Ti(salen)-catalyzed enantioselective sulfoxidation using hydrogen peroxide as a terminal oxidant

Article abstract of DOI:10.1016/S0040-4039(01)00590-1

(R,R)-Di-μ-oxo Ti(salen) 4 was found to serve as an efficient catalyst for asymmetric oxidation of various sulfides with hydrogen peroxide. For example, oxidation of methyl phenyl sulfide by using 4 as the catalyst in the presence of a urea·H₂O₂ adduct showed high enantioselectivity of 94% ee. The high enantioselectivity of this reaction was considered to be related to the cis-β-structure of a monomeric Ti(salen) species generated from 4 in a methanol-hydrogen peroxide solution.

Full text of DOI:10.1016/S0040-4039(01)00590-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3873–3876
Ti(salen)-catalyzed enantioselective sulfoxidation using hydrogen
peroxide as a terminal oxidant
Bunnai Saito and Tsutomu Katsuki*
Department of Chemistry, Faculty of Science, Graduate School, Kyushu University 33, CREST,
JST (Japan Science and Technology), Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
Received 14 March 2001; revised 2 April 2001; accepted 6 April 2001
Abstract—(R,R)-Di-m-oxo Ti(salen) 4 was found to serve as an efficient catalyst for asymmetric oxidation of various sulfides with
hydrogen peroxide. For example, oxidation of methyl phenyl sulfide by using 4 as the catalyst in the presence of a urea·H2O2
adduct showed high enantioselectivity of 94% ee. The high enantioselectivity of this reaction was considered to be related to the
cis-b-structure of a monomeric Ti(salen) species generated from 4 in a methanol–hydrogen peroxide solution. © 2001 Elsevier
Science Ltd. All rights reserved.
Optically active sulfoxides serve as various chiral auxil-
iaries in organic synthesis, and much effort has been
directed toward the development of enantioselective
sulfoxidation (Scheme 1).1 Kagan et al.2 and Modena et
al.3 have independently reported highly enantioselective
sulfoxidation by using titanium–tartrate complexes
modified with H2O and tartrate as the catalyst, respec-
tively. Various titanium–chiral diol complexes have also
been reported to serve as the catalyst for enantioselec-
tive sulfoxidation.4 Furthermore, (salen)–vanadium and
–titanium complexes have been used as the catalyst.5
For these oxidations, alkyl hydroperoxides have been
used as the terminal oxidant; however, use of hydrogen
peroxide is desirable from the viewpoints of atom
efficiency and ecological benignity. Jacobsen et al.
reported that asymmetric oxidation of sulfides with
hydrogen peroxide was catalyzed with modest enan-
tioselectivity by using chloro(salen)manganese(III) com-
plex as the catalyst.6 Recently, Bolm et al. reported that
a vanadium–chiral Schiff base complex served as the
catalyst for asymmetric sulfoxidation, showing good
enantioselectivity.7,8 However, there is still room for
improvement of the reaction especially in terms of
enantioselectivity.
O-
S+
catalyst, ROOH or H2O2
S
R2
R1
R2
R1
We recently reported that the second-generation
(salen)manganese(III) complex 1 was an efficient cata-
Scheme 1.
R
O-
S+
N
O
N
S
Mn+
1 (1 mol%), PhI=O
Me
Me
O
Ph
3'
3
CH3CN, r.t.
NO2
NO2
MeO
OMe
Ph
S
94% ee, 94%
-
PF6
1
MeO
OMe
Scheme 2.
Keywords: di-m-oxo (salen)titanium complex; asymmetric catalysis; asymmetric sulfoxidation; sulfides; hydrogen peroxide.
* Corresponding author. Fax: +81 92 642 2607; e-mail: katsuscc@mbox.nc.kyushu-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00590-1

3874
B. Saito, T. Katsuki / Tetrahedron Letters 42 (2001) 3873–3876
O-
S+
2 (4 mol%), H2O2
S
Ph
Me
N
R
Ph
Me
MeOH, r.t.
Cl
Ti
N
O
N
10% ee
O
OH
Cl
3'
3
O
O
Ph
Ph
N
O
N
O
N
O
R
Ti
Ti
O
O
B
Cl
A
2
Scheme 3.
lyst for the asymmetric oxidation of alkyl aryl sulfides
(Scheme 2) in which iodosylbenzene was used as the
terminal oxidant.9 However, the reaction with hydrogen
peroxide as the terminal oxidant was sluggish.
dimer structure C.10 We expected that complex C would
give the desired B if it was treated with hydrogen
peroxide in methanol (Scheme 4). Thus, we synthesized
the di-m-oxo species 3 according to the Belokon’ proce-
dure (Scheme 5). We also converted complex 2 to the
corresponding di-m-oxo (salen)titanium complex 4,
according to the same procedure. The formation of the
di-m-oxo species 4 was confirmed by FABMS analysis
(m/z=1778.55). With complex 4 in hand, we first exam-
ined oxidation of methyl phenyl sulfide. As we
expected, the oxidation with aqueous hydrogen perox-
ide (31%) in the presence of 4 proceeded with good
enantioselectivity of 76% ee. However, as the peroxo
species B was considered to be equilibrated with
hydroperoxo(hydroxo)titanium species D in the pres-
ence of water (Scheme 6), we next examined the oxida-
tion with a urea·hydrogen peroxide adduct (UHP) in
place of aqueous hydrogen peroxide. The reaction pro-
ceeded smoothly to give the sulfoxide in good yield
with considerably improved enantioselectivity of 94%
ee. The reaction with 3 as the catalyst was also exam-
To take advantage of the high asymmetry-inducing
ability of second-generation (salen)manganese(III) com-
plexes, we examined asymmetric oxidation using other
metallosalen complexes as the catalyst and hydrogen
peroxide as the terminal oxidant. Since Fujita et al. had
reported that a (salen)titanium(IV) complex serves as
the catalyst for asymmetric sulfoxidation,5 we first
examined the oxidation of methyl phenyl sulfide with
the second-generation (salen)titanium(IV) complex 2 as
catalyst and aqueous hydrogen peroxide in methanol
(Scheme 3). However, only poor enantioselectivity was
observed. Although the mechanism of this reaction was
unclear, a hydroperoxotitanium species A was consid-
ered to be the active species, in which the salen ligand
adopted
a
square-planar coordination and the
hydroperoxo moiety has high conformational freedom.
Accordingly, regulation of its conformation was consid-
ered to be indispensable for achieving high enantiose-
lectivity. On the other hand, if the distal oxygen of the
hydroperoxo moiety is coordinated to the titanium ion,
the configuration of the moiety is fixed, though the
salen ligand is forced to adopt a cis-b structure B.
O
O
O Ti
N
N
O
H2O2
B
N Ti
O
O
N
MeOH
Recently, Belokon’ et al. reported that a di-m-oxo
(salen)titanium complex, which served as an efficient
catalyst for asymmetric hydrocyanation, had a cis-b
C
Scheme 4.
Cl
N
O
N
Ti
H2O, Et3N
H2O, Et3N
CH2Cl2
3
4
t-Bu
O
Bu-t
2
Cl
3'
3
CH2Cl2
m/z= 1778.55
Bu-t
t-Bu
O-
S+
catalyst (2 mol%), H2O2 (1 eq.)
MeOH
S
Ph
Me
Ph
Me
4, aqueous H2O2, 25 °C: 76% ee, 82%
4, UHP, 25 °C: 94% ee, 71%
3, aqueous H2O2, 25 °C: 10% ee, 41%
4, UHP, 0 °C: 98% ee, 78%
Scheme 5.

B. Saito, T. Katsuki / Tetrahedron Letters 42 (2001) 3873–3876
3875
OH
and benzyl methyl sulfide was also smoothly effected
OH
Ti
O
H2O
under the same reaction conditions (Scheme 7).11
N
N
O
N
OH
N
O
Ti
O
+
B
OH
O
-H2O
O
Preparation of (R,R)-di-m-oxo complex 4 and typical
experimental procedure for the oxidation of sulfides
with 4 as the catalyst are described below.
Deq
Dax
Scheme 6.
Preparation of (R,R)-di-m-oxo complex 4: To a solu-
tion of complex
2
(262 mg, 0.27 mmol) in
Table 1. Asymmetric sulfoxidation of methyl aryl sulfides
by urea·hydrogen peroxide
dichloromethane, were added two drops of water and
triethylamine (77 ml, 0.54 mmol) and the mixture was
stirred at room temperature overnight. The resulting
pale yellow solution was washed with water, dried
over magnesium sulfate, and concentrated in vacuo to
yield complex 4 (167 mg, 69%) as a yellow solid.
O-
S+
4 (2 mol%), UHP (1 eq.)
S
Ar
Me
Ar
Me
MeOH, 0 °C, 24 h
Entry
Sulfide (Ar)
Yield (%)a
% ee
Oxidation of p-chlorophenyl methyl sulfide (Table 1,
entry 4): (R,R)-di-m-oxo complex 4 (3.6 mg, 2.0 mmol)
was dissolved in methanol and the solution was
cooled to 0°C. To this solution were added
urea·hydrogen peroxide (9.4 mg, 0.1 mmol) and sub-
sequently p-chlorophenyl methyl sulfide, and the mix-
ture was stirred at this temperature for 24 h. The
mixture was concentrated in vacuo and the residue
was chromatographed on silica gel (hexane:ethyl
acetate=1:1–3:7) to give p-chlorophenyl methyl sulf-
oxide (15.4 mg, 88%). The enantiomeric excess of
the sulfoxide was determined to be 99% ee by HPLC
analysis using Daicel Chiralcel OB-H (hexa-
ne:i-PrOH=4:1).
1
2
3
4
5
p-MeOC6H4
p-BrC6H4
o-BrC6H4
p-ClC6H4
78
93
89
88
92
96b
96c
97c
99c
92d
p-O2NC6H4
a Isolated yield.
b Determined by HPLC analysis (Daicel Chiralcel OB-H, hexane/i-
PrOH=1:1).
c Determined by HPLC analysis (Daicel Chiralcel OB-H, hexane/i-
PrOH=4:1).
d Determined by HPLC analysis (Daicel Chiralcel OJ, hexane/i-
PrOH=7:3).
O-
S+
In conclusion, we were able to demonstrate that
(R,R)-di-m-oxo Ti(salen) 4 served as an efficient cata-
lyst for the asymmetric oxidation of sulfides with
hydrogen peroxide as the terminal oxidant. The
mechanism of the present reaction and the structure
of the active peroxo titanium species are now under
investigation.
4 (2 mol%), UHP (1 eq.)
S
S
*
Ph
Ph
MeOH, 0 °C, 24 h
93% ee, 91%
4 (2 mol%), UHP (1 eq.)
MeOH, 0 °C, 24 h
Ph
*
Ph
S+
O-
93% ee, 72%
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Scheme 7.
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