h-BN@Copper(II) nanomaterial catalyzed cross-coupling reactions between sulfoximines and N-(phenylthio)-succinimide under mild condition

Article abstract of DOI:10.1016/j.catcom.2018.04.021

A novel and efficient method for the synthesis of N-S substituted sulfoximines has been established with h-BN-supported copper(II) nanomaterial as the catalyst. Catalyzed by this heterogeneous catalyst, the desired products were obtained with wide scope of substrates, good to excellent yields, free ligand and low-toxicity solvent. Moreover, after being reused ten times, there is almost no significant loss of its catalytic activity.

Full text of DOI:10.1016/j.catcom.2018.04.021

Accepted Manuscript
h-BN@Copper(II) nanomaterial catalyzed cross-coupling
reactions between sulfoximines and N-(phenylthio)-succinimide
under mild condition
Yan Lin, L.Ü. Guanghui, Yanzhao Liu, Yang Zheng, Ruifang Nie,
Li Guo, Yong Wu
PII:
S1566-7367(18)30159-6
doi:10.1016/j.catcom.2018.04.021
CATCOM 5394
DOI:
Reference:
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
23 March 2018
19 April 2018
27 April 2018
Please cite this article as: Yan Lin, L.Ü. Guanghui, Yanzhao Liu, Yang Zheng, Ruifang
Nie, Li Guo, Yong Wu , h-BN@Copper(II) nanomaterial catalyzed cross-coupling
reactions between sulfoximines and N-(phenylthio)-succinimide under mild condition.
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ACCEPTED MANUSCRIPT
h-BN@Copper(II) nanomaterial catalyzed cross-coupling reactions between
sulfoximines and N‑(phenylthio)-succinimide under mild condition
a
b
a
a
a
a
a
Yan Lin, Guanghui LÜ, Yanzhao Liu, Yang Zheng, Ruifang Nie, Li Guo* and Yong Wu*
a. Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal
Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, P. R. of
China.
b. Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Hubei, Shiyan,
442000, PR China
E-mail: guoli@scu.edu.cn; wyong@scu.edu.cn

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Abstract
A novel and efficient method for the synthesis of N‑S substituted sulfoximines has been
established with h-BN-supported copper(II) nanomaterial as the catalyst. Catalyzed by this
heterogeneous catalyst, the desire products were obtained with wide scope of substrates, good to
excellent yields, free ligand and low-toxicity solvent. Moreover, after being reused ten times, there
is almost no significant loss of its catalytic activity.
Keywords N-sulfenyl sulfoximines, hexagonal boron nitride, copper, cross-coupling,
recyclable, water

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1
. Introduction
As a class of important organosulfur-nitrogen containing compounds, sulfoximines have
attracted considerable attention since the discovery of the sulfonimidoyl function in 1949 [1]. In
general, sulfoximines are one kind of monoaza analogues of sulfones, and the amphoteric nitrogen
offers an additional point for the structure modification [2]. Due to the high reactivity of the
nitrogen and stereogenic sulfur atom, sulfoximines have been applied as useful building blocks for
organocatalysts [3], chiral auxiliaries [4, 5] and chiral ligands [6, 7]. Recently, sulfoximines were
also used as directing group in transition metal-catalyzed C-H functionalizations [8, 9].
Furthermore, sulfoximines also showed potential biological activity in many sides [10].
Scheme 1 Pathway for the construction of N-S substituted sulfoximines
With the increasing importance in organic synthesis and chemical industry, more and more
efforts were focused on the synthesis of sulfoximine derivatives. Inspiringly, a number of modern
and efficient methods about N-H bond modification of sulfoximines have been reported and the
N-C bond formations of sulfoximines were well developed. For example, the N-alkylations [11],
N-arylation [12, 13], N-cyanation [14, 15], N-acylation [16, 17] and N‑alkynylation [18, 19] have
been established in the past few ten years. Those reports greatly enriched the structural complexity
and molecular multiplicity of sulfoximines. Conventionally, N-sulfenyl sulfoximines were
synthesized from the reactions of N-sulfenyl sulfoximines and arylsulfonyl chloride [20]. Recently,
some new synthetic routes about N-sulfenyl sulfoximines were reported. In 2015,
N-trifluoromethylthiolated sulfoximines were synthesized by Carsten Bolm’s team [21].
Somewhat later, copper-catalyzed N-thioetherification of sulfoximines were obtained [22]. More
recently, Zeng and co-works reported iodine and hydrogen peroxide-catalyzed intermolecular S–
H/N–H dehydrocoupling reaction in sulfoximines [23]. Almost at the close of time, our team also

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focuses on the modification of sulfoximines and a one-pot cascade N-S bond formation method to
prepare directly N-sulfenyl sulfoximines with thiophenols were established [24]. Compared with
the traditional sulfoximines synthesis methods (arylsulfonyl chloride was needed), those
homogeneous catalysts have been established for the construction of such structures, but they may
be also limited by the catalyst recovery, difficulty in separation and create hazardous waste. With
the development of catalysis chemistry, many researches were focused on the heterogeneous
catalyst which was considered as a valuable tool to overcome these issues.
In the modern era of organic synthesis, there are increasing demands for using
environmentally benign catalysts and solvents in chemistry reactions, and high molecular
materials are gaining more and more attention in heterogeneous catalysis system due to their
excellent abilities in catalyst separation and recovery, mild reaction conditions and low-toxic
nature [25, 26]. Among these materials, hexagonal boron nitride (h-BN) interestingly exhibits
excellent activity. It is similar in many ways to graphene with high thermal tolerance, excellent
chemical stability and wide band gap independent of morphology [27, 28]. In addition, h-BN was
also considered as a supporting material to synthesize heterogeneous catalyst. Last year, we had
developed a novel and green heterogeneous nanomaterial h-BN@γ-CD@Cu(OAc) as an efficient
2
and recoverable catalyst which was used in the multicomponent 1,3-dipolar cycloaddition reaction
[29]. Due to our continuous interest in the heterogeneous catalyst and sulfoximines, here we
introduce this efficient catalyst into the aqueous cross-coupling reaction to synthesis N-sulfenyl
sulfoximines.
2
. Experimental
General Procedure for the Synthesis of N-Thiosuccinimides: N-Chlorosuccinimide (1.0
equiv.) was added to a stirred solution of thiol (1.0 equiv.) in anhydrous toluene (4 mL toluene/1.0
mmol thiol) at 25 °C under an argon atmosphere. The color of the resulting heterogenous mixture
was transformed to yellow-orange after stirring at 25 °C for 45 min. A solution of Et N (1.0 equiv.)
3
in anhydrous toluene (1.6 mL toluene/1.0 mmol of Et N) was then added over 45 min with a
3
syringe pump. The resulting heterogeneous mixture was stirred at 25 °C for 12 h and then diluted
with diethyl ether (12 mL ether/1.0 mmol of thiol). The resulting white precipitate was filtered off.
The filtrate was concentrated under reduced pressure to produce a yellow/orange semisolid residue,
which was purified by silica gel column chromatography to obtain the N-Thiosuccinimides.
General Procedure for the Synthesis of N-Sulfenyl sulfoximines (3aa-3ja)：To a 25 ml
round-bottom flask equipped with a magnetic stir bar, commercially available solutions of
EtOH:H O=1:1 ( 3mL : 3mL ) were added to a mixture of sulfoximines (50 mg, 0.23 mmol, 1.00
2
equiv.), N-tiosuccinimides (142.8 mg, 0.69 mmol, 3.00 equiv.) and h-BN@γ-CD@Cu (20 mol%,

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240 mg ) under air. The reaction mixture was stirred at rt for 24 h. After completion of the reaction
(monitored by TLC), the reaction mixture was filtered and washed with ethyl acetate to recycle the
h-BN@γ-CD@Cu.The filtrate was diluted with H O (10 mL), extracted with ethyl acetate (3 x 10
2
mL). The combined organic extracts were washed with brine and dried over anhydrous
Na SO .After that concentrated under reduced pressure and the residue was purified by flash
2
4
column chromatography on silica gel using a mixture of PE/EtOAc and 0.3% trimethylamine as
the eluent to obtain the N-sulfenyl sulfoximines products.
The h-BN@γ-CD@Cu was prepared according to reported procedure [29].
3
. Results and discussion
At the beginning of our investigation, the reaction conditions were screened with diphenyl
sulfoximine (1aa) as the model substrate. First, in the presence of h-BN@γ-CD@Cu(OAc)2,
diphenyl sulfoximine was reacted with different sulfur sources such as benzenethiol (2a),
1
,2-diphenyldisulfane
trimethyl(phenylthio)silane (2d), S-phenyl ethanethioate (2e) and S-phenyl methanesulfonothioate
2f) in the mixture solvents H O-EtOH at room temperature for 24 h. Regrettably, the expected
(2b),
S-phenyl
4-methylbenzenesulfonothioate
(2c),
(
2
product N-sulfenyl sulfoximine (3aa) was not observed (Table 1, entries 1-6). On the contrary,
when 1aa was treated with N‑(phenylthio)-succinimide (2g), compound 3aa was obtained with 93%
yield (Table 1, entry 7). For the optimization of the amount of h-BN@γ-CD@Cu(OAc) used in
2
2+
the model reaction, 0.2 equivalent (the contents of Cu )was found to be adequate, as neither
larger nor smaller amount showed better yields (Table 1, entries 8-10). Next, we searched the
optimal ratio of the reaction substrate in this reaction and 1:3 equivalent weights of 1aa and 2g
was the superlative proportion to prepare product (Table 1, entries 11–13). In addition, when the
mixed solvents were replaced by a single organic solvent or water will result in a decrease in
yields (Table 1, entries 14–17). Furthermore, some common copper salts were also tested in this
reaction and the yield of 3aa was significantly reduced compared with h-BN@γ-CD@Cu(OAc)2
(Table 1, entries 18–22).

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a
Table 1 Optimization of the reaction conditions
Entry
R-SPh (equiv)
Cat. Cu
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
2a
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@ Cu(II)
h-BN@Cu(II)
CuI
Et(OH)
Et(OH)
Et(OH)
Et(OH)
Et(OH)
Et(OH)
Et(OH)
Et(OH)
Et(OH)
Et(OH)
Et(OH)
Et(OH)
Et(OH)
Et(OH)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
:H
:H
:H
:H
:H
:H
:H
:H
:H
:H
:H
:H
:H
2
2
2
2
2
2
2
2
2
2
2
2
2
O=1:1
O=1:1
O=1:1
O=1:1
O=1:1
O=1:1
O=1:1
O=1:1
O=1:1
O=1:1
O=1:1
O=1:1
O=1:1
0
0
2b
2c
0
2d
0
2e
0
2f
0
2g
93
b
2g
65
c
2g
75
d
1
1
1
1
1
1
1
1
1
1
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
2g
92
2g (1.2)
2g (1.5)
2g (2.0)
2g
65
69
80
50
2g
H
2
O
75
2g
Isopropanol
DCM
30
2g
trace
13
2g
Et(OH)
Et(OH)
Et(OH)
Et(OH)
Et(OH)
2
2
2
2
2
:H
2
:H
2
:H
2
:H
2
:H
2
O=1:1
O=1:1
O=1:1
O=1:1
O=1:1
2g
Cu
2
O
26
2g
CuO
15
2g
CuNO
3
35
2g
Cu(OAc)
2
34
a
Reaction condition: 1aa (50 mg, 0.23 mmol), 2 (0.69 mmol, 3 equiv), cat Cu (the contents of
2
+
b
c
Cu , 0.046 mmol, 0.2 equiv), in solvent (6 mL), r.t, under air, 24 h; Cat. Cu (0.05 equiv); Cat.
d
e
Cu (0.1 equiv); Cat. Cu (0.3 equiv); Isolated yields.

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a
Table 2 Reaction of sulfoximines with N‑(phenylthio)-succinimide
a
2+
Reaction condition: 1a (50 mg, 0.23 mmol), 2 (0.69 mmol), cat Cu (the contents of Cu ,
b
0
.046 mmol, 0.2 equiv), in EtOH:H O (3 mL:3 mL), rt, under air, 24 h; Isolated yields; Isolated
2
yield at 5 mmol scale reaction.
With the optimal reaction condition in hand, a range of reactions were carried out to expand
the scope of substituted sulfoximine, the results were shown in Table 2. First, diphenyl
sulfoximines with either electron-donating or electron-withdrawing groups were reacted with N‑
(phenylthio)-succinimide. The desired products were obtained in good to excellent yields and the
electrical effects have no significant effect on those reactions (Table 2, 3aa-3bh). Additionally,
S-phenyl-S-pyridyl-sulfoximine (Table 2, 3ca) and S-phenyl-S-naphthalene-sulfoximine (Table 2,
3
da) were reacted smoothly to deliver the desired pruducts. Inspiringly, both of
S-aryl-S-alkyl-sulfoximines and dialkyl sulfoximines were efficiently coupled with N ‑
phenylthio)-succinimide in moderate to excellent yields (Table 2, 3ea-3fb). The practicability of
(
this procedure was evaluated with 1aa (1.086 g, 5 mmol), giving the product 3aa in 92% yield and
the amount of catalyst was decreased to 0.1 equiv.

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a
Table 3 Reaction of diphenyl sulfoximine with N-thiosuccinimides
a
2+
Reaction condition: 1a (50 mg, 0.23 mmol), 2 (0.69 mmol), cat Cu (the contents of Cu , 0.046
mmol, 0.2 equiv), in EtOH:H O (3 mL:3 mL), rt, under air, 24 h; Isolated yields
2
In addition, substituted N-(phenylthio)-succinimides were tested in this reaction.
N-(phenylthio)-succinimide with electron-donating groups- methyl, methoxyl, tertiary-butyl
(Table 3, 3ga-3gd) or electron-withdrawing groups- cyano, cyanyl (Table 3, 3ha and 3hb) all
afforded the expected products with good to excellent yields. However, the halogens, especially
chlorinum substituted N-(phenylthio)-succinimide generate the desired product in lower yield
(Table 3, 3hc and 3hd). Moreover, N-(pyridylthio)-succinimide and N-(benzylthio)-succinimide
also successfully transformed to the products in high yield (3ia, 3ja).
Yield %
3aa
1
00
92
92
91
9
0
89
8
5
8
1
81
80
7
9
79
8
6
4
2
0
0
0
0
0
Runs
0
1
2
3
4
5
6
7
8
9
10
Fig. 1 Reuse of catalyst in the synthesis of 3aa

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Fig. 2 Recyclability of h-BN@γ-CD@Cu(OAc) in the reactions between 1 and 2g
2
The further study to check the recovering and reusing of catalyst were also performed. After
completion of the reaction, h-BN@γ-CD@Cu(OAc) was separated by filtration, and washed with
2
ethyl acetate until all the produce residuals were completely removed. The catalyst was reused
directly in the new reaction. As the number of cycles increasing, the yield decreased slightly. But,
it is worthy noting that, a good yield 79% was obtained even if the catalyst was recycled for 10
times (Figure 1). In addition, the recycling experiments were also carried out in which the
substrate would be changed after each catalytic run. As shown in Figure 2, performing the reaction
between 1aa and 2g, the desired product 3aa was obtained with 92% yield. Then, the catalyst was
separated and treated with S-phenyl-S-methyl-sulfoximine (1ea) and 2g, delivering 3ea in 90%
yield. With the same operation, the catalyst was continuously used in the reaction between 1fb and
2g, an excellent yield 91% of 3fb occurred. Thus, it is reasonable to believe that the catalyst can
be repeatedly used and the using of recycle catalyst between different types of substrates has no
significant influence.
4
. Conclusion
In conclusion, we have successfully reported the heterogeneous h-BN supported
copper-mediated cross-coupling reaction to synthesis N-sulfenyl sulfoximines. This synthesis
offers the corresponding products with good yields and excellent functional group tolerance. More
importantly, this catalyst can be easily separated by filtration and even if recycled ten times, the
activity was almost no significant decrease. In addition, the catalyst can be used between different
types of substrates in the recycling experiments. The study to apply this catalyst in other
environmentally friendly recyclable reaction is ongoing in our laboratory.
Acknowledgements
We are grateful for the support from the National Natural Science Foundation of China
(NSFC) (grant numbers 81373259, 81573286 and 81602954) and the Fundamental Research

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Funds for the Central Universities (grant number YJ201561).

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Highlights

The synthesis of N-sulfenyl sulfoximines catalyzed by h-BN@γ-CD@Cu(OAc)2
is developed

This methodology has a broad substrate scope and good to excellent yields.


The catalyst could be reused ten times.
The reaction was performed under aqueous solution and room temperature