Vanadium-catalyzed enantioselective sulfoxidation and concomitant, highly efficient kinetic resolution provide high enantioselectivity and acceptable yields of sulfoxides

Article abstract of DOI:10.1002/adsc.200505259

Simple, inexpensive, preformed vanadium-Schiff base complexes were facilely prepared and used in enantioselective sulfoxidation. Both the amount of aqueous H₂O₂ and reaction time greatly influenced the ee values and yields of chiral sulfoxides. High enantioselectivities (up to 99% ee) and reasonable yields (>40%) for various chiral sulfoxides were achieved by combining enantioselective sulfoxidation and appropriate concomitant kinetic resolution.

Full text of DOI:10.1002/adsc.200505259

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DOI: 10.1002/adsc.200505259
Vanadium-Catalyzed Enantioselective Sulfoxidation and
Concomitant, Highly Efficient Kinetic Resolution Provide High
Enantioselectivity and Acceptable Yields ofSul fo xides
a,
a
a
a
b
Qingle Zeng, * Heqing Wang, Tongjian Wang, Yimin Cai, Wen Weng,
a,
Yufen Zhao *
a
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen
61005, Peopleꢀs Republic of China
3
Phone/fax: (þ86)-592-218-5780; e-mail: qlzeng@xmu.edu.cn, yfzhao@xmu.edu.cn
b
Department of Chemistry, Zhangzhou Teachersꢀ College, Zhangzhou 363000, Peopleꢀs Republic of China
Received: June 28, 2005; Accepted: August 15, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Simple, inexpensive, preformed vanadium-
Schiff base complexes were facilely prepared and
used in enantioselective sulfoxidation. Both the
amount of aqueous H O and reaction time greatly
2
2
influenced the ee values and yields of chiral sulfox-
ides. High enantioselectivities (up to 99% ee) and
reasonable yields (>40%) for various chiral sulfox-
ides were achieved by combining enantioselective
sulfoxidation and appropriate concomitant kinetic
resolution.
Scheme 1. Vanadium-catalyzed enantioselective oxidation of
sulfides
Keywords: asymmetric catalysis; kinetic resolution;
Schiff bases; sulfoxides; vanadium
The kinetic resolution of racemic sulfoxides, and oxi-
dation of sulfides accompanying kinetic resolution cata-
lyzed by titanium often gave high ee values of sulfoxides,
[
4b,8]
but low yields.
Recently Chan developed a one-pot,
Optically pure sulfoxides are a valuable class of com- titanium-catalyzed tandem sulfoxidation and kinetic
pounds, which are extensively used as chiral auxiliaries resolution process, which proceeded at different tem-
[
1]
and intermediates in current organic synthesis, and peratures and gave extremely high ee values and accept-
[
2]
[9]
also for important drugs, such as esomeprazole. Cata- able yields of chiral sulfoxides.
lytic enantioselective oxidation of sulfides is an efficient
Katsuki found that 10% sulfone was observed in the
[
1a,3]
synthetic method for chiral sulfoxides.
Recently, the case of methyl p-nitrophenyl sulfide as substrate during
[
5c]
enantioselective oxidation of sulfides catalyzed by chiral vanadium-catalyzed sulfoxidation; and Bolm found
[
4]
complexes of transition metals, such as titanium, vana- that when p-methoxybenzoic acid or its lithium salt
[5]
[6]
[7]
dium, iron, manganese, has been extensively re- was added in the iron complex, 10–15% sulfones were
[6b]
searched. In particular, Bolm found that vanadium- observed in cases of>90% ee sulfoxides obtained,
Schiff base complexes derived from chiral tert-leucinol which suggests that kinetic resolution could occur dur-
are effective catalysts for sulfoxidation with aqueous ing vanadium- and iron-catalyzed sulfoxidation. To our
H O2 as an environmentally friendly oxidant knowledge, vanadium-catalyzed enantioselective oxi-
2
[5a]
[5b]
[5c]
[5d]
(
Scheme 1). Berkessel, Katsuki, Anson, and dation of sulfides and concomitant kinetic resolution
[5e] [10]
Ahn improved the Bolmꢀs protocol. However, the has not yet been studied in detail.
Schiff base ligands are usually derived from expensive During the continuation of our studies on enantiose-
[
11]
chiral tert-leucinol or 1-amino-2-indanol and complicat- lective sulfoxidation, we envisagedthat, by combining
ed salicylaldedhyde analogues, which decreases their appropriate kinetic resolution and enantioselective sul-
practical value.
foxidation, complexes of simple Schiff bases and vanadi-
Adv. Synth. Catal. 2005, 347, 1933 – 1936
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1933

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Qingle Zeng et al.
Scheme 2. Synthesis of chiral Schiff bases and preformed vanadium-Schiff base complexes.
um might provide chiral sulfoxides with high ee values as similar ee values and yields (entries 7, 10 and 11).
well as acceptable yields. Among them, two simple complexes 6c and 6d derived
In the previous studies, 50 mol % excess amounts of from salicylaldehyde and phenylalaninol and isoleuci-
the expensive ligands were usually adopted in the vana- nol were adopted for further investigation in the sulfox-
[
5]
dium-catalyzed sulfoxidation. The excess ligands were idation accompanying kinetic resolution.
wasted and the in situ catalysts made elucidation of the The ees were slightly increased when 2 mol % 6c and
We managed to prepare 6d were used (data not given). When 5 mol % 6c and 6d
the preformed vanadium-Schiff base complexes without and 1.2 equivs. H O were used, much higher ee values
[
5 g]
mechanism more difficult.
2
2
the need for excess ligands (Scheme 2).
were achieved (82.5%ee for 6d) (Table 2, entries 3 and
In this paper we report the synthesis of simple, inex- 4). Therefore the effect of aqueous H O on the oxida-
2
2
pensive, preformed chiral vanadium-Schiff base com- tion of the model substrate thioanisole was screened
plexes and their application in asymmetric sulfide oxida- (Table 2). When the amount of 30% H O was raised
2
2
tion accompanying kinetic resolution.
from 0.8 to 2.0 equiv, ee values increased steadily (en-
Generally, when a salicylaldehyde 3 (1 equiv.) was re- tries 1, 3, 5 and 7 for 6c; entries 2, 4, 6 and 8 for 6d).
acted with a chiral amino alcohol 4 (1 equiv.) in anhy-
drous methanol, the yellow-colored simple chiral Schiff
1
base 5 was instantly formed, which is pure enough for H
Table 1. The effects of the preformed catalysts and the in situ
NMR determination. Then 1 equiv. of VO(acac) was
[a]
2
catalysts.
added to the Schiff base solution, and a brown to violet
precipitate or solution was formed after 3 hours under
reflux. After removal of methanol, the vanadium-Schiff
base complex 6 was obtained. The complexes 6c and 6d
[
b]
Entry Ligand or complex Substrate Yield [%] ee [%]
[c]
1
2
3
4
5
6
7
8
9
0
1
5a
5a
6a
5b
6b
5c
6c
5c
6c
6d
6e
1a
1a
1a
1a
1a
1a
1a
1b
1b
1a
1a
93
60
93.5
50
82.6
94.1
76.0
95.0
82.4
86.3
78.1
39
27
45.3
29
51.4
55.6
59.2
56.3
60.1
55.7
55.9
[c]
5
1
were characterized by IR, FAB-FT-ICR-MS, and
V
[c]
NMR. In order to compare them with the in situ cata-
lysts, chiral Schiff bases derived from 3,5-di-tert-butylsa-
licylaldedyde and chiral phenylalaninol and valinol
were prepared with a similar procedure.
Some preformed catalysts and some in situ catalysts
were tested in the oxidation of thioanisole (1a) and p-
chlorophenyl methyl sulfide (1b). The results are
showed in Table 1. The data of Table 1 show that pre-
formed catalysts gave slightly higher enantioselectivity
in the asymmetric oxidation of 1a (entries 3 vs. 1, 2; 5
vs. 4; 7 vs. 6) and of 1b (entries 9 vs. 8). Probably VO
1
1
[a]
Reaction conditions: the in situ catalyst from VO(acac)
0.01 mmol) and Schiff base ligand (0.015 mmol) or vana-
dium-Schiff base complexes (0.01 mmol), thioanisole
1 mmol) and aqueous H O (30%; 1.1 mmol) in CH Cl
2
2
(
(
2
2
2
(
acac) and Schiff bases had not completely been trans-
2
at 08C for 4 hours, unless otherwise mentioned.
formed into complexes with stirring for a short time at
room temperature before aqueous H O was added,
[
[
b]
The ee values were determined by HPLC. The absolute
configuration was assigned by comparison with literature
2
2
and then the residual VO(acac) was turned into diper-
2
values. All of the major isomers are in the S form.
c]
[5f, g]
oxovanadium [VO(O )O H], which oxidized sulfides
2
2
Data cited from literature:
1 mol % VO(acac)2,
1.5 mol % Schiff base, at 18C for 1 hour and then at
208C for 12 hours or 15 hours.
into racemic sulfoxides. Several simple, preformed va-
nadium-Schiff base complexes 6c, 6d and 6e exhibited
1934
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Adv. Synth. Catal. 2005, 347, 1933 – 1936

Enantioselective Sulfoxidation and Concomitant, Efficient Kinetic Resolution
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Table 2. The effects of the amount of aqueous H O on enan-
Table 3. The effects of time on enantioselective sulfoxidation
and accompanying kinetic resolution catalyzed by 6c and
6d.
2
2
tioselective sulfoxidation and concomitant kinetic resolution
[a]
[a]
catalyzed by 6c and 6d.
[
b]
[b]
Entry
H O [equivs.]
Catalyst
Yield [%]
ee [%]
Entry
Time [h]
Catalyst
Yield [%]
ee [%]
2
2
1
2
3
4
5
6
7
8
0.8
0.8
1.2
1.2
1.6
1.6
2.0
2.0
6c
6d
6c
6d
6c
6d
6c
6d
68.5
64.4
72.8
78.2
60.3
58.4
41.2
40.6
63.3
67.3
72.4
82.5
83.6
90.0
98.9
99.0
1
2
3
4
5
6
7
8
2
2
4
4
6
6
8
8
6c
6d
6c
6d
6c
6d
6c
6d
69.4
66.4
65.1
52.4
46.3
48.7
41.2
40.6
77.0
73.1
85.8
91.0
91.0
93.5
98.9
99.0
[
a]
[a]
Reaction conditions: vanadium complexes (0.01 mmol),
thioanisole (1 mmol) and 30% H O (0.8 mmol to
Reaction conditions: vanadium complexes (0.05 mmol),
thioanisole (1 mmol) and 30% H O (2.0 mmol) in CH Cl
2
2
2
2
2
2
2
.0 mmol) in CH Cl at 08C for 8 hours.
at 08C for the given time.
See Table 1.
2
2
[
b]
[b]
See Table 1.
But the yields increased in the beginning when H O in- Table 4. Substrates tested in enantioselective sulfoxidation
2
2
and accompanying kinetic resolution catalyzed by vana-
dium-Schiff base complexes 6c and 6d.
creased from 0.8 to 1.2 equivs. (entries 1 and 3 for 6c; en-
[a]
tries 2 and 4 for 6d), and then decreased when H O rose
2
2
from 1.2 to 2.0 equivs. (entries 3 to 8). The reason for this
is that an insufficient amount of H O cannot completely
[b]
Entry
Substrate
Catalyst
Yield [%]
ee [%]
2
2
1
2
3
4
5
6
7
8
9
1a
1a
1c
1c
1d
1d
1b
1b
1e
1e
6c
6d
6c
6d
6c
6d
6c
6d
6c
6d
65.1
52.4
59.4
62.3
76.3
77.2
60.3
31.2
58.8
58.6
85.8
91.0
81.2
86.1
76.8
78.0
92.1
99.2
86.4
83.2
transform the sulfide into the sulfoxide (entries 1 and 2),
and surplus H O causes kinetic resolution of the result-
2
2
ing sulfoxide (entries 5 to 8). During the course of the
kinetic resolution, vanadium-Schiff base complexes
mainly transformed the undesired (R)-form sulfoxide
into sulfone, and higher concentration of aqueous
H O accelerated the progress. Thus, the sulfoxide pre-
2
2
dominant in the (S)-form was obtained in up to 99%ee
as well as more than 40% yield (entries 7 and 8).
Next we screened the effect of reaction time for the
oxidation of thioanisole with 2.0 equivs. of H O cata-
10
[a]
Reaction conditions: vanadium complexes (0.05 mmol),
sulfide (1 mmol) and 30% H O (2.0 mmol) in CH Cl at
2
2
2
2
2
2
lyzed by 6c and 6d (Table 3). When the time was in-
creased from 2 hours to 8 hours, yields of the sulfoxide
decreased steadily but ee values boosted up rapidly (en-
tries 1, 3, 5 and 7 for 6c; entries 2, 4, 6 and 8 for 6d). The
0
8C for 4 hours.
[b]
See Table 1.
rapid increase of ee values implies that the kinetic reso- PhSMe, ee values decreased slightly and yields remained
lution of the resulting sulfoxide catalyzed by the vanadi- relatively stable when p-TolSMe (1c) was used (entries 3
um complexes were of extremely high efficiency, that is, vs. 1, 4 vs. 2). In the case of p-MeOC H SMe (1d), ee val-
6
4
oxidation of the undesired isomer of the resulting sulf- ues decreased evidently (76–78% ee), but yields (76–
oxide was highly selectivity. 77%) are higher (entries 5 vs. 1, 6 vs. 2). When p-ClC H4
6
Besides, the tendency of yields indicates that 2 hours SMe (1b) was used as substrate, large improvements of
were enough to completely oxidize thioanisole (1a) un- enantioselectivity (92–99%ee) and lower yields were ob-
der the reaction condition, and suggests that the rate of served. These results suggest that electron-donating
oxidation of thioanisole (1a) catalyzed by the preformed groups on the phenyl group of the substrates slow down
complexes was very fast.
the rate of sulfoxidation and kinetic resolution, while
High ee values (85–91% ee) and good yields (52– electron-drawing substituents on the phenyl group of
5%) have been achieved after 4 hours (entries 3 and the substrates accelerate the reaction rate of sulfoxida-
). Taking into account the acceptable yields of chiral tion and kinetic resolution when vanadium-Schiff base
6
4
sulfoxides and the different reaction rates for various complexes are used as catalysts. It is interesting that high-
sulfides, 4 hours was the reaction time of choice for other er enantioselectivity (83–86%ee) and yield (58%) were
substrates.
obtained for PhSBn (1e). As a whole, for various sub-
Based on the above investigations, 2.0 equivs. of 30% strates, the ee values were good to excellent, and yields
H O and 4 hours were adopted for sulfoxidation of other were good when the inexpensive, preformed 6c and 6d
2
2
substrates (Table 4). Relative to the model substrate were used as catalysts (entries 1 to 8).
Adv. Synth. Catal. 2005, 347, 1933 – 1936
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1935

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Qingle Zeng et al.
In conclusion, we have successfully developed cheap and optical active p-PhSOMe, and some chiral HPLC diagrams
of racemic and optical active p-ClPhSOMe.
preformed complexes from simple Schiff bases and
VO(acac) and a practical process for high ees and
2
acceptable yields of chiral sulfoxides. In the course of
Acknowledgements
enantioselective sulfoxidation, the kinetic resolutions
catalyzed by the preformed complexes were of high effi-
ciency, and the kinetic resolution provided high enantio-
selectivities as well as good yields of PhSOMe. Further-
more, the catalysts are generally efficient for the enan-
tioselective oxidation of various substituted sulfides.
The derived principles are probably suitable for other
vanadium catalysts in asymmetric sulfoxidation.
We would like to thank National Foundation Science and Tech-
nology (No. 20132020) and China Postdoctoral Science Foun-
dation for supporting this work.
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[
2
2
5
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2
2
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1936
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ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2005, 347, 1933 – 1936