rather slow and requires the coaddition
of 3 mol% of rather expensive TEMPO for the in situ
formation of catalytic quantities of the corresponding
ketone. This prompted us to search for other ruthenium
catalysts for the racemization of chiral alcohols.
10
11
12d
13d
14d
79
tert-Amyl alcohol 75 (48)
Toluene 41 (15)
a Reaction conditions: (S)-1-phenylethanol (1 mmol), catalyst 8 (10
mmol), co-catalyst, solvent (3 mL), N2 atmosphere, T=70°C, 24 h.
b Numbers in parentheses are amounts added in mmol.
c E.e.s13 based on HPLC results; numbers in parentheses are e.e.s
after 48 h.
2.2. Ruthenium complex with bidentate nitrogen ligand
Chiral ruthenium(II) compounds with general structure
7 have been extensively reported as catalysts for the
asymmetric transfer hydrogenation of prochiral
ketones.4,6 These complexes are synthesized from
[RuCl2(p-cymene)]2 and a chiral bidentate nitrogen lig-
and. We reasoned, therefore, that the corresponding
achiral ruthenium complex 8 (R1=R2=H) would be
likely to be an efficient catalyst for the racemization of
alcohols.
d Catalyst 8 (15 mmol).
e 1,8-Diazabicyclo[5.4.0]undec-7-ene.
f 1,4-Diazabicyclo[2.2.2]octane.
leads to a substantial increase in activity (entries 2 and
3). The choice of base was found to be essential. For
example, racemization of (S)-1-phenylethanol with 8 in
the presence of other bases resulted in much lower
activities (entries 7–11). In addition, TEMPO could
also be used as co-catalyst although the activity was
found to be lower than with KOH (entry 12).
The requirement for a strong base, such as KOH, can
be rationalized on the basis of Scheme 3. The role of
the base is to abstract a proton from the amino-group
of the ligand, resulting in the formation of the active
catalyst 9. However, when in the racemization the
preformed compound 9 was used, less activity was
observed, i.e. 50% e.e. was obtained with 9 after 24 h
compared to the 22% in the case of the in situ formed
catalyst. Analogous to Ru/TEMPO, we propose that
this interesting system is also based on a hydrido-metal
mediated hydrogen transfer mechanism (Scheme 3).
As the results in Table 2 show, compound 8 alone is
inactive as a catalyst for the racemization of (S)-1-
phenylethanol (entry 1). Addition of a base (KOH) as
co-catalyst (which itself is inactive as a catalyst) to 8
As with the Ru/TEMPO system, the solvent played an
important role (Table 2; entries 2, 4 and 5).17 The best
results were obtained in tert-amyl alcohol. In contrast,
Scheme 3. Racemization catalyzed by active catalyst 9.

882
A. Dijksman et al. / Tetrahedron: Asymmetry 13 (2002) 879–884
toluene proved to be the best solvent when TEMPO
was used as co-catalyst (entries 12–14). Based on the
results presented above, we selected KOH as the co-cat-
alyst and tert-amyl alcohol as the solvent and per-
formed the ruthenium-catalyzed racemization of some
chiral secondary benzylic alcohols,18 other than (S)-1-
phenylethanol. For (S)-indan-1-ol 5 and (S)-a-tetralol
6, complete racemization was observed within 48 h. On
the other hand, in the racemization of (R)-1-(1%-naph-
thyl)-ethanol 3 and (R)-1-phenylbutan-1-ol 4 e.e.s of 20
and 35%, respectively, were obtained. Fortunately,
these alcohols could also be fully racemized by prolong-
ing the reaction time to 4 days.
2.3. Dynamic kinetic resolution
Both RuCl2(PPh3)3/TEMPO and [TosN(CH2)2NH2]-
RuCl(p-cymene)/KOH are active and selective catalysts
for the racemization of chiral secondary (benzylic) alco-
hols. Initial attempts to combine lipase-catalyzed
acylation with these catalytic racemization systems in
either tert-amyl alcohol or tert-butyl alcohol were not
successful, i.e. only enantioselective acylation and no
racemization-activity was observed. It was subsequently
shown that both the lipase and the acyl donor had a
negative influence on the ruthenium-catalyzed racemiza-
tion. The ruthenium catalyst was deactivated by the
enzyme as well as the acyl donor in alcoholic solvents as
was shown in separate experiments (Table 3; entries 1–3).
Another interesting application is the cis/trans isomer-
ization of cyclic alcohols. For example, cis-4-tert-butyl-
cyclohexanol was converted to a cis/trans (55/45)
mixture within 24 h. We are currently examining the
scope of the cis/trans isomerization of cyclic alcohols.
Because of this we re-examined the racemization results
and decided to repeat the experiments mentioned above
in the more apolar solvent toluene. Unfortunately no
improvements were observed for RuCl2(PPh3)3/TEMPO.
On the other hand, racemization was observed in the
presence of either the lipase or the acyl donor using
[TosN(CH2)2NH2]RuCl(p-cymene)/KOH as the cata-
lytic system (Table 3; entries 4–6). However, in the
desired dynamic kinetic resolution, again only enantiose-
lective acylation was observed (Table 4, entries 2 and 3).
Table 3. Racemization of (S)-phenylethanol in the pres-
ence of additivesa
Entry
1
Co-catalystb Solvent
Additivec
E.e. (%)d
0
KOH
tert-Amyl
–
alcohol
Toluene
Toluene
2
3
4
5
6
7
8
9
Nov435
AcD
–
Nov435
AcD
–
99 (99)
99 (96)
13 (10)
4 (0)
89 (79)
42 (15)
63 (45)
72 (63)
As discussed above (Table 2), TEMPO can be used
instead of KOH as the co-catalyst in combination with
[TosN(CH2)2NH2]RuCl(p-cymene) 8. With this combi-
nation, racemization was observed in the presence of
either lipase or acyl donor (Table 3; entries 7–9). More-
over, in contrast to the other two systems, in situ
racemization occurred in the desired dynamic kinetic
resolution (Table 4; entries 4–5).
TEMPO
Nov435
AcD
a Reaction conditions: (S)-1-phenylethanol (1 mmol), catalyst 8 (15
mmol), tert-butanol (3 mL), N2 atmosphere, T=70°C.
b KOH (30 mmol) or TEMPO (45 mmol).
c Nov435=50 mg Novozym 435; AcD=2 mmol p-chlorophenyl acet-
ate.
3. Conclusion
d E.e.s13 based on HPLC results; numbers in parentheses are e.e.s
after 48 h.
In summary, we have developed three new catalytic
systems which are capable of catalyzing the racemization
Table 4. Dynamic kinetic resolution of 1-phenylethanola
Entry
Catalytic system
Conv. (%)b 1-phenylethanol
Yieldb,c 1-phenylethyl acetate (%)
1
2
3
4
5
RuCl2(PPh3)3/TEMPOd
8/KOHe
61
61
68
79
91
56
55
57
63
76
8/KOHf
8/TEMPOg
8/TEMPOd
a Reaction conditions: 1-phenylethanol (1 mmol), p-chlorophenyl acetate (3 mmol), Ru-catalyst (50 mmol), KOH (30–50 mmol) or TEMPO
(50–150 mmol), Novozym 435 (50 mg), toluene (3 mL), p-cymene (0.2 mmol-internal standard), N2 atmosphere, T=70°C, 48 h.
b Conversion and yield based on GC results; conversion corresponds to total phenylethanol (PE) disappeared after 48 h relative to internal
standard, conv.={[(mmol PE)t=0 h−(mmol PE)t=48 h]/(mmol PE)t=0}×100%; yield corresponds to {mmol (1-phenylethyl acetate)t=48 h/(mmol
PE)t=0}×100%. Difference between conversion of PE and yield of ester is accounted for by oxidation of 1-phenylethanol to acetophenone. Mass
balance obtained was close to 100% in all cases.
c E.e. of 1-phenylethyl acetate >99% in all cases.
d TEMPO (150 mmol).
e 8 (15 mmol) and KOH (30 mmol).
f KOH (50 mmol).
g TEMPO (50 mmol).

A. Dijksman et al. / Tetrahedron: Asymmetry 13 (2002) 879–884
883
of chiral secondary alcohols. However, only one of
these systems, [TosN(CH2)2NH2]RuCl(p-cymene)/
KOH (0.40 g, 7.1 mmol) in dichloromethane (7 mL) was
stirred for 5 min at room temperature. Water (7 mL) was
added and the two layers were separated. The organic
layer was washed with water (7 mL) and dried over
CaH2. The solvent was removed in vacuo to give a
purple powder (0.35 g, 77%). 1H NMR (300 MHz,
CDCl3, TMS) l 7.73 (d, 2H, 3JHH=8.4 Hz, 2{p-
tosyl}Hortho), 7.25 (d, 2H, 3JHH=8.4 Hz, 2{p-
tosyl}Hmeta), 5.70 (broad, 2H, 2{p-cymene}Hmeta), 5.50
(broad, 2H, 2{p-cymene}Hortho), 3.02 (broad, 2H,
TosNCH2), 2.83 (m, 1H, {p-cymene}CH(CH3)2), 2.75
(broad, 2H, CH2NH2), 2.40 (s, 3H, {p-tosyl}CH3), 2.32
TEMPO, is able to catalyze the in situ racemization of
chiral secondary alcohols during enzymatic acylation.
Using this system, enantiomerically pure (>99% e.e.)
1-phenylethyl acetate was obtained in 83% selectivity at
91% conversion. The only side product observed was
acetophenone, formed by oxidation of the substrate by
the TEMPO co-catalyst.
4. Experimental
4.1. General
3
(s, 3H, {p-cymene}CH3), 1.23 (d, 6H, JHH=6.9 Hz,
{p-cymene}CH(CH3)2).
19
20
RuCl2(PPh3)3 and [RuCl2(p-cymene)]2 were pre-
pared according to literature. TEMPO was purchased
from the Aldrich Chemical Co. and used without fur-
ther purification. Novozym 435 is a commercially avail-
able immobilized Candida Antarctica Lipase B.
4.5. General procedure and analysis for the racemization
of secondary (benzylic) alcohols
A typical reaction was carried out as follows: (S)-1-
phenylethanol (121 mL, 1.0 mmol), RuCl2(PPh3)3 (10
mmol; 9.6 mg) and TEMPO (30 mmol; 4.7 mg) were
dissolved in tert-butanol (3 mL) and heated under a
nitrogen atmosphere to 70°C. The reaction was moni-
tored with time by taking samples (50 mL). The samples
were diluted with n-hexane (1 mL), dried over Na2SO4
and centrifuged. The e.e. of the alcohol was determined
using HPLC-analysis (CHIRALCEL OD or OB-H 25
cm×0.46 cm column; eluent: n-hexane/iso-propanol (95/
5 or 90/10 v/v); flow rate: 0.6 mL/min). On the other
hand, the selectivity of the reaction was determined
using GC-analysis (50 m×0.53 mm CP-WAX 52 CB
column).
4.2. N-p-Toluenesulfonylethylenediamine
A mixture of p-toluenesulfonyl chloride (1.91 g, 10
mmol) in dichloromethane (25 mL) was slowly added to
a stirred solution of ethylenediamine (6.0 g, 100 mmol)
in dichloromethane (25 mL). The resulting mixture was
stirred for another 15 min, washed twice with distilled
water (25 mL) and dried over CaH2. The solvent was
removed in vacuo to give a fine white powder (1.62 g,
76%). 1H NMR (300 MHz, CDCl3, TMS) l 7.75 (d, 2H,
3JHH=8.1 Hz, 2Hortho), 7.31 (d, 2H, 3JHH=8.4 Hz,
2Hmeta), 2.95 (dd, 2H, JHH=7.2 Hz and JHH=6.0 Hz,
TosNHCH2), 2.79 (dd, 2H, 3JHH=7.2 Hz and 3JHH=6.3
Hz, CH2NH2), 2.43 (s, 3H, CH3), 1.40 (broad, 2H, NH2).
3
3
4.6. General procedure for the dynamic kinetic resolution
of 1-phenylethanol
4.3. [N-p-Toluenesulfonylethylenediamine]RuCl-
(p-cymene) 8
A typical reaction was carried out as follows: A mixture
of 1-phenylethanol (1.0 mmol; 121 ml), Ru complex 8 (15
mmol, 7.3 mg), TEMPO (45 mmol, 7.0 mg), 50 mg
Novozym 435 and p-chlorophenyl acetate (3.0 mmol) in
toluene (3 mL) was heated under a nitrogen atmosphere
to 70°C. The reaction was monitored with time by taking
samples (50 mL). The samples were diluted with n-hexane
(1 mL), dried over Na2SO4 and centrifuged. For analysis
see Section 4.5. Use of p-chlorophenyl acetate, iso-pro-
penyl acetate and vinyl acetate did not lead to satisfac-
tory results.
A mixture of N-p-toluenesulfonylethylenediamine (0.22
g, 1.0 mmol), [RuCl2(p-cymene)]2 (0.31 g, 0.5 mmol) and
triethylamine (0.28 mL) in 2-propanol (30 mL) was
heated under reflux for 1 h. After cooling to ambient
temperature, 2-propanol and the excess of triethylamine
were removed in vacuo and the residue was dissolved in
dichloromethane (30 mL). The resulting orange solution
was washed two times with water (15 mL) and dried over
Na2SO4. The solvent was removed in vacuo to give an
orange powder (0.32 g, 66%). 1H NMR (300 MHz,
CDCl3, TMS) l 7.76 (d, 2H, 3JHH=8.4 Hz, 2{p-
tosyl}Hortho), 7.31 (d, 2H, 3JHH=8.1 Hz, 2{p-
tosyl}Hmeta), 5.70 (broad, 2H, 2{p-cymene}Hmeta), 5.50
(broad, 2H, 2{p-cymene}Hortho), 3.02 (broad, 2H,
TosNCH2), 2.80 (m, 1H, {p-cymene}CH(CH3)2), 2.75
(broad, 2H, CH2NH2), 2.34 (s, 3H, {p-tosyl}CH3), 2.15
(s, 3H, {p-cymene}CH3), 1.57 (s, 2H, NH2), 1.27 (d, 6H,
3JHH=6.6 Hz, {p-cymene}CH(CH3)2).
Acknowledgements
We gratefully acknowledge the IOP (Innovation-Ori-
ented Research Program) for financial support.
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