Oxidative kinetic resolution of heterocyclic sulfoxides with a porphyrin-inspired manganese complex by hydrogen peroxide

Article abstract of DOI:10.1016/j.tetlet.2017.12.012

We have successfully reported here the low loading porphyrin-inspired high-valent manganese (IV)-oxo complex was applied in oxidative kinetic resolution (OKR) of racemic heterocyclic sulfoxides using the environmentally benign hydrogen peroxide for the first time. This approach allows for rapid OKR (0.5 h) of a variety of racemic sulfoxides (including pyridine, pyrimidine, pyrazine, thiazole, benzothiazole, thiophene) in excellent enantioselectivity (up to > 99% ee), simultaneously generating the corresponding sulfones in high yield (up to 80%). The catalytic system also showed an unexceptionable chemoselectivity for the sulfoxide substrates with hydroxyl groups in which only the sulfoxide group was oxidized. The practical utility of the method has been demonstrated in the OKR of gram-scale sulfoxides.

Full text of DOI:10.1016/j.tetlet.2017.12.012

Tetrahedron Letters 59 (2018) 156–159
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidative kinetic resolution of heterocyclic sulfoxides with a porphyrin-
inspired manganese complex by hydrogen peroxide
b,
Jinchuang Yang a,b, Lianyue Wang b, Ying Lv b, Ning Li b,c, Yue An a, , Shuang Gao
⇑
⇑
a College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, China
b Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
c College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004, Henan, China
a r t i c l e i n f o
a b s t r a c t
Article history:
We have successfully reported here the low loading porphyrin-inspired high-valent manganese (IV)-oxo
complex was applied in oxidative kinetic resolution (OKR) of racemic heterocyclic sulfoxides using the
environmentally benign hydrogen peroxide for the first time. This approach allows for rapid OKR
(0.5 h) of a variety of racemic sulfoxides (including pyridine, pyrimidine, pyrazine, thiazole, benzothiazole,
thiophene) in excellent enantioselectivity (up to > 99% ee), simultaneously generating the corresponding
sulfones in high yield (up to 80%). The catalytic system also showed an unexceptionable chemoselectivity
for the sulfoxide substrates with hydroxyl groups in which only the sulfoxide group was oxidized. The
practical utility of the method has been demonstrated in the OKR of gram-scale sulfoxides.
Ó 2017 Elsevier Ltd. All rights reserved.
Received 3 November 2017
Revised 28 November 2017
Accepted 2 December 2017
Available online 5 December 2017
Keywords:
Oxidative kinetic resolution
Heterocyclic sulfoxides
Manganese
Porphyrin-inspired
Sulfone
Introduction
the conversion of racemic sulfoxide. So it is a great of significance
to explore a highly efficient method of OKR of racemic sulfoxides to
The nonracemic sulfoxides are extensively used as chiral auxil-
iaries, ligands and intermediates in modern organic synthesis
chemistry and valuable well-marketed pharmaceutical (e.g.,
esomeprazole, modafinil).1 Therefore, the efficient synthesis of
enantiopure sulfoxides have aroused great interest to numerous
chemists.2 Although the synthesis of chiral sulfoxides is mainly
carried out through the asymmetric oxidation of thioether since
the initial breakthrough completed in asymmetric thioether oxida-
tion by the groups of Kagan and Modena in 1984,3 it is a high
research value how to convert racemic sulfoxides to optically pure
sulfoxides because the synthesis of the racemic sulfoxides is
becoming increasingly concise and can be purchased in lower
prices.4 The tiny sulfones which has wide industrial utility were
often found to form in the most of the process of conventional
asymmetric oxidation of thioether.5 Sulfone moieties are widely
used in medicine (e.g., bicalutamide, eletriptan, and Vioxx), plas-
tics, herbicides, basic organic synthesis and other industries.6 To
date, the method of synthesis of sulfones is really scanty except
sulfides directly oxidized into sulfones in organic synthesis.7 And
the oxidative kinetic resolution (OKR) can be a perfect method to
be used for obtaining both chiral sulfoxides and sulfones from
acquire high ee value of sulfoxides and high yield of sulfones. To
the best of our knowledge, several cases of the OKR of racemic sul-
foxides in the literature involve metal-salen complex (e.g. tita-
nium,1f vanadium,8 iron,9 aluminum,10 and copper11
) with
hydrogen peroxide have been reported. The optical purity of aryl
alkyl sulfoxides up to >99% ee have been achieved (such as
Maguire,12 Zeng and Zhao13 and Chan14). But the above catalytic
systems have apparent disadvantages, including limited substrate
scope or long reaction times (Scheme 1). And the existing report
mostly focused on the OKR of aromatic sulfoxides, the OKR of hete-
rocyclic sulfoxides have not been reported yet. As we all know, the
sulfoxide substances with heteroatoms are more difficult to be car-
ried out in a electrophilic reaction. Therefore, to develop a efficient
catalytic system for the OKR of heterocyclic sulfoxides is still an
attractive target.
We have developed a porphyrin-inspired manganese complexes
with hydrogen peroxide way to conduct catalytic oxidation of sul-
fide to chiral sulfoxide.15 We found a oxidation kinetic resolution
process should exist in the oxidation reaction. Here we reported
a high-efficiency method of OKR involves porphyrin-inspired man-
ganese complexes with hydrogen peroxide to applicate in the
desymmetrization of racemic heterocyclic sulfoxides. With the
low-loading catalyst (0.01 equiv), higher efficiency(0.5 h), more
moderate reaction condition(ꢀ30 °C), and more green oxidant
⇑
Corresponding authors.
E-mail addresses: anyue_11@163.com (Y. An), sgao@dicp.ac.cn (S. Gao).
https://doi.org/10.1016/j.tetlet.2017.12.012
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.

J. Yang et al. / Tetrahedron Letters 59 (2018) 156–159
157
for 0.5 h. When tert-butyl hydroperoxide was used as a oxidant,
the chiral sulfoxide 1b was obtained in 14% yield and 73% ee
(Table 1, entry 1). Substituting oxidant with two another peroxide
oxidants including cumyl hydroperoxide and 49% hydrogen perox-
ide result in a significant upgrade in yield (entry 2,3). Hydrogen
peroxide provided the best result (entry 3). Subsequently, we
demonstrated that 2 equiv of H2O2 can be achieved the pleasant
result when the oxidant quantity was investigated (entry 4–8).
Except for L2, further ligand screening investigations were
focused on L1, L3, L4 and L5. Among them, we failed to get a better
result than L2 from the ligands containing chiral amino alcohol
introductory oxazoline moieties (Table 1, entries 9–12). Moreover,
we also tested pivalic acid as additive, but the effect is unsatisfac-
tory than aca (entry 13).
Under the established optimized conditions, we took the initia-
tive to investigate the substrate scope for a series of representative
sulfoxides (Table 2). An efficient conversion which varieties of
racemic pyridyl sulfoxides into the corresponding chiral sulfoxides
and sulfones within a short time in appreciable yields with excel-
lent enantioselectivities could be happened (1b–5b and 1c–5c).
The excellent enantioselectivity and high yields are independent
to the electronic character and site of the substituents on the aro-
matic ring with heteroatoms. It is more attention, good yields and
excellent enantioselectivity were retained when methyl was
replaced by a longer alkyl chain (propyl and isobutyl) (3b, 3c and
4b, 4c). Obviously, a higher ee value could be achieved when the
substrates of pyrimidinyl and pyrazinyl sulfoxides were involved
in the reaction (6b–11b, 6c–11c). Stimulated by good results, the
thiazolyl and thienyl sulfoxides caused our attention. Satisfactorily,
the same good results still can be obtained (12b, 13b and 16b).
Scheme 1. Challenges in oxidative kinetic resolution of sulfoxides.
(H2O2), a wide range of sulfoxides in high ee value were obtained
by the OKR of heterocyclic sulfoxides along with the corresponding
sulfones in high yield. The OKR of heterocyclic sulfoxides are per-
fectly carried out and some new optically pure sulfoxides and sul-
fones were obtained. And the OKR of the sulfoxide substrates with
hydroxyl groups demonstrate that this catalytic system has a
favorable chemoselectivity. The further practical utility has
achieved in the OKR of omeprazole and gram-scale sulfoxides.
Results and discussion
Initially, we selected 2-(methylsulfinyl)pyridine(1a) as the
model substrate to explore the feasibility of oxidant. Mn(OTf)2
(1.4 mg, 0.004 mmol) and L2 (2.0 mg, 0.004 mmol) were dissolved
in acetonitrile (1.5 mL) , and the mixture was stirred at room tem-
perature for 12 h. To the solution of manganese complex were
added substrate (0.4 mmol), 0.2 equiv of adamantane carboxylic
acid(aca) (14.4 mg, 0.08 mmol), and 65% aqueous tert-butyl
hydroperoxide (28.8 mg, 0.32 mmol). Then decreased the temper-
ature to ꢀ30 °C, and the reaction mixture was stirred at ꢀ30 °C
Table 1
Screening of Reaction Condition.
Entry
ligand
additive
H2O2 (equiv)
yield(%)a
ee(%)b
1c
2d
3
4
5
6
7
8
9
10
11
12
13e
L2
L2
L2
L2
L2
L2
L2
L2
L1
L3
L4
L5
L2
aca
aca
aca
aca
aca
aca
aca
aca
aca
aca
ca
–
–
14
35
46
34
27
25
23
17
36
58
62
81
38
73
39
48
60
71
73
78
83
57
26
48
9
0.8
1.2
1.6
1.8
2.0
2.2
2.0
2.0
2.0
2.0
2.0
aca
–
44
a
b
c
The yield were determined by GC and nitrobenzene as interior label.
The ee values were determined by chiral HPLC.
Tert-Butyl hydroperoxide (0.8 equiv).
Cumyl hydroperoxide (0.8 equiv).
d
e
P ivalic acid.

158
J. Yang et al. / Tetrahedron Letters 59 (2018) 156–159
Table 2
Substrate Scope of Oxidative Kinetic Resolution of Sulfoxides.
a
Isolated yield.
b
The ee values were determined by chiral HPLC.
c
The sulfone(7c) needs to be stored under N2 at 0 °C, so we cannot get the product in our experimental conditions.6g
Furthermore, in order to display the high efficiency of the oxidized
system, we tested the sterically hindered heterocyclic benzyl sul-
foxides. Fortunately, the hodiernal oxidation could also be favour-
ably applied to heterocyclic benzyl sulfoxides, the corresponding
chiral sulfoxides and sulfones were acquired with high yields and
excellent enantioselectivity (>99% ee, 14b, 14c and 15b, 15c).
In addition, we selected the substrate 17a and 18a with hydro-
xyl groups as the reactants and extended the reaction time to 1 h.
We found only 17b, 17c and 18b, 18c were obtained and no CAH
bond and OAH bond oxidazed product were obtained (proved by
GC–MS). It indicated that the catalytic system showed a favorable
chemoselectivity (Scheme 2).
In order to explore the applicability of the methodology, the
OKR of omeprazole was carried out and 30% yield esomeprazole
that is a chiral proton pump inhibitor for the treatment of gastroe-
sophageal reflux disease1a was obtained in 89% ee with 3.0 equiv
H2O2 (Scheme 3).
Scheme 3. Synthesis of Esomeprazole.
To further evaluate the practicability prospect of the catalytic
system, the OKR of thiazole derivative 12a and pyridine derivative
15a were amplified to gram-scale under the optimized conditions,
furnishing the conceivable product 12b with 32% yield and 87% ee,
12c 67% yield and 15b was provided with 30% yield and 98% ee,
15c 69% yield (Scheme 4).
We suggested that the OKR mechanism was the similar to our
previous study (Scheme 5).5b,5c First, the original conversion is
(L)Mn(II) to the intermediate M. Then, the intermediate
M
Scheme 2. Evidence Experiment of Chemoselectivity.
Scheme 4. Gram-scale Oxidative Kinetic Resolution of Sulfoxide 12a and 15a.

J. Yang et al. / Tetrahedron Letters 59 (2018) 156–159
159
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2017.12.012.
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phyrin-inspired Mn-oxo complex and hydrogen peroxide for the
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heterocyclic sulfoxide substrates was occurred in a mild reaction
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Financial support from the Higher Education Research Program
of the Education Department of the Liaoning Province of
China (No. L2014421), Liaoning Normal University is gratefully
acknowledged.
A. Supplementary data
Experimental procedures, analytical data, and copies of the 1H
and 13C NMR spectra and ee value for all products (1b–18b) and
(1c–18c).