Copper-catalyzed: N -thioetherification of sulfoximines using disulfides

Article abstract of DOI:10.1039/c6cc06359d

A novel copper-catalyzed N-thioetherification of sulfoximines under mild reaction conditions was developed. In this procedure, the N-S bond formation was achieved using readily available disulfides as the sulfur source.

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Copper-catalyzed N-thioetherification of sulfoximines using disulfides
Hui Zhu, Jin-Tao Yu*and Jiang Cheng*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
C-S or heteroatom-S bonds, in terms of their chemical stability,
50 synthetic availability and less odorous.5a,12,13 Thus, in this paper,
we wish to describe the methodology of the copper-catalyzed N-
thioetherification of sulfoximines using disulfides as sulfur
source (Eq 3, Scheme 1).
5
A novel copper-catalyzed N-thioetherification of sulfoximines
under mild reaction conditions was developed. In this
procedure, the N-S bond formation was achieved using
readily available disulfides as sulfur source.
Organosulfur compounds play key and irreplaceable roles in
10 biochemical processes,1 serving as versatile intermediates in
organic synthesis2 and function as crucial structures in material
science.3 This fact prompted widespread investigations on the
synthesis of sulfur-containing molecules over the years.4
However, in comparison with the well-developed C-S bond
15 formation, the construction of heteroatom-S bonds, especially the
N-S bond has not yet been actively explored. There were only a
few examples dealing with the formation of N-S bond, which is
an important linkage that widely exists in many bioactive and
synthetic useful molecules. For example, Taniguchi reported the
20 copper-catalyzed reaction of secondary amines with diaryl
disulfides or aryl thiols towards sulfenamides.5 The synthesis of
compounds with N-S bond in cyclic motif, such as the bioactive
benzoisothiazolones, could be realized by condensation of 2-
(chlorocarbamoyl)phenyl hypochlorothioites with amines,6 metal-
25 catalyzed reaction of 2-halo-arylamides/benzamides with proper
S sources7 or catalytic dehydrogenative N−H/S−H coupling
reaction of 2-mercaptobenzamides.8
55
Scheme 1. Sulfoximines based construction of N-S bond
With this idea in mind, we chose diphenylsulfoximine (1a)
and diphenyl disulfide (2a) as the model substrates to find the
optimal reaction conditions. To our delight, in the presence of
60 Na2CO3 in DMSO, CuCl and CuCl2 were both valid catalysts,
giving the N-phenylthio product 3aa in 60% and 62% yields,
respectively (entries 1 & 2, Table 1). Cu2O and CuO were unable
to catalyze this transformation, while CuI gave a higher yield
(entries 3-5, Table 1). Inspired by this result, other bases were
65 screened and NaOAc was proved with best efficiency with 88%
yield of 3aa (entries 6-12, Table 1). Blank experiments revealed
that, the reaction could occur without any base albeit in lower
yield, but no product was obtained in the absence of any copper
catalyst (entries 10 & 11, Table 1). Decrease the catalyst loading
70 to 15 mol%, the yield dropped to 76%, and the yield didn’t
increase obviously if 30 mol% CuI was used (entry 9, Table 1).
Other common solvents, such as trifluoromethylbenzene, DCE,
chlorobenzene and DMF were not as effective as DMSO (entries
15-18, Table 1). The N-thioetherification could occur in the
75 atmosphere of O2, but in lower yield. No increase of yield was
observed at higher temperature (entry 9, Table 1).
As a special kind of imine, sulfoximines show significant
bioactivities in medicinal chemistry and have attracted
30 considerable attention in crop protection.9 Additionally, they can
be chemically modified by N-substitution to afford complex
structures with fine-tuning chemical and physical properties.10
Among those works, the construction of N-S bond was developed
by Bolm through two-step N-trifluoromethylthiolation of
35 sulfoximines
trifluoromethanethiolate
using
NBS
(Eq
followed
Scheme
by
1).10a
silver
1,
N-
Sulfenylsulfoximines are important intermediates in organic
synthesis. In the case of direct N-thioetherification of
sulfoximines, traditional methods required the employment of
40 arylsulfonyl chloride as the sulfur source (Eq 2, Scheme 1).11
This procedure suffered from limited substrate scope and the
employment of odorous, highly toxic and corrosive agents such
as thiols and chlorine gas. Therefore, the development of an
efficient and environmentally benign protocol, by which a diverse
45 library of N-sulfenylsulfoximines could be produced using
readily available starting materials under mild conditions, would
be highly desirable. Disulfides are frequently used as efficient
sulfur source in the thiolation/thioetherification processes to form
Table 1. Screening the optimal conditionsa
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DOI: 10.1039/C6CC06P35a9gDe 2 of 4
Entry Catalyst
Additive
Na2CO3
Na2CO3
Na2CO3
Solvent
DMSO
Yield (%)
60
Scheme 2. Substrate scope of sulfoximines in N-thioetherificationa
CuCl
CuCl2
Cu2O
CuO
CuI
1
2
3
4
5
6
7
8
62
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
trace
trace
69
Na2CO3
Na2CO3
K2CO3
Cs2CO3
tBuOK
CuI
36
trace
trace
CuI
CuI
88 (72)b (58)c
(76%)d (89)e
9
CuI
NaOAc
DMSO
75
83
87
56
0
10
11
12
13
14
15
16
17
18
CuI
CuI
CuI
CuI
--
LiOAc
KOAc
CsOAc
--
DMSO
DMSO
DMSO
DMSO
DMSO
PhCF3
DCE
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
trace
trace
0
CuI
CuI
CuI
CuI
PhCl
20
DMF
a
Reaction conditions: 1 (0.1 mmol), 2a (0.1 mmol, 1 equiv.), CuI (20
a
Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol, 1 equiv.), catalyst
35 mol%), NaOAc (3 equiv.) in DMSO (2 mL) at 60 oC for 15 h, sealed tube,
(20 mol%), additive (3 equiv.) in solvent (2 mL) at 60 oC under air for 15
h, isolated yields. b At 80 oC. c Under O2. d 15 mol% CuI. e 30 mol% CuI.
isolated yields. b Scale-up reaction using 1 mmol of 1a.
Scheme 3. Substrate scope of disulfides in N-thioetherificationa
After the establishment of the optimized reaction conditions,
the substrate scopes and limitations of this N-thioetherification
procedure were investigated, as shown in Scheme 2 and 3. As
expected, a series of S,S-diarylsulfoximines with either electron-
donating or electron-withdrawing substituents all good reaction
partners to give the corresponding N-thioetherificated
5
10 sulfoximines in good yields (3aa-3fa, Scheme 2). In addition,
alkyl aryl sulfoximines also reacted smoothly to deliver the
desired products although in relatively lower yields (3ga-3ka,
Scheme 2). Interestingly, S-aryl-S-methyl-sulfoximines with
electron-withdrawing groups on ortho- or para-position of phenyl
15 gave relatively higher yields (3ia-3ka). Moreover, the tolerance
of halogen provided convenient handles for further
functionalizations (3da-3fa, 3ja, 3ka). The practicability of this
procedure was further evaluated using 1 mmol of 1a, giving the
product 3aa in a comparable 76% yield.
20
Next, the scope of disulfides was investigated as shown in
Scheme 3. Diaryl disulfides with methyl, methoxy, nitro, chloro
and carbonyl groups all reacted well with diphenyl sulfoximines
leading to N-sulfenylsulfoximines with various aryls on S atom
(3ab-3aj). Diaryl disulfides with electron-donating substituent on
25 para-position of phenyl or with electron-withdrawing substituent
on meta-position of phenyl were less reactive (3ab, 3ac, 3ag &
3ah). It was worth to note that diheteroaryl disulfides such as
di(thiophen-2-yl) disulfide (2k) also react smoothly under
optimized conditions provided 3ak in 74% yield. Unfortunately,
30 when dialkyl disulfides were used, no corresponding products
were detected even reacted for prolonged time.
Reaction conditions: 1a (0.1 mmol), 2 (0.1 mmol), CuI (20 mol%),
o
b
40 NaOAc (3 equiv.) in DMSO (2 mL) at 60 C for 15 h, sealed tube.
2
Equivalents of disulfide was used.
2
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In order to gain some insights into the reaction mechanism,
control experiments were conducted as shown in Scheme 2.
(BM2012110) and Advanced Catalysis and Green
Manufacturing Collaborative Innovation Center, Changzhou
Firstly, the transformation was not obviously affected after 3 45 University for financial supports.
equivalents of 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO)
5
was added to the reaction as radical scavenger, thus the radical
pathway could be ruled out (Eq (a), Scheme 4). Next, 2
equivalents of PhSCu(I) was subjected to the reaction, and the
thioetherification product was isolated in 81% yield in the
presence of NaOAc in DMSO (Eq (b), Scheme 4), which was
Notes and references
School of Petrochemical Engineering, Jiangsu Key Laboratory of
Advanced Catalytic Materials & Technology, Jiangsu Province Key
Laboratory of Fine Petrochemical Engineering, Changzhou University,
50 Changzhou 213164, P. R. China
E-mail: yujintao@cczu.edu.cn; jiangcheng@cczu.edu.cn
† Electronic Supplementary Information (ESI) available: See DOI:
10.1039/b000000x/
10 comparable with the result obtained under standard conditions.
This result indicated that PhSCu(I) maybe performed as crucial
intermediate in this N-thioetherification process.
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Scheme 4. Mechanistic studies.
15
Based on the above mentioned experimental results and
former reported works,14 the mechanism was outlined in Scheme
5. Initially, copper(I) catalyst coordinates to the diaryl disulfide
(2a) to generate sulfonium ion intermediate 4. Then 4 is
subsequently attacked by the nucleophilic sulfoximine anion
4
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90
Scheme 5. Proposed mechanism.
95
30
In summary, we have demonstrated a copper-catalyzed N-
thioetherification of sulfoximines under mild reaction
conditions using the less toxic and readily available disulfides
as sulfur source.
A
series of synthetic useful N-
100
105
110
arylthiosulfoximines with various functional groups were
35 obtained in moderate to good yields. This work represents a
promising avenue to access N-sulfenylsulfoximines and is an
important complement to sulfoximine chemistry.
We thank the National Natural Science Foundation of China
(nos. 21672028 and 21572025), the Natural Science
40 Foundation for Colleges and Universities of Jiangsu Province
(nos. 16KJB150002 and 15KJA150001), Jiangsu Key
Laboratory of Advanced Catalytic Materials and Technology
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