Catalytic asymmetric and chemoselective aerobic oxidation: Kinetic resolution of sec-alcohols

Article abstract of DOI:10.1016/S0040-4039(00)00787-5

Optically active (nitroso)(salen)ruthenium(II) chloride (2) was found to be an efficient catalyst for aerobic oxidation of racemic secondary alcohols under irradiation with a halogen or fluorescent lamp, which proceeded with good enantiomer-differentiation (k(rel) = 11-20). Furthermore, no epoxidation was observed in the oxidation of racemic 4-phenyl-3-buten-2-ol. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00787-5

Tetrahedron Letters 41 (2000) 5119±5123
Catalytic asymmetric and chemoselective aerobic oxidation:
kinetic resolution of sec-alcohols
Kouta Masutani, Tatsuya Uchida, Ryo Irie and Tsutomu Katsuki*
Department of Chemistry, Faculty of Science, Graduate School, Kyushu University 33, Hakozaki, Higashi-ku,
Fukuoka 812-8581, Japan
Received 17 April 2000; revised 10 May 2000; accepted 12 May 2000
Abstract
Optically active (nitroso)(salen)ruthenium(II) chloride (2) was found to be an ecient catalyst for aerobic
oxidation of racemic secondary alcohols under irradiation with a halogen or ¯uorescent lamp, which pro-
ceeded with good enantiomer-di€erentiation (k =11±20). Furthermore, no epoxidation was observed in
rel
the oxidation of racemic 4-phenyl-3-buten-2-ol. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Ru±salen complex; aerobic oxidation; kinetic resolution.
Oxidation is a fundamental organic reaction and is widely used for organic synthesis, especially for
functionalization of organic molecules. Today, various kinds of oxidation such as hydroxylation,
epoxidation, and dihydroxylation can be performed in a highly enantioselective manner by using
a catalytic amount of an optically active transition metal complex as the catalyst in the presence of
1
a stoichiometric terminal oxidant. Although a variety of oxidants have been used as stoichio-
metric ones, molecular oxygen is the most suitable in terms of atom economics as well as being
environmentally friendly. Thus, aerobic oxidation or oxidation with molecular oxygen has been
extensively studied for many years.1a
Although many strategies have been developed for oxidation with molecular oxygen as stoichio-
metric oxidant, methodology for transition metal-mediated asymmetric aerobic oxidation is still
limited in number.
Mukaiyama et al. reported the ®rst asymmetric epoxidation using an optically active (salen)-
manganese(III) or (aldiminato)manganese(III) complex as the catalyst in the presence of molecular
2
oxygen and a reductant such as pivalaldehyde. Bolm et al. applied this methodology to asymmetric
Baeyer±Villiger reaction by using an optically active copper Schi€±base complex as the catalyst
3
and achieved good enantioselectivity. On the other hand, Groves et al. reported that a (dioxo)-
ruthenium±porphyrin complex catalyzed aerobic epoxidation in the absence of a co-reductant.4
An asymmetric version of this reaction has been reported by Che et al., but the turnover number
*
Corresponding author. Fax: +81 92 642 2607; e-mail: katsuscc@mbox.nc.kyushu-u.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00787-5

5
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5
of the reaction is moderate (<20 times at maximum). Wacker oxidation was also carried out in
6
an enantioselective manner with chiral palladium complexes as catalyst. Oxidation of 2-naphthol
derivatives with a chiral copper complex as the catalyst under oxygen atmosphere was reported by
7
Hashimoto et al. to give the corresponding binol derivatives with good enantioselectivity. More
recently, Beller et al. and Krief et al. independently reported Sharpless asymmetric dihydroxylation
with molecular oxygen in the absence8a or presence of benzyl phenyl selenide, in which molecular
oxygen oxidized selenide to selenoxide that, in turn, oxidized Os(VI) to Os(VIII) species.8
We recently disclosed that optically active (R,S)-(nitroso)(salen)ruthenium(II) complex 1 serves
as a potent catalyst for enantioselective epoxidation in the presence of 2,6-dichloropyridine N-oxide
b
9
under irradiation of incandescent light in dry air (Scheme 1, Eq. (1)). With this result in hand, we
next examined epoxidation of 4-phenyl-3-buten-2-ol under the same conditions except for using
0
10
tetramethylpyrazine N,N -dioxide (TMPNO, 50 mol%) which is also a good stoichiometric
oxidant for epoxidation (Eq. (2)). The reaction was slow but, unexpectedly, OH-oxidation was
found to occur in preference to epoxidation (OH-oxidation:epoxidation=ca. 3:1, Eq. (2)).1
Furthermore, the reaction under irradiation with a halogen lamp gave ketone exclusively with
modest di€erentiation of the enantiomers of the alcohol (krel (k /k )=2.3, Eq. (2)) but, surpris-
1,12
R
S
ingly, the conversion (67%) of the alcohol was found to exceed the amount of the consumed
0
N,N -dioxide [53.9%: formation of pyrazine N-oxide (42.7%) and pyrazine (5.6%)]. This sug-
gested that molecular oxygen partly served as a stoichiometric oxidant. Thus, we examined
aerobic oxidation of secondary alcohols (Eq. (3)).
ꢀ
1†
2†
ꢀ
ꢀ3†
Scheme 1.

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The aerobic oxidation of racemic 4-phenyl-3-buten-2-ol was ®rst carried out in the presence of
complex 1 in benzene under irradiation with a halogen lamp as an illuminant (Table 1, entry 1).13
The reaction proceeded chemoselectively to give the corresponding ketone and no epoxidation
was observed. However, the relative reaction rate was only modest (k =3). We also examined
rel
the same reaction with a ¯uorescent or incandescent lamp as the illuminant. The reaction with
¯
uorescent lamp gave the same result as that with a halogen lamp, while the reaction with an
incandescent lamp was sluggish. Therefore, the following reactions were carried out with a
uorescent lamp. The oxidation of racemic 4-phenyl-3-buten-2-ol was next carried out by using
¯
complex 2 as the catalyst instead of 1, and considerably improved krel was observed (entry 2). The
reaction with complex 3 bearing a Jacobsen-type chiral salen ligand was slow and less selective
(krel=1.3) (entry 4). To optimize the reaction, we examined the e€ect of the solvent on krel with
complex 2 as the catalyst and 4-phenyl-3-buten-2-ol as a test material. Although the solvent e€ect
was small, aromatic solvents like benzene, toluene, or chlorobenzene generally gave better results
than other solvents such as THF and ethyl acetate. Kinetic resolution of 4-phenyl-3-buten-2-ol
was best e€ected in chlorobenzene (entry 3). Substrates for the present reaction are not limited to
allylic alcohols. Benzylic alcohol, propargylic alcohol and dialkyl carbinol were also oxidized and
resolved eciently, though the reaction of dialkyl carbinol was a little slower than those of other
activated alcohols (entries 4, 5, and 6). The best solvent varied with substrates, and eciency of
kinetic resolution also varied with substrates. Under the optimized conditions, relative reaction
rates ranged from 11 to 20 (Fig. 1). Although the reactions were quenched at some point when
conversion exceeded 55%, they were all still proceeding at those points. These results indicate
that turnover numbers of the reactions are at least >27.5.
Table 1
Catalytic asymmetric aerobic oxidation of racemic secondary alcoholsa

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Figure 1.
Although the reaction mechanism is unclear at present, it is noteworthy that 1-phenyl-2,2-
dimethylpropan-1-ol bearing a bulky t-butyl group next to the carbinol carbon was not oxidized
under the present conditions. This suggests that coordination of a hydroxyl group is essential for
the oxidation and it occurs in the coordination sphere of the ruthenium ion. In accord with this,
the reactions in polar solvents are very slow: the reaction in THF or acetone was sluggish and no
reaction occurred in acetonitrile. The con®guration of all the unreacted alcohols in the reactions
with complex 2 was R (Table 1), indicating that the sterically small acetylenic group behaved as
though they were larger than the methyl group. This suggests that stereochemistry of the present
oxidation is controlled not only by a steric factor but also by another factor such as p±p anti-
bonding interaction which also participates in stereocontrol of the Mn±salen catalyzed epoxidation
of conjugated ole®ns.1
5,16
Furthermore, the oxo-ruthenium species which is considered to be the
9
active species in Ru±salen catalyzed epoxidation under irradiation of incandescent light, does
not seem to participate in the present reaction, because OH-oxidation and epoxidation compete
under such conditions as described above but only OH-oxidation proceeds under the present
conditions. In connection with this issue, it is also noteworthy that tetramethylpyrazine N,N -
dioxide is slowly decomposed under irradiation with a halogen lamp (t =18 h). This partly
0
1/2
explains why OH-oxidation prevails upon irradiation with a halogen lamp, but the desired OH-
oxidation itself is accelerated under irradiation with a ¯uorescent or halogen lamp.17
Typical experimental procedure is exempli®ed with kinetic resolution of racemic 4-phenyl-3-
butyn-2-ol: To a solution of racemic 4-phenyl-3-butyn-2-ol (14.6 mg, 0.10 mmol) in chlorobenzene
(1.0 ml) was added bicyclohexyl (16.6 mg, 0.10 mmol) as an internal standard for GLC analysis.
An aliquot (50 ml) of this solution was taken out of the ¯ask as a zero point and passed through a
pad of silica gel which was washed out with a small amount of hexane:ethyl acetate (8:2). The
eluate was submitted to GLC analysis.
To the remnant solution was added complex (2, 2.0 mg, 2.0 mmol) and the mixture was stirred
in air for 17 h at room temperature under irradiation of ¯uorescent light (100 V, 25 W). To
remove the complex, the mixture was ®ltered through a pad of silica gel which was washed with
hexane:ethyl acetate (8:2). The ®ltrate was submitted to GLC analysis to determine conversion of
the alcohol to be 65.3%, then concentrated and chromatographed on silica gel (hexane:ethyl

5
123
acetate=8:2). The fractions containing the alcohol were collected and an aliquot of the solution
was submitted to HPLC analysis using optically active column (Daicel Chiralcel OD-H, hexane:
2
-propanol=15:1) to determine the enantiomeric excess of the unreacted alcohol to be >99.5%
ee. The remaining solution was concentrated to isolate the unreacted alcohol in 30% yield.
In conclusion, we were able to disclose that aerobic enantiomer-di€erentiating oxidation of
racemic secondary alcohols was eciently promoted by using (R,R)-(nitroso)Ru±salen complex 2
as the catalyst under irradiation of ¯uorescent light. Further study on the reaction mechanism is
now proceeding in our laboratory.
Acknowledgements
Financial support from a Grant-in-Aid for Scienti®c Research from the Ministry of Education,
Science, Sports, and Culture, Japan, is gratefully acknowledged.
References
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