Electro-oxidative kinetic resolution of sec-alcohols by using an optically active N-oxyl mediator

Article abstract of DOI:10.1016/S0040-4039(00)01419-2

Electro-oxidative kinetic resolution of sec-alcohols mediated with a catalytic amount of an optically active N-oxyl was performed by use of a simple undivided cell under constant current conditions. The selectivity factor (S-value) increased remarkably when the reaction was performed at lower temperatures. The optically active N-oxyl was recovered and used repeatedly without any change in efficiency and selectivity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01419-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8131–8135
Electro-oxidative kinetic resolution of sec-alcohols by using
an optically active N-oxyl mediator
Manabu Kuroboshi, Hiroshi Yoshihisa, Mariana N. Cortona, Yusuke Kawakami,
Zake Gao and Hideo Tanaka*
Department of Applied Chemistry, Faculty of Engineering, Okayama University Tsushima-naka 3-1-1, Okayama,
Okayama 700-8530, Japan
Received 19 July 2000; accepted 18 August 2000
Abstract
Electro-oxidative kinetic resolution of sec-alcohols mediated with a catalytic amount of an optically
active N-oxyl was performed by use of a simple undivided cell under constant current conditions. The
selectivity factor (S-value) increased remarkably when the reaction was performed at lower temperatures.
The optically active N-oxyl was recovered and used repeatedly without any change in efficiency and
selectivity. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: kinetic resolution; electrochemistry; oxidation; alcohols.
The preparation of chiral sec-alcohols is of importance for synthesis of chiral bioactive
compounds and function materials. Among the methodologies developed for this purpose so
far,1 oxidative kinetic resolution using a chiral oxidant is a promising access to enantio-enriched
alcohols from their racemates.2 Electrochemical oxidation of alcohols has been well recognized
as an environment-benign method since a catalytic amount of oxidant is enough to complete the
oxidation through in situ electrochemical regeneration of the oxidant. Electrochemical kinetic
resolution of sec-alcohols has been also developed by using an optically active N-oxyl com-
pound as a mediator such as 2,3 electrodes modified with a chiral N-oxyl,4 and a combination
of an achiral N-oxyl-modified electrode and chiral amine, e.g. sparteine.5 Most of these reactions
were, however, carried out in a divided cell; hence, a high concentration of a supporting
electrolyte, such as a quaternary ammonium salt, was indispensable to attain a practically
significant current of electricity, causing serious environmental problems in a practical scale of
the electrolysis. Satisfactory selectivities (S value)6 were obtained only when N-oxyl was
immobilized in a polymer matrix on the electrode under strict control of the electrode potential.
Electrolysis in a simple undivided cell under constant current conditions is much more desirable
* Corresponding author. Tel: +81-86-251-8074; fax: +81-86-251-8079; e-mail: tanaka95@cc.okayama-u.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01419-2

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in the practical sense. We investigated electro-oxidation of alcohols in a double mediatory
system comprising halide salts and N-oxyl compounds which can be operated in a simple
undivided cell.7 In this report electro-oxidative kinetic resolution of sec-alcohols in a CH2Cl2–
H2O two-phase system involving bromide salts and an optically active N-oxyl mediator 1 is
described. This is the first example of enantioselective electro-oxidation achieved in an undivided
cell under constant current conditions, offering a simple operation for achieving high current
efficiency as well as satisfactory selectivities (S=13–20) (Scheme 1).
Scheme 1. Electro-oxidative kinetic resolution of sec-alcohols using an optically active N-oxyl mediator
The optically active N-oxyl 1 was prepared according to the literature.8 A typical procedure
of the kinetic resolution is as follows (Table 1, entry 1): A mixture of ( )-1-phenyl-1-ethanol 3a
(0.56 mmol) and 1 (0.005 mmol) in a two-phase solution of CH2Cl2 (4 mL) and a saturated aq.
NaHCO3 (4 mL) containing 20w% of NaBr was placed in a beaker-type undivided electrolysis
Table 1
Kinetic resolution of (9)-1-phenyl-1-ethanol 3a. Reaction temperature and selectivity
Entry
Temp/°C
4a
3a
Sc
Yield%a
Yield%a
Ee (R)/%b
1
2
3
4
5
−15
−10
−5
0
57
55
46
40
52
43
45
53
57
47
91
74
52
44
16
16.4
8.9
6.3
5.7
1.6
18
a Isolated yields.
b Ee% were determined by HPLC using chiral column Daicel ChiralCel OD-H.
c S=ln[(1−C)(1−ee)]/ln[(1−C)(1+ee)] where ee is the fractional enantiomeric excess and C is the conversion.

8133
cell. Two Pt plate electrodes (1.0×1.5 cm2) were immersed into the aqueous layer. Electrolysis
was carried out at −15°C under constant current density (15 mA/cm2). After passage of 1.5
F/mol of electricity (ca 1.5 h),9 the mixture was poured into saturated aq. NaHCO3, extracted
with EtOAc, and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo,
and the residue was chromatographed on a silica gel column to give the starting material 3a
(43%) and the corresponding ketone 4a (57%). The recovered (R)-enriched 3a was analyzed to
be 91%ee by HPLC equipped with a chiral column Daicel ChiralCel OD-H. The selectivity
factor, S value, was 16.4, which is much higher than that observed in the literature8 (0°C, 87%
conv., 87%ee, S=7.1).
The ee% of 3a and S value decreased significantly with increasing reaction temperature (Table
1). When the electrolysis was attempted at below −15°C, a part of the solvent was frozen and,
consequently, no appreciable dc current could be passed and the electro-oxidation did not
proceed at all.
The present optically active N-oxyl mediated electro-oxidation was successfully applied to the
kinetic resolution of phenethyl alcohol derivatives 3 with a catalytic amount of 1. Representative
results are summarized in Table 2. When the aryl group of 3 was substituted with a chlorine,
bromine, or alkyl group, stereoselectivity of the recovered 3 was high (3b, 3c, 3d). On the other
hand, alkoxyl-substituted phenethyl alcohols (3e, 3f) were easily oxidized but in low ee% and S
value. The low S value for the alkoxylated substrates may be due to non-enantioselective
oxidation such as direct oxidation. Indeed, when the electro-oxidation of 1-(4-
methoxyphenyl)ethanol 3e was performed without the N-oxyl 1, a significant amount (ca 50%)
of 4-methoxyphenyl methyl ketone was formed after passage of 2 F/mol of electricity, whereas
no appreciable oxidation of 1-(4-chlorophenyl)ethanol was observed.
Table 2
Oxidation of phenethyl alcohol derivatives 3 using the optically active N-oxyl 1
a Isolated yields.
b Determined by HPLC equipped with chiral column.
c S=ln[(1−C)(1−ee)]/ln[(1−C)(1−ee)] where ee is the fractional enantiomeric excess and C is the conversion.
It is noteworthy that the optically active mediator 1 could be recovered after electrolysis and
used repeatedly without any appreciable change in efficiency and selectivity (Table 3). In each of
the entries, the N-oxyl 1 was recovered almost quantitatively after the electro-oxidation.

8134
Table 3
Recycle usage of the optically active N-oxyl 1
Entry
4a
3a
Sc
Yield%a
Yield%a
Ee (R)/%b
1
2
3
52
53
52
43
42
46
91
90
90
16
16
17
a Isolated yields.
b Determined by HPLC equipped with chiral column.
c S=ln[(1−C)(1−ee)]/ln[(1−C)(1+ee)] where ee is the fractional enantiomeric excess and C is the conversion.
Although the reaction mechanism is not clear at present, an optically active N-oxoammonium
species would be formed from oxidation of N-oxyl 1 and/or N-hydroxyl with the bromonium
species [Br+] generated by electro-oxidation of the bromide ion in aqueous media (Scheme 1).
The N-oxoammonium would react with the alcohol 3 to give an intermediate A.7b As the N-oxyl
1 is optically active, intermediate complexes with (R)-3 (AR3/1) and (S)-3 (AS3/1) are
diastereomers of each other. Kinetic resolution might occur at this complex-formation stage:
The steric environment of 1 would prefer the formation of the intermediate AS3/1 rather than the
intermediate AR3/1.8 The ketone 4 may be formed by hydride transfer in the intermediate AS3/1
,
and (S)-3 may be preferentially consumed. As a result, (R)-3 might be retained predominantly.
In conclusion, electro-oxidative kinetic resolution of sec-alcohol using an optically active
N-oxyl 1 proceeds smoothly in a CH2Cl2–H2O two-phase system to give optically active
sec-alcohols in high recovery and high ee%. The electrolysis can be performed in a simple
undivided cell under self-potential controlled conditions. The enantiomeric selectivity was
increased when the electro-oxidation was carried out at lower temperature (−15°C). The catalyst
1 can be used repeatedly without any change in efficiency and selectivity.
References
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Chiral Auxiliaries and Ligands in Asymmetric Synthesis; John Wiley & Sons: New York, 1995.
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8135
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6. Selective factor: S=ln[(1−C)(1−ee)]/ln[(1−C)(1+ee)] where ee is the fractional enantiomeric excess of recovered 2a
and C is the conversion.2
7. (a) Inokuchi, T.; Liu, P.; Torii, S. Chem. Lett. 1994, 1411. (b) Inokuchi, T.; Matsumoto, S.; Torii, S. J. Org. Chem.
1991, 56, 2416. (c) Inokuchi, T.; Matsumoto, S.; Nishiyama, T.; Torii, S. J. Org. Chem. 1990, 55, 462. (d) Idem,
Synlett 1990, 57.
8. Rychnovsky, S. D.; McLernon, T. L.; Rajapakse, H. J. Org. Chem. 1996, 61, 1194. Although kinetic resolution of
sec-alcohols with an optically active 1 and sodium hypochlorite was attempted, the selectivity was not necessarily
high enough.
9. When 1.0 F/mol of electricity was passed, the ketone 4a and alcohol 3a were obtained in 37 and 61% yields,
respectively.
.