Racemization of secondary alcohols catalyzed by ruthenium: Application to chemoenzymatic dynamic resolution

Article abstract of DOI:10.1016/j.tetasy.2011.10.007

In this paper, we have shown that the [RuCl₂(p-cymene)] ₂ complex associated with simple hemisalen ligands is able to racemize (S)-1-phenylethanol. The influence on the racemization process of the ligand's structure as well as the nature of a co-catalyst have been evaluated and optimized. This [RuCl₂(p-cymene)]₂/Ligand/TEMPO racemization system was then associated with the Candida Antarctica B lipase in order to carry out dynamic kinetic resolution experiments on rac-phenylethanol. This led us to identify the best conditions for effective DKR, which was then applied to various secondary benzylic and aliphatic alcohols. It was thus possible to obtain (R)-1-cyclohexylethyl acetate from rac-1-cyclohexylethanol in quantitative conversion and with high enantioselectivity (98%).

Full text of DOI:10.1016/j.tetasy.2011.10.007

Tetrahedron: Asymmetry 22 (2011) 1790–1796
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Racemization of secondary alcohols catalyzed by ruthenium: application
to chemoenzymatic dynamic resolution
Mounia Merabet-Khelassi a, Nicolas Vriamont b, Louisa Aribi-Zouioueche a, , Olivier Riant b,
⇑
⇑
a Equipe de Synthèse Asymétrique et Biocatalyse, LCOA, Université Badji Mokhtar-Annaba, B.P12, 23000 Annaba, Algeria
b Institute of Condensed Matter and Nanosciences Molecules, Solids and reactivity (IMCN/MOST), Université Catholique de Louvain, Bâtiment Lavoisier, Pl. Louis Pasteur, 1,
bte 3, 1348 Louvain La Neuve, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
In this paper, we have shown that the [RuCl2(p-cymene)]2 complex associated with simple hemisalen
ligands is able to racemize (S)-1-phenylethanol. The influence on the racemization process of the ligand’s
structure as well as the nature of a co-catalyst have been evaluated and optimized. This [RuCl2(p-
cymene)]2/Ligand/TEMPO racemization system was then associated with the Candida Antarctica B lipase
in order to carry out dynamic kinetic resolution experiments on rac-phenylethanol. This led us to identify
the best conditions for effective DKR, which was then applied to various secondary benzylic and aliphatic
alcohols. It was thus possible to obtain (R)-1-cyclohexylethyl acetate from rac-1-cyclohexylethanol in
quantitative conversion and with high enantioselectivity (98%).
Received 20 September 2011
Accepted 18 October 2011
Available online 19 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
The first examples of ruthenium-lipase systems for the DKR
of racemic alcohols were developed by Williams et al. using
During the past ten years, efficient methods for deracemization
have been developed and offer new pathways for the production of
enantioenriched molecules with high yields and selectivities.1 One
of the most popular methods developed so far is the combination
of lipases, which is able to select an enantiomer of a racemic alco-
hol through acylation, with a metal complex catalyst that allows
the racemization of the starting alcohol. This so-called dynamic ki-
netic resolution2 has been developed as a very efficient method for
the production of enantiomerically enriched alcohols. As this pro-
cess can be considered as atom economic, and combines two dif-
ferent reactions in a one pot procedure, it is now well recognized
to integrate some basic principles of green chemistry (Scheme 1).3
the [Ru(PPh3)Cl2] complex which exhibited only moderate activ-
ity.4 Later on, Park et al.5 and Bäckvall et al.6 reported on the
synthesis of new active complexes on a wide range of substrates
and further optimization has shown that ruthenium complexes
are amongst the most efficient to carry out such processes
(Scheme 2, I and II).7 Shvo’s ruthenium dimer complex III was
also studied extensively for the DKR process with noticeable
success.8
There are only a few examples in the literature where simple
ruthenium complexes such as [RuCl2(p-cymene)]2 IV have been
used for the dynamic kinetic resolution of secondary alcohols. Park
et al. used it for the successful racemization of allylic alcohols, but
harsh reaction conditions were needed.9 This complex is inexpen-
sive and might prove valuable for large scale applications.10 We
have previously used this precursor for the enantioselective reduc-
tions of ketones in water,11 and have also found that this complex
could racemize phenylethanol when associated with hemisalen
type ligands during the base catalyzed enantioselective reduction
of ketones in isopropanol.12
Ruthenium complex IV was studied by Sheldon with a mono-
tosylated diamine ligand and KOH or TEMPO as a co-catalyst,
and was previously shown to be an efficient catalyst for the aerobic
oxidation of alcohols.13 It was also associated to a tri-amine ligand
by Trauthwein14 and used successfully in the dynamic kinetic res-
olution of various racemic benzylic alcohols with a Candida Antarc-
tica B lipase (CAL-B). The DKR was carried out at 80 °C in toluene
over 45 h. A 50% fold excess of the corresponding ketone needed
to be added to the reaction media to obtain the acylated alcohol
Fast
SR
PR
kR
Theoretical yield : 100% PR
kS >> kR
krac
M
krac~kR
Slow
kS
PS
SS
Scheme 1. Dynamic kinetic resolution.
⇑
Corresponding authors. Fax: +213 0 38871712 (L.A.Z.); +32 010474168 (O.R.).
E-mail addresses: louisa.zouioueche@univ-annaba.org (L. Aribi-Zouioueche),
olivier.riant@uclouvain.be (O. Riant).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.10.007

M. Merabet-Khelassi et al. / Tetrahedron: Asymmetry 22 (2011) 1790–1796
1791
O
O
Ph
Ru
Ph
Ph
H
H
Ph
Ph
Ph
Ph
Cl
Ph
Ph
Ph
Ph
Cl
Ru
Ru
Ph
Ru
Ph
CO
CO
Cl
PPh3
PPh3
Ru
OC
Ru
Cl
Cl
OC
Cl
OC
OC
IV
I
II
III
Scheme 2.
with good conversion. Thus, the simple ruthenium precursor
[RuCl2(p-cymene)]2, cannot racemize the alcohols without the
addition of an appropriate ligand or by activation with triethyl-
amine and oxygen. Thus there is still a need for inexpensive and
tunable ligands that could activate this complex for the efficient
racemizations of alcohols and that could be applied to the DKR of
racemic alcohols by combination with lipases.
Based on our preliminary observations that simple hemisalen li-
gands could effectively activate ruthenium dimer IV toward the
racemization of 1-phenylethanol, we decided to investigate this
family of ligands, which can be synthesized in a straightforward
manner by simple condensation of a salicylaldehyde and an achiral
amino alcohol, diamine, or aminophenol. A small library of eight li-
gands L2–L9 bearing electron active substituents on the aromatic
ring was then prepared in order to investigate the potential influ-
ence of electronic effects on the course of racemization of a model
enantioenriched alcohol (Scheme 3). While saturated ligand L3
was obtained by the reduction of L2 with sodium borohydride in
methanol to investigate the influence of the coordination of the in-
ner nitrogen atom, L8 and L9 were prepared to study the influence
of the third coordination alcohol ligand on the hemisalen structure.
2. Results and discussion
For the first time, we have investigated the racemization of a
model chiral alcohol (S)-1-phenylethanol (S)-1 by the combination
of a simple precursor [RuCl2(p-cymene)]2 [Ru] coordinated with li-
gands L2–L9 (Scheme 4). We have optimized this racemization
reaction according to the key reaction parameters, prior to combin-
ing it with the CAL-B lipase resolution acylation.
2.1. Racemisation of (S)-1 by the catalytic system [Ru]/TEMPO
We first evaluated the ruthenium/co-catalyst ratio in order to
optimize the racemization power of our catalytic system. Racemi-
zation experiments were carried out in various solvents on a mmol
scale of (S)-1 (>99.5% ee) with a 5 mol % loading of the metal pre-
cursor and various quantities of a chosen co-catalysts (TEMPO,
KOH, NEt3). Various racemization experiments were carried out
with the small library of ligands L2–L9 and monitored by chiral
GC analysis. As stated earlier, those ligands had different electroac-
tive substituents on the aromatic ring and some further variations
on coordinating capacities.
N
OH
NH
OH
OH
N
OH
N
OH
OH
O2N
OH
Br
OH
L5
L2
L3
L4
N
OH
N
OH
N
NHMe
N
OH
Cl
OH
OH
OH
MeO
OH
L6
L9
L7
Scheme 3.
L8
Cl
O
OH
OH
L
[RuCl2(p-cymène)]2 /
(S)
+
solvent; 24h; 70°C
co-catalyst A or B
1
1a
(S)-
1
( )-
A
B
cat. 2.5 mol%
L / [Ru] = 1
KOH
[Ru]
TEMPO /
= 1 or 3
N
O.
Scheme 4.

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M. Merabet-Khelassi et al. / Tetrahedron: Asymmetry 22 (2011) 1790–1796
The results from Table 1 showed that in the absence of a co-cat-
(entries 6 and 7); whereas the replacement of an amino alcohol
alyst, the ruthenium precursor had no ability to racemize the start-
ing alcohol (S)-1. The reaction was carried out in isopropanol as a
solvent in order to initiate the catalytic cycle by transferring a hy-
dride ligand to the ruthenium catalyst. The addition of 1 equiv of
TEMPO (per ruthenium atom) allowed the racemization to proceed
with an aminophenol in L9, had a detriment effect on the racemi-
zation process
Dee = 59% (entry 13). Some typical behaviors in the
first few reaction hours of the [Ru]/L systems are given below
(Fig. 1).
slowly with a
in the reaction media. Increasing the [Ru]/TEMPO to 3 increases the
racemization efficiency to ee = 71%, albeit with the formation of
4% of acetophenone. When toluene was used as the solvent instead
of isopropanol, the racemization efficiency of the catalyst increases
Dee = 31; after 24 h, no acetophenone was detected
Racemisation experiments
100
without L,
D
L4, L5, L8,
L9
95
90
85
80
75
70
L2, L6
dramatically (Dee = 93%) and the alcohol was almost completely
racemized after 24 h. However, with this catalytic system, a large
amount of acetophenone (25%) was detected in the reaction media.
Toluene was then kept as a solvent and a 1:3 ratio of [Ru]/TEMPO
was used for further experiments and the ligands L2–L8 were then
tested keeping those optimized conditions. The measurements
show a clear influence of the structure of the ligands on the race-
mization efficiencies of the resulting catalyst.
L3
L7
When KOH was used with ligand L2 (entry 5), the racemization
process was almost complete after 6 h at room temperature with a
0
1
2
3
4
5
6
7
time (h)
D
ee = 82. When TEMPO was used for activation of the ruthenium
Figure 1.
catalyst, various amounts of acetophenone were also detected in
the reaction media. The amount of ketone depended on the struc-
ture of the ligand and the best chemoselectivity in favor of the
alcohol was observed for L5 and L7 (entries 9 and 11). On the other
hand, the best racemisation efficiency was obtained for ligands L2,
This preliminary work on the influence of the structural param-
eters of the ligands on the racemization power of their correspond-
ing ruthenium complexes shows some guidelines on the more
efficient structures. However, in order to gather information for
the optimization of the process, we decided to evaluate the library
of ligands in a standard DKR of a model racemic alcohol. From for-
mer evaluations in our laboratory, toluene was selected for the
DKR experiments since isopropanol was not a suitable solvent.
D
ee = 85% (entry 6) and L6, Dee = 89% (entry 10), the former yield-
ing the best chemoselectivity. The substitution on the aromatic
ring of L2 by an electron donating group (L6) had little influence
on the racemization efficiency of the resulting catalysts. However,
a strong decrease in the racemization efficiency was observed with
ligands L5, L7 and L8, 24% <
Dee < 35% (entries 9, 11 and 12).
2.2. Dynamic kinetic resolution of ( )-1-phenylethanol by the
[Ru]/L/TEMPO system with CAL-B
The significant decrease of the racemization efficiency might be
explained by the decrease of the ketone concentration in the reac-
tion media, which seems necessary to initiate the racemization
mechanistic cycle. This hypothesis might be supported by the ki-
netic racemization profile over time. We have found an induction
period is required as it is initially very slow before a significant
amount of the ketone is formed and then a rapid increase of the
racemization process is observed.
In the standard procedure, 2.5 mol % of [RuCl2(p-cymene)]2,
5 mol % of ligand and 3 equiv of co-catalyst per Ru atom were dis-
solved under an inert atmosphere (Ar) in dry toluene (2 mL) at
70 °C (Scheme 5). Next, 1 mmol of rac-phenylethanol and 3 equiv
of p-chlorophenylacetate (p-CPA) or isopropenyl acetate (IA) as
acylating agents were added to the mixture under stirring, respec-
tively after 5 and 15 min. After 3 days at this temperature, the reac-
tion mixture was quenched with saturated NH4Cl and extracted
Finally, the reduction of the imine function leading to ligand L3,
had little influence on the racemization process 74% <
Dee < 85%
Table 1
Racemization experiments of (S)-1 with the [Ru]/L/co-catalyst system
Entry
Solventa
Ligand
Co-catalyst
eeib (%)
eefb (%)
[1/1a]b
D
eec
1
2
3
4
5
6
7
8
9
10
11
12
13
i-Propanol
i-Propanol
i-Propanol
Toluene
i-Propanol
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
—
—
—
—
L2
L2
L3
L4
L5
L6
L7
L8
L6
—
99.5
99.5
99.5
99.5
88
99.5
99.5
99.5
99.5
99.5
99.5
99.5
99.5
99.5
68
28.5
6
6
14
26
30
64
100/0
100/0
96/4
75/25
100/0
80/20
82/18
83/17
92/8
76/24
98/2
85/15
78/22
0
TEMPOd
TEMPOe
TEMPOe
KOH
31
71
93
82
85
74
69
35
89
34
24
94
TEMPOe
TEMPOe
TEMPOe
TEMPOe
TEMPOe
TEMPOe
TEMPOe
TEMPO/Et3Nf
10.5
65.5
75
5
a
1 mmol of (S)-phenylethanol, 2.5 mol % of [RuCl2(p-cymene)2]2, 5 mol % of ligand and 50
l
mol of TEMPO in 3 mL of toluene.
b
GC measurement on a CHIRALSIL-DEX CB column (25 m; 0.25 mm; 0.25
lm). In cases with 99.5% ee: this enantiomer was obtained by enzymatic kinetic resolution of ( )-
1. In cases with 88% ee: the enantiomer was obtained by the asymmetric reduction of acetophenone.
c
Racemization efficiency
TEMPO/Ru = 1.
TEMPO/Ru = 3.
D
ee = eei À eef. eei = initial enantiomeric excess before racemization. eef = enantiomeric excess obtained after racemization.
d
e
f
0.05 mL added as an additive.

M. Merabet-Khelassi et al. / Tetrahedron: Asymmetry 22 (2011) 1790–1796
1793
T=70°C; t=72h
OH
OH
OAc
O
L
[RuCl2(p-cym)]2 /
CAL-B, toluene
(S)
(R)
(R)
+
co-catalyst A, B or C
acylating agent
B
A
2
1
1a
cat. 2.5 mol%
KOH
L
[Ru]
= 1
/
TEMPO / [Ru] = 3
C
N
O.
Na2CO3
Scheme 5.
with Et2O. The organic layers were combined, dried over Na2SO4
and evaporated under vacuum. The yield and ee were determined
by chiral GC analysis. As stated earlier, the library of ligands was
tested in the DKR reaction in order to find the most efficient and
CAL-B compatible catalytic system. The details of the reaction
conditions and related results are given in Table 2.
2.3. Dynamic kinetic resolution of secondary alcohols with the
[Ru]/L2/TEMPO system associated to CAL-B
The conditions for an efficient association of the [Ru]/L2/TEMPO
system and CAL-B have been set up for rac-phenylethanol. We ap-
plied the same experimental DKR conditions to a range of second-
ary alcohols in order to validate our system. The results are listed
in Table 3.
At first, we considered the performance of L2 under various
conditions. Although the best selectivity and ee were obtained
with the KOH/p-CPA system, the yield was particularly low (en-
try 1). On the other hand, the TEMPO/p-CPA system offered an
excellent yield combined with good selectivity and ee (entry
2), which was expected from preliminary evaluation (Table 2).
This demonstrates that there is a strong influence of the co-cat-
alyst on the racemization process and that the nature of the
acylating agent partially controls the reaction. Turning L2 into
L3 by reduction of the imine moiety sharply diminished both
the conversion and the ee of the process (entry 5). The p-chloro-
phenyl acetate displayed better conversion than isopropenyl ace-
tate, as shown in entries 2 and 3, and 6 and 7. In this last case,
the ee decreased too. It is noteworthy that very few DKR simul-
taneously using the [RuCl2(p-cymene)]2 and the IA have been re-
ported to date. The internal oxido–reduction process of the
whole reaction, required for the racemization step, seemed to
be sensitive to electronic factors since an electron withdrawing
or electron donating group on the phenol ring modified the
selectivity (entries 6 and 9). Under the usual TEMPO/p-CPA con-
ditions, ligands L5, L7, L8 and L9 (entries 8, 10, 11 and 12)
exhibited high selectivities and good ee’s, albeit with only mod-
erate conversions. The two best DKR systems shown in Table 2
were obtained with L2 and L6, offering similarly attractive re-
sults. We decided to keep L2 as the standard candidate for fur-
ther experiments because of its simpler structure.
The [RuCl2(p-cymene)]2/L2/TEMPO racemization system,
when associated to CAL-B, is able to carry out the dynamic ki-
netic resolution of secondary alcohols with satisfactory effi-
ciency. The conversions reported in Table 3 are indeed higher
than 90%, except for one case (77%, entry 2) and are quantitative
for three alcohols (entries 4, 6 and 7). Nevertheless, these values
occurred with moderate selectivities to those usually observed,
as indicated by the acetate/ketone ratio. This production of ke-
tone likely originates in the oxido–reduction process between
the secondary alcohol and the corresponding ketone, required
for the racemization reaction, prior to the acylation. High enanti-
oselectivities of 97–98% were reached with three bicyclic alco-
hols as well as with 1-cyclohexylethanol (alcohols 5, 6, 7 and
9, entries 3, 4, 5 and 7). A moderate enantioselectivity was
achieved with 1-(4-ethoxyphenyl)ethanol (alcohol 4, entry 2)
while it was very low with 1-(4-methoxyphenyl)ethanol (alcohol
3, entry 1) and
a-tetralol 8 (entry 6). The [RuCl2(p-cymene)]2/L2/
TEMPO racemization system, associated to CAL-B is thus able to
transform a benzylic alcohol into its enantiomerically enriched
corresponding acetate. A noteworthy result was found with 1-
cyclohexylethanol (alcohol 9, entry 7) since both the conversion
and the selectivity were complete. Moreover, the enantioselectiv-
ity reached 98%. Particularly, in this the resulting (R)-acetate was
isolated in a 94% yield.
3. Conclusion
Table 2
We have developed a catalytic racemization system for second-
ary alcohols based on the simple metallic precursor [RuCl2(p-cym-
ene)]2 and TEMPO as the co-catalyst. It has been shown that the
association with various salenol ligands L2–L9 could dramatically
improve the racemization power of the system, even if a significant
amount of acetophenone was created during the process. The
[RuCl2(p-cymene)]2/Ligand/TEMPO racemization system was then
associated with the Candida Antarctica B lipase in order to carry
out dynamic kinetic resolution experiments on rac-phenylethanol.
The results of these DKR experiments demonstrated that L2 was
the best ligand of our library since its very simple structure al-
lowed both high conversion (70–91%) and enantioselectivity
(93.5–96%) to be obtained in the resulting acetate. Moreover, these
outcomes were associated to low amounts of ketone in the reaction
mixture (acetate/ketone ratio: 88:12 to 93:7). We have also evalu-
ated our [RuCl2(p-cymene)]2/Ligand/TEMPO/CAL-B system in the
DKR of some secondary alcohols of interests. The best result was
[Ru]/L/TEMPO system combined to CAL-B for the DKR of 1-phenylethanol
Entrya
Ligand
Co-catalyst
Acyl. agent
Cc (%)
[2/1a]c
ee(R) (%)
c
1
2
3
4
5
6
7
8
9
L2
L2
L2
L2
L3
L4
L4
L5
L6
L7
L8
L9
KOH
p-CPA
p-CPA
IA
p-CPA
p-CPA
p-CPA
IA
p-CPA
p-CPA
p-CPA
p-CPA
p-CPA
61
91
70
87
57
93
76
75
88
70
54
70
100/0
88/12
93/7
92/8
97/3
79/21
90/10
94/6
97/3
95/5
92/8
94/6
99.5
93.5
91
96
84
97
78
92
95
TEMPO
TEMPO
Na2CO3
b
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
10
11
12
91
89
88
a
1 mmol of rac-1-phenylethanol and 3 equiv of acylating agent in dry toluene
(2 mL) under Ar, 70 °C, 3 days.
b
Addition of 1 equiv Na2CO3.
GC measurements on a CHIRALSIL-DEX CB column (25 m; 0.25 mm; 0.25 lm).
c

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M. Merabet-Khelassi et al. / Tetrahedron: Asymmetry 22 (2011) 1790–1796
Table 3
DKR of secondary alcohols with the [Ru]/L2/TEMPO system associated to CAL-B
a
Entrya
Substrate
Product
Ca (%)
Acetate/ketoneb
60/40
ee((R)-acetate) (%)
OH
OAc
OAc
OAc
1
98
35
MeO
EtO
MeO
EtO
OH
2
3
4
77
96
70/30
80/20
67/33
73
97
97
OH
OH
OAc
100
MeO
MeO
OH
OAc
5
6
7
100
91
75/25
98
7
OH
OAc
87/13
100
100/0 (94%)b
98
OH
OAc
a
GC measurements on a CHIRALSIL-DEX CB column (25 m; 0.25 mm; 0.25
Isolated yield.
lm).
b
obtained with 1-cyclohexylethanol. In this last case, both quantita-
tive conversion and selectivity with high enantioselectivity (98%).
tion evolution and enantiomeric excess of alcohol were monitored
by taking samples for CG analysis. The samples were diluted with
diethyl ether and washed with a saturated solution of NH4Cl, and
filtered on silica before injection.
4. Experimental
4.1. General
4.3. General procedure for the dynamic kinetic resolution of
alcohols 1–9
NMR spectra were recorded on Brucker spectrometers
(300 MHz for 1H, 75 MHz for 13C). Chemical shifts are reported in
d ppm from tetramethylsilane with the solvent resonance as the
internal standard for 1H NMR and chloroform-d (d 77.0 ppm) for
13C NMR. Coupling constants (J) are given in Hertz. The following
abbreviations classify the multiplicity: s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, br = broad signal. The mass
spectra were obtained from the mass-service at Université catho-
lique de Louvain (FINNIGAN-MAT TSQ 7000 and FINNIGAN-MAT
LQC spectrometers). IR spectra were recorded on a Shimadzu
FTIR-8400S spectrometer. Optical rotations were determined using
a Perkin-Elmer 241 Polarimeter at room temperature using a cell of
1 dm length and k = 589 nm. The chemical analysis of the reaction
mixture was performed by gas chromatography (ThermoFinnigan
Trace GC) equipped with an automatic autosampler and using a
The reaction was carried out under an argon atmosphere at
70 °C for 72 h in
[RuCl2(p-cymene)2]2 (15 mg), 5 mol % of ligand, 150
a
dry Schlenk tube with 2.5 mol % of
mol of
l
TEMPO (23 mg) and 40 mg of CAL-B in 2 mL of toluene. After
5 min, 1 mmol of racemic alcohol was added. The mixture took
a red color. After 15 min, 3 mmol of p-chlorophenylacetate were
added to the red reaction mixture. The reaction conversion and
enantiomeric excess of the alcohol were monitored by taking
samples for CG analysis. The samples were diluted with diethyl
ether and washed with a saturated solution of NH4Cl, and fil-
tered on silica. After 72 h, the dark reaction mixture was filtered
on Celite, washed with a saturated solution of NH4Cl and ex-
tracted with ether. The organic layers were dried over Na2SO4,
and concentrated in vacuo.
CHIRALSIL-DEX CB column (25 m; 0.25 mm; 0.25 lm).
4.4. General procedure for the synthesis of the ligands
4.2. General procedure for the racemisation of 1-phenylethanol
A round bottomed flask was loaded with 1 equiv of amino-alco-
hol in 5 mL of ethanol. Next, 1 equiv of aldehyde and a few drops of
acetic acid were added. The reaction mixture was stirred at reflux
for 12 h. At the end of the reaction, the mixture was concentrated
in vacuo. Purification by flash chromatography on silica gel or re-
crystallization was carried out if necessary.
Racemization was carried out under an argon atmosphere at
70 °C for 1 day. A dry Schlenk tube was loaded under argon with
1 mmol of (S)-phenylethanol (121
ene)2]2 (15 mg), 5 mol % of ligand and 50
(7.6 mg) in 3 mL of toluene. The mixture took a red color. The reac-
l
L), 2.5 mol% of [RuCl2(p-cym-
l
mol of TEMPO

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1795
4.4.1. (E)-2-((1-Hydroxy-2-methylpropan-2-ylimino)methyl)
phenol
OH); 6.79–6.92 (m, 3H aromatic); 8.34 (s, 1H, CH imine); 13.4 (s,
1H, OH). 13C NMR (75 MHz, CDCl3): d (ppm) = 23.57; 55.94;
61.11; 71.15; 114.9; 117.95; 118.34; 119.61; 151.88; 155.8; 162.
MS (D-ESI; m/z): 224.28 ([M+1]+, 100%).
1 equiv of salicylaldehyde (1 g: 8.19 mmol); 1 equiv of 2-ami-
no-2-methylpropan-1-ol (0.79 g). The product was obtained as a
dark yellow solid in a 95% yield. IR (film, cmÀ1):
m = 736.76;
756.04; 794.62; 852.48; 887.19; 921.91; 1056.92; 1114.78;
1145.64; 1280.65; 1627.81; 2896.88; 2927.74; 2970.17; 3363.62.
1H NMR (300 MHz, CDCl3): d (ppm) = 1.33 (s, 6H, 2 Â CH3); 1.445
(s, 2H, 2 Â OH); 3.59 (s, 2H, CH2–OH); 6.83–6.94 (m, 2H aromatic);
7.25–7.33 (m, 2H aromatic); 8.37 (s, 1H, CH imine). 13C NMR
(75 MHz, CDCl3): d (ppm) = 23.56; 60.92; 71.00; 117.49; 118.207;
118.58; 131.69; 132.52; 162. MS (D-ESI; m/z): 194.2 ([M+1]+,
100%).
4.4.6. (E)-2,4-Dichloro-6-((1-hydroxy-2-methylpropan-2-
ylimino) methyl phenol
1 equiv of 2.5-dichlorosalicylaldehyde (2 g); 1 equiv of 2-ami-
no-2-methylpropan-1-ol. The product was obtained as deep yellow
crystals in a 97% yield. IR (film, cmÀ1):
m
= 736.76; 852.48; 894.91;
1018.34; 1080.06; 1141.78; 1207.36; 1454.23; 1473.51; 1504.37;
1643.24; 3263.33. 1H NMR (300 MHz, Acetone d6):
d
(ppm) = 1.40 (s, 6H, 2 Â CH3); 2.89 (sl, 1H, OH); 3.62 (s, 2H, CH2–
OH); 4.50 (sl, 1H, OH); 7.39–7.43 (m, 2H aromatic); 8.56 (s, 1H,
imine). 13C NMR (75 MHz, acetone-d6): d (ppm) = 22.83; 60.66;
69.32; 118; 118.52; 124.22; 130.10; 132.21; 161.92; 162.27;
205.31. MS (D-ESI; m/z): 262.20 ([M]+, 100%).
4.4.2. (E)-2-((1-Hydroxy-2-methylpropan-2-ylamino) methyl)-
4-nitrophenol
1 mmol of ligand L2 with 1.5 equiv of NaBH4 in 5 mL of ethanol.
The product was obtained, after the standard work up, as a white
solid in a 90% yield. IR (film, cmÀ1):
m
= 732.9; 756.04; 779.19;
4.4.7. (E)-2-(2-Hydroxybenzylideneamino) phenol
864.05; 1049.2; 1180.35; 1257.5; 1369.37; 1589.23; 1820.68;
1897.82; 2966.31; 3301.91; 3367.48; 3386.77. 1H NMR
(300 MHz, CDCl3): d (ppm) = 1.13 (s, 6H, 2 Â CH3); 3.46 (s, 2H,
CH2–OH); 3.89 (s, 2H, CH2–NH); 5.16 (sl, 3H, NH + 2 Â OH); 6.71–
6.80 (ma, 2H aromatic); 6.93–6.96 (d, J = 7.11 Hz, 1H aromatic);
7.1–7.14 (t, J = 7.47 Hz, 1H aromatic). 13C NMR (75 MHz, CDCl3):
d (ppm) = 23.10; 45.49; 54.34; 68.80; 116.56; 119.105; 123.38;
128.07; 128.66; 158.15. MS (D-ESI; m/z): 196.15 ([M+1]+, 100%).
1 equiv of 2-aminophenol (2 mmol; 0.218 g); 1 equiv of salicy-
aldehyde. The product was obtained as red crystals in a 97% yield.
IR (film, cmÀ1):
m = 783.05; 902.62; 1026.06; 1137.92; 1222.79;
1242.07, 1272.93, 1303.79; 1415.65; 1458.08; 1485.09; 1527.52;
1593.09; 1631.67; 1809.1; 2935.46; 3047.32. 1H NMR (300 MHz,
DMSO): d (ppm) = 6.85–6.98 (ma, 2H aromatic); 7.09–7.15 (ma,
2H aromatic); 7.34–7.41 (ma, 2H aromatic); 7.59–7.62 (ma, 2H aro-
matic); 8.96 (s, 1H, imine); 9.73 (sl, 1H, OH); 13.78 (sl, 1H, OH). 13
C
NMR (75 MHz, DMSO): d (ppm) = 116.97; 117.15; 119.19; 119.97;
120.05; 128.51; 132.77; 133.29; 135.42; 151.58; 161.18; 162.16.
MS (D-ESI; m/z): 214.32 ([M+1]+, 100%).
4.4.3. (E)-2-((1-hydroxy-2-methylpropan-2-ylimino) methyl)-4-
nitrophenol
1 equiv of 5-nitrosalicylaldehyde (2 g; 11.97 mmol); 1 equiv
(1.06 g); 1 equiv of 2-amino-2-methylpropan-1-ol. The product
was obtained as yellow solid in a 95% yield. IR (film, cmÀ1):
4.5. Synthesis of 4-chlorophenyl acetate
m
= 736.76; 837.05; 1080.06; 1134.07; 1207.36; 1292.22;
155.57 mmol de para-chlorophenol (20 g), 1.1 equiv of Et3N and
1.5 equiv of anhydride acetic. After the standard work up, the ace-
tate is obtained as an uncolored oil, in a 95% yield. IR (film, cmÀ1):
1326.93; 1353.94; 1519.8; 1542.95; 1604.66; 1650.95; 2094.55;
3193.9; 3618.21. 1H NMR (300 MHz, DMSO): d (ppm) = 1.35 (s,
6H, 2 Â CH3); 3.33 (sl, 1H, OH); 3.42–3.43 (d, J = 4.68Hz; 2H,
CH2–OH); 5.41 (sl, 1H, OH); 6.52–6.55 (d, J = 9.69 Hz; 1H aromatic);
7.99–8.00 et 8.02–8.03 (dd, J = 2.7 Hz; 1H aromatic); 8.53–8.54 (d,
J = 2.88 Hz; 1H aromatic); 8.80–8.84 (d, J = 11.49 Hz; 1H, imine).
13C NMR (75 MHz, DMSO): d (ppm) = 23.39; 39.13; 39.69; 39.97;
40.25; 40.52; 40.8; 60.57; 68.35; 113.56; 123.61; 129.77; 133.59;
133.74; 164.88; 179.47. MS (D-ESI; m/z): 239,34 ([M+1]+, 100%).
m
= 682.75; 717.47; 798.47; 840.91; 906.48; 941.2; 1010.63;
1087.78; 1164.92; 1485.09; 1758.96. 1H NMR (300 MHz, CDCl3):
d (ppm) = 2.28 (s, 3H, H3C–C@O); 7.02–7.05 (d, J = 8.7Hz, 3H aro-
matic); 7.32–7.35 (d, J = 8.7Hz, 3H aromatic). 13C NMR (75 MHz,
CDCl3): d (ppm) = 8.64; 21.03; 46.17; 116.85; 123.00; 129.20;
129.46; 131.14; 149.15; 169.24. MS (CI; m/z): 170.1 ([M]+, 100%).
4.6. Chiral GC analysis
4.4.4. (E)-4-Bromo-2-((1-hydroxy-2-methylpropan-2-ylimino)
methyl) phenol
The chemical analysis was performed by gas chromatography
(ThermoFinnigan Trace GC) equipped with an automatic autosam-
pler and using a CHIRALSIL-DEX CB column (25 m; 0.25 mm;
1 equiv of 5-bromosalicylaldehyde (2 g; 9.95 mmol); 1 equiv
(0.88 g) of 2-amino-2-methylpropan-1-ol. The product was ob-
tained as a yellow solid in a 96% yield. IR (film, cmÀ1):
m
= 732.9;
821.62; 921.91; 1056.92; 1280.65; 1481.23; 1481.23; 1566.09;
1631.67; 3278.76; 3988.52. 1H NMR (300 MHz, CDCl3):
0.25 lm).
d
4.6.1. Phenylethanol
(ppm) = 1.16 (s, 2H, 2 Â OH); 1.31 (s, 6H, 2 Â CH3); 3.56 (s, 2H,
CH2–OH); 6.74–6.77 (m, 1H aromatic); 7.32–7.34 (m, 2H aro-
matic); 8.25 (s, 1H, CH imine). 13C NMR (75 MHz, CDCl3): d
(ppm) = 23.53; 24.48; 24.67; 53.06; 61.02; 69.33; 70.41; 109;
119.4; 120.07; 133.85; 135.54; 161.02; 162.93; 179.35. MS (D-
ESI; m/z): 272.07 ([M]+, 100%).
Isotherm 140 °C. tR: (R)-phenylethanol = 3.90 min; (S)-
phenylethanol = 4.07 min.
4.6.2. 1-(4-Methoxyphenyl) ethanol
Isotherm 135 °C. Debit: 1.2 mL/min. tR1 = 12.682 min.
tR2 = 13.52 min.
4.4.5. (E)-2-((1-Hydroxy-2-methylpropan-2-ylimino)methyl)-4-
methoxy phenol
4.6.3. 1-(4-Ethoxyphenyl) ethanol
Isotherm 155 °C. tR1 = 13.058 min. tR2 = 13.90 min.
1 equiv of 5-methoxysalicylaldehyde (2 g); 1 equiv of 2-amino-
2-methylpropan-1-ol. The product was obtained as a brown solid
4.6.4. 2-(Naphthalen-2-yl)ethanol
in a 94% yield. IR (film, cmÀ1):
m
= 736.76; 921.91; 1037.63;
1153.35; 1269.07; 1326.93; 1492.8; 1589.23; 1635.52; 2966.31;
3390.63. 1H NMR (300 MHz, CDCl3):
(ppm) = 1.32 (s, 6H,
2 Â CH3); 3.60 (s, 2H, CH2–OH); 3.79 (s, 3H, O–CH3); 3.83 (s, 1H,
Isotherm 170 °C. tR1 = 10.183 min. tR2 = 10.535 min.
d
4.6.5. 1-(6-Methoxynaphthalen-2-yl) ethanol
Isotherm 180 °C. tR1 = 17.185 min. tR2 = 17.747 min.

1796
M. Merabet-Khelassi et al. / Tetrahedron: Asymmetry 22 (2011) 1790–1796
4.6.6. 1-Indanol
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tR2 = 51.945 min.
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4.6.8. 1-(Phenylethyl) acetate
Isotherm 140 °C. tR1 = 2.980 min. tR2 = 3.162 min.
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4.6.10. 1-(4-Ethoxyphenyl)ethyl acetate
Isotherm: 155 °C. tR1 = 12.19 min. tR2 = 13.368 min.
4.6.11. 1-(Naphthalen-2-yl) ethyl acetate
Isotherm: 170 °C. tR1 = 8.63 min. tR2 = 8.935 min.
4.6.12. 1-(6-Methoxynaphthalen-2-yl) ethyl acetate
Isotherm: 180 °C. tR1 = 16.165 min. tR2 = 16.612 min.
4.6.13. 2,3-Dihydro-1H-inden-yl acetate
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tR2 = 46.992 min.
4.6.14. 1,2,3,4-Tetrahydronaphthalen-1-yl acetate
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4.6.15. 1-Cyclohexylethylacetate
Isotherm: 125 °C. tR1 = 4.88 min. tR2 = 5.473 min.
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Algerian Ministry of Education and Scientific Research (FNR
2000 and PNR), Université catholique de Louvain and FNRS are
gratefully acknowledged for financial support of this work. UCL is
acknowledged for a grant ‘cooperation au développement’.