Enantioselective oxidation of racemic secondary alcohols catalyzed by chiral Mn(III)-salen complex with sodium hypochlorite as oxidant

Article abstract of DOI:10.1016/j.catcom.2013.11.007

Chiral Mn(III)-salen complex catalyzed oxidative kinetic resolution (OKR) of secondary alcohols has been achieved with cheap and easily available sodium hypochlorite (NaClO) as oxidant. The novel protocol is very efficient for the OKR of a variety of secondary alcohols at room temperature.

Full text of DOI:10.1016/j.catcom.2013.11.007

Catalysis Communications 45 (2014) 114–117
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
Enantioselective oxidation of racemic secondary alcohols catalyzed by
chiral Mn(III)-salen complex with sodium hypochlorite as oxidant
⁎
Yuecheng Zhang, Qiao Zhou, Wenchan Ma, Jiquan Zhao
School of Chemical Engineering and Technology, Hebei University of Technology, Tianjin 300130, People's Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 August 2013
Received in revised form 16 October 2013
Accepted 3 November 2013
Available online 14 November 2013
Chiral Mn(III)-salen complex catalyzed oxidative kinetic resolution (OKR) of secondary alcohols has been
achieved with cheap and easily available sodium hypochlorite (NaClO) as oxidant. The novel protocol is very
efficient for the OKR of a variety of secondary alcohols at room temperature.
© 2013 Elsevier B.V. All rights reserved.
Keywords:
Enantioselective oxidation
Chiral Mn(III)-salen complex
Sodium hypochlorite
Secondary alcohols
1. Introduction
Corey and his co-workers [25] made detailed investigations on the
mechanism of Xia's system for the OKR of alcohols. Some of the salient
Enantiomerically pure secondary alcohols are useful chiral auxil-
iaries and intermediates in the pharmaceutical, agrochemical, and fine
chemical industries [1–3]. Generally, they have been prepared by
many methods, including asymmetric hydrogenation of prochiral ke-
tones catalyzed by metal complexes [4,5], enzymatic kinetic resolution
of racemic secondary alcohols through acylation–deacylation reac-
tions [6], and nonenzymatic kinetic resolution [7]. Among the known
processes, the oxidative kinetic resolution (OKR) of racemic alcohols
to obtain enantioenriched alcohols is an attractive and efficient method
[8–17]. Many catalysts or catalytic systems with excellent or good
resolution results, including (−)-sparteine-Pd(II), sparteine analogues-
Pd(II), N-heterocyclic carbine(NHC)-Pd(II), chiral difunctional-Ir com-
plexes, chiral(ON)-Ru(salen) complexes and chiral Mn(III)-salen com-
plexes, have been developed [18]. The OKR of alcohols with chiral
Mn(III)-salen complexes as catalysts and (diacetoxyiodo) benzene
(PhI(OAc)2) as terminal oxidant in the presence of potassium bromide
was first established by Xia et al. in 2003 [19–22]. The system for the
OKR of alcohols has the advantages of easy availability and handling of
the chiral Mn(III)-salen complexes. However, it also has the disadvantage
of using stoichiometric PhI(OAc)2 as oxidant which is poor in atom econ-
omy, very expensive and unfriendly to the environment. Recently,
N-bromosuccinimide (NBS) was used as oxidant to replace PhI(OAc)2 in
the chiral Mn(III)-salen complex catalyzed OKR of alcohols and proved
very efficient for the oxidative kinetic resolution of a variety of secondary
alcohols, including ortho-substituted benzylic alcohols [23,24].
features of the proposed mechanism are as follows: (1) A positive bro-
mine species Br2 or HOBr is generated under the reaction conditions
by oxidation of bromide ion with PhI(OAc)2. (2) It is the positive bro-
mine species that oxidizes the Mn(III)-salen complex to a dibromo-
Mn(V) species. (3) The dibromo-Mn(V) species enantioselectively
converts one enantiomer of the racemic alcohols to a ketone and left an-
other alcohol. These conclusions are supported by the facts that PhI(OAc)2
and KBr can be replaced by Br2 or HOBr as the stoichiometric oxidant in
the enantioselective oxidation. Although highly enantioselective oxida-
tions can be carried out with Br2 or HOBr as stoichiometric oxidant in-
stead of PhI(OAc)2, using stoichiometric Br2 or HOBr as the oxidant will
suffer from the inherent disadvantages of low atom efficiency (less than
50%) of bromine and environmental pollution due to one equivalent of
HBr as by-product being produced, and inconvenience in use from the
perspective of synthesis. In light of the oxybromination reaction devel-
oped recently [26–29] and Corey's mechanism about Xia's system for
the OKR of alcohols, we envisioned a new system with catalytic amount
of Br2 as cycling agent and stoichiometric NaClO as oxidant for the OKR
of alcohols catalyzed by the Jacobsen's chiral Mn(III)-salen complex [30]
(Fig. 1) in the biphasic CH2Cl2/H2O medium in the presence of KOAc.
Herein, we report the successful resolution examples by employing the
cheap and convenient system.
2. Experimental
2.1. Materials and apparatus
Hydrogen peroxide and sodium hypochlorite were obtained from
Tianjin Fuchen Chemical Reagent Factory, China. All the chemicals
⁎
Corresponding author. Tel.: +86 22 60202926/60204279; fax: +86 22 60202926.
E-mail address: zhaojq@hebut.edu.cn (J. Zhao).
1566-7367/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.catcom.2013.11.007

Y. Zhang et al. / Catalysis Communications 45 (2014) 114–117
115
“green” chemistry perspective [31,32], the best choice would be either
molecular oxygen or hydrogen peroxide since water would be the
only by-product in oxidation. Besides, molecular oxygen, as the most
abundant and cheapest oxidant, was successfully used to replace
PhI(OAc)2 in the oxidation of alcohols with Br2 as active oxidant [33].
Additionally, the cheap and easily available hydrogen peroxide was
also applied to the oxidation of HBr in literature [34,35]. Therefore, we
first tested molecular oxygen and hydrogen peroxide respectively as
oxidants in the OKR of α-phenylethanol. It is disappointing that no
enantioselective oxidation occurred in both cases (Table 1, entries 1,
2). Then another oxidant tert-butyl hydroperoxide (TBHP) was tried
again, a failure was received too (Table 1, entry 3). Finally, we used so-
dium hypochlorite as oxidant to carry out the reaction, a delightful re-
sult was obtained (Table 1, entry 4). In the initial experiment the
enantioselectivity reached about 100% when the conversion of
α-phenylethanol was kept 62.8%. Though sodium hypochlorite is not
good compared to molecular oxygen and hydrogen peroxide as oxidant
from an environmental point of view, it is still a good choice due to its
cheapness and easy availability. Besides, the main by-product in the reac-
tion is sodium chloride, which can be recycled in large scale chemical pro-
cess. Only NaClO as oxidant is efficient in the reaction can be explained as
NaClO can oxidize Br− to Br2 in the catalytic cycle in basic medium, how-
ever, acidic medium is necessary for the same transformation with the
other tested oxidants.
N
N
Mn
Cl
O
O
Fig. 1. Structure of Jacobsen's chiral Mn(III)-salen complex.
were used as received. The secondary alcohols were obtained from
Alfa Aesar China (Tianjin) Co., Ltd. Samples were analyzed on a
Shandong Lunan Ruihong Gas Chromatograph (SP-6800A) equipped
with a hydrogen flame detector and a chiral column (Cyclodex-β,
30 m × 0.25 mm (i.d.), 0.25 μm). HPLC experiments were performed
on Agilent-1260 plus (Daicel Chemical Industries, Tokyo Japan)
equipped with a 1260-DAD detector and a normal Daicel Chiralcel
OD-H column, ø4.6 × 250 mm.
2.2. Catalytic procedure
The initial experimental results indicated that NaClO was feasible to
replace PhI(OAc)2 in the OKR of α-phenylethanol, therefore, we investi-
gated it in detail. Corey [25] pointed that slow addition of oxidant to pre-
vent the detrimental build up of HBr was very important in the chiral
Mn(III)-salen complex catalyzed OKR of alcohols. Thus, we inspected
the effect of the addition time of NaClO on the OKR of α-phenylethanol.
The results are shown in Fig. 2. It can be seen that both the conversion
and the enantiomeric excess increased with extending the addition time
of NaClO as expected, when the addition time of NaClO was 40 min,
both of them reached their maximums, and did not increase with
prolonging the addition time of NaClO. Thus, we chose 40 min as the suit-
able addition time of NaClO in the subsequent experiments.
In a typical process, a mixture of ( )-1-phenylethanol (0.122 g,
1 mmol), chiral Mn(III)-salen complex (0.0127 g, 2 mol%), Br2 (4.1 μL,
8 mol%), KOAC (0.1962 g, 2 mmol), CH2Cl2 (2.0 mL), and water
(4.0 mL) was magnetically stirred in a 10-mL two-necked flask at
20 °C. The oxidant NaClO (0.289 g, 0.80 mmol) was then added slowly
within 40 min, and the reaction was monitored by GC/HPLC equipped
with a suitable chiral column.
2.3. Analysis of the reaction mixture
After the addition of ( )-1-phenylethanol, chiral Mn(III)-salen
complex, CH2Cl2, H2O and Br2, 10 μL of the organic phase was removed
and put into a 10 mL of volumetric flask, the mixture 1 was dissolved
with mobile phase to constant volume. After the addition of NaClO,
another 10 μL of the organic phase was removed and put into a 10 mL
of volumetric flask, the mixture 2 was dissolved with mobile phase to
constant volume. The conversion of ( )-1-phenylethanol was deter-
mined by HPLC with single-point external standard method. HPLC
conditions: Hexane/i-ProH = 95: 5 (v/v), 1.0 mL/min, 210 nm, 20 °C.
The OKR of various secondary alcohols was explored with the novel
catalytic system. The results are summarized in Table 2.
It can be observed from Table 2 that most of the tested substrates
were smoothly resolved with good to excellent enantioselectivity
comparable to those obtained from Xia's catalytic system in literature
[19–22]. Similar to the results in literature [19–22], the OKR of
α-phenylethanol and its derivatives including 1-(4-fluorophenyl)
ethanol, 1-(4-chlorophenyl)ethanol, 1-(4-bromophenyl)ethanol,
1-(4-methylphenyl) ethanol, proceeded readily with excellent
Conversionð%Þ
Table 1
the peak area of mixture 1−the peak area of mixture 2
Choice of oxidant with α-phenylethanol as substrate.a
¼
the peak area of mixture 1
ð1Þ
ð2Þ
ꢀ100%
R‐S
eeð%Þ ¼
ꢀ 100%
R þ S
lnð1−ConvÞð1−eeÞ
lnð1−ConvÞð1 þ eeÞ
krel
¼
:
ð3Þ
d
Entry
Oxidant
Dosage (mmol)
Conv (%)b
ee (%)c
krel
Besides, the conversion of ( )-1-phenylethanol was also deter-
1
2
3
4
O2–NaNO2–Br2
H2O2
TBHP
Oxygen ball
0.70
0.80
3.37
5.57
26.37
62.85
13.48
7.34
12.06
~100
−1.94
−9.88
2.26
–
mined by GC with area normalization method. GC conditions: column
temperature: 100 °C, injector 220 °C, detector: 220 °C, pressure:
0.05 MPa.
NaClO
0.80
a
Reaction conditions: α-phenylethanol 1 mmol, Mn(III)-salen 0.02 mmol, Br2
0.08 mmol, KOAc 2 mmol, CH2Cl2 2 mL, H2O 4 mL, reaction temperature 20 °C, reaction
time 40 min (the oxidants were added within 40 min).
3. Results and discussion
b
The conversion was determined by GC with area normalization method.
Determined by GC with a chiral column.
krel = ln[(1 − Conv)(1 − ee)]/ln[(1 − Conv)(1 + ee)].
c
In principle any oxidants able to oxidize HBr to Br2 are candidates for
the chiral Mn(III)-salen complex catalyzed OKR of alcohols. From a
d

116
Y. Zhang et al. / Catalysis Communications 45 (2014) 114–117
Table 2
OKR of various secondary alcohols.a
100
80
60
40
20
0
100
80
60
40
20
0
d
Entry
1e
Substrates
Conv (%)b
46.9
ee (%)c
84.3
krel
Conv
ee
120.2
2f
55.5
85.9
14.6
0
10
20
30
40
50
Addition Time of NaClO (min)
Fig. 2. Optimization of the addition time of NaClO.
3g
4g
5g
6g
7g
8h
61.8
60.1
56.0
64.5
29.8
47.5
93.4
96.9
95.2
95.4
19.7
82.1
12.1
18.1
25.2
11.2
3.3
enantioelectivity (Table 2 entries 3–6). For example, a conversion of
64.5% and ee of 95.4% were received in case of 1-(4-methylphenyl)
ethanol as substrate. However, this system was not efficient in the
OKR of substrate having a strong electron donating substituent at
the para position. Only a conversion of 29.8% and ee of 19.7% were
obtained in case of 1-(4-methoxyphenyl)-1-ethanol as substrate
(Table 2, entry 7). The results indicated that the electrostatic prop-
erties of the substituents have influence on the reaction.
51.9
This system also showed good performances on the OKR of substrate
with a substituent ortho to the -hydroxyethyl. For instance, the ee and
9i
48.8
50.4
52.6
53.4
66.9
20.2
11.8
67.6
11.3
1.8
krel for the OKR of 1-(2-chlorophenyl)-1-ethanol were 82.1% and 51.9
(Table 2, entry 8). These results are compared to the ones received
with NBS as oxidant [23], and much higher than the ones (3.0% and
1.6) with PhI(OAc)2 as oxidant [19]. It is difficult to tell what causes
this improvement. Same as the cases with PhI(OAc)2 as oxidant the
alcohols with a long aliphatic carbon chain were oxidized with poor selec-
tivity. The longer the carbon chain is, the lower enantioselectivity is re-
ceived (Table 2, entries 1, 10, 11). Besides, this system is also effective in
the OKR of the secondary alcohols with fused-rings (Table 2 entries 12–
14). In case of 1-(2-naphthyl)ethanol as substrate, the enantioselectivity
was 85.2% when the conversion was kept 52.4%. Hence, the newly devel-
oped OKR system, Mn(III)-salen/Br2/NaClO, remains the excellent perfor-
mances of Mn(III)-salen/PhI(OAc)2 developed by Xia et al. [19–22]. To
demonstrate practicality of this methodology, a multigram scale reaction
was carried out with α-phenylethanol as substrate. Similar results were
received when the loading amount of α-phenylethanol was increased
to 50 mmol (Table 2, entry 2).
10i
11i
12i
1.4
7.6
13i
14i
54.0
52.4
75.4
85.2
10.1
21.1
Based on our experimental results and the knowledge in literature
[25,33], we propose a mechanism for the novel catalytic system cata-
lyzed OKR of alcohols (Scheme 1).
In the OKR process, the Br− from Br2 previously added in catalytic
amount replaces Cl− of complex 1 to give complex 2. Complex 2 reacts
with Br2 to generate dibromo-Mn(V) species 3 and HBr. The generated
HBr is oxidized by NaClO to regenerate Br2, meanwhile, the species 3
enantioselectively converts one enantiomer of the racemic alcohols
to a ketone remaining another enantiomer to complete the OKR as
described by Corey [25].
a
Reaction conditions: substrate 1 mmol, KOAc 2 mmol, CH2Cl2 2 mL, H2O 4 mL, reaction
temperature 20 °C, reaction time 40 min.
b
The conversion was determined by HPLC with single-point external standard method.
Determined by HPLC with Daicel Chiralcel OD-H column.
krel = ln[(1 − Conv)(1 − ee)]/ln[(1 − Conv)(1 + ee)].
1 mol% of Mn(III)-salen complex, 6 mol% Br2, 0.80 equiv of NaClO.
c
d
e
f
α-Phenylethanol 50 mmol, 1 mol% of Mn(III)-salen complex, 6 mol% Br2, 0.90 equiv of
NaClO, CH2Cl2 100 mL, H2O 200 mL.
g
1 mol% of Mn(III)-salen complex, 6 mol% Br2, 1.00 equiv of NaClO.
2 mol% of Mn(III)-salen complex, 8 mol% Br2, 1.00 equiv of NaClO, reaction time
h
100 min.
4. Conclusions
i
2 mol% of Mn(III)-salen complex, 8 mol% Br2, 0.80 equiv of NaClO.
In conclusion, we replaced PhI(OAc)2 with cheap and easily available
NaClO as oxidant to construct a novel chiral Mn(III)-salen catalyzed sys-
tem for the OKR of secondary alcohols. The novel system exhibited sim-
ilar performances with that with stoichiometric PhI(OAc)2 as oxidant.
This system was very effective for the OKR of α-phenylethanol and its
derivatives as well as secondary alcohols with fused-rings under mild
reaction conditions.

Y. Zhang et al. / Catalysis Communications 45 (2014) 114–117
117
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