Synthesis of asymmetrical thioethers with sulfinamides as the sulfenylation agent under metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2018.10.038

Using sulfinamides as a new reagent for preparation of asymmetrical thioethers has been developed under metal-free conditions. The reactions proceeded smoothly without the use of stinky thiophenol, highly toxic sulfonyl chloride or oxidant. Such a simple, efficient transformation provides an attractive approach to various diaryl sulfides in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2018.10.038

Accepted Manuscript
Synthesis of Asymmetrical Thioethers with Sulfinamides as the Sulfenylation
Agent under Metal-free Conditions
Long-jun Ma, Guang-xun Li, Jin Huang, Jin Zhu, Zhuo Tang
PII:
S0040-4039(18)31256-5
https://doi.org/10.1016/j.tetlet.2018.10.038
TETL 50348
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 August 2018
19 October 2018
22 October 2018
Please cite this article as: Ma, L-j., Li, G-x., Huang, J., Zhu, J., Tang, Z., Synthesis of Asymmetrical Thioethers
with Sulfinamides as the Sulfenylation Agent under Metal-free Conditions, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.10.038
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Synthesis of Asymmetrical Thioethers with Sulfinamides as the
Sulfenylation Agent under Metal-free Conditions
Long-jun Ma, [a,b] Guang-xun Li, *[c] Jin Huang, [c] Jin Zhu, *[a] and Zhuo Tang *[c]
aChengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, Sichuan 610041(China)
E-mail: jinzhu@cioc.ac.cn
bUniversity of Chinese Academy of Sciences, Beijing 100049, P. R. China
cNatural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Science, Chengdu,
Sichuan 610041(China) E-mail: ligx@cib.ac.cn; E-mail: tangzhuo@cib.ac.cn
Abstract: Using sulfinamides as a new reagent for preparation of asymmetrical thioethers has
been developed under metal-free conditions. The reactions proceeded smoothly without the use of
stinky thiophenol, highly toxic sulfonyl chloride or oxidant. Such a simple, efficient transformation
provides an attractive approach to various diaryl sulfides in good to excellent yields.
Keywords: Sulfinamides; Sulfenylation agent; Metal-free; Asymmetrical thioethers
Introduction
Asymmetrical thioethers, widely used in medicine, bioactive substances1-3 (e.g. Potential anti-
inflammatory compounds1, LFA-1 antagonists2 and DHFR inhibitors3, Figure 1) and functional
materials4 (e.g. BTNT and BTBT, Figure 1) are an important class of active compounds 5-12
.
N
Cl
COOEt
S
S
N
Cl
N
N
H
Cl
Cl
NH2
S
O
Potential anti-inflammatory compound
LFA-1 Antagonist
LFA-1 Antagonist
S
NH2
Ar
S
N
S
S
N
S
BTBT
H2N
N
BTNT
H
DHFR Inhibitors
Onganic semiconductor
Onganic semiconductor
Figure 1 Applications of asymmetrical thioethers
Therefore, many researchers have been focusing on developing a novel, practical, and highly
efficient methods for the construction of asymmetrical thioethers. These methods can be
categorized according to the sulfur source. One is the transition-metal catalyzed cross couplings of
disulfides (RSSR) or thiols (RSH) with aryl halides, pseudo halides or arylboronic acids, where

transition-metal catalysts mainly focus on palladium13-21, copper22-26, zinc27, iron 28-30, nickel31-36
,
cobalt37, and rhodium38-40. However, most of these methods have disadvantages like harsh reaction
conditions, metal toxicity and high costs, which make it difficult to ensure that these methods
could be applied on a large scale. Another method typically relies on the coupling of sulfenyl
chlorides with organo zinc41 or Grignard reagents42,43. However, new sulfenylation agents such as
sulfonyl hydrazide44-49, sulfonyl chloride50,51, sulfinic acid52,53 or others54-60 have also appeared.
Although these new sulfurizing agents replaced the malodorous mercaptans, they still require
transition metals and prefunctionalized arenes (e.g., aryl halides) or oxidants, (e.g. (a), Scheme 1).
Sulfinamide, an easily prepared and stable compound, has been found to have many important
functions such as key compounds in the preparation of amines, efficient catalysts. What's more,
sulfinamide was used as a radical donor recently61. Previously, we have develop an interesting
method for synthesis of sulfenamide with sulfinamide as sulfurizing agent62 (e.g. (b), Scheme 1 ).
Here, we developed another example for synthesis of asymmetrical thioethers with
arylsulfinamide as sulfurizing reagent (e.g. (c), Scheme 1 ).
Previous work by others
(a)
C(sp2)-H thioarylation
Metal
or
oxidizing agent
"S"
S
H
R
+
R
"S"= SH, SAr, S(O)2Cl, S(O)2NHNH2, SO2Na, SBn, SSO3Na, SO2H, S-succinimide
prefunctionalized ArX expensive reagents
hazardous substrances or metals residual
(b)
Our previous work
O
R
HBCat, DMAP
Toluene, N2
80 oC
NH2
S
S
+
N
H
NH2
R
This work
(c)
NH2
S
HBCat( 1.0 eq)
DMAP ( 0.10eq)
NH2
NH2
O
R
+
R
Ar
Ar
Toluene, N2
S
100 o
C
no malodorous mercaptan
metal-free and ligand-free
no oxidant required
asymmetric thioether with amino in ortho position
Scheme 1 Examples of sulfenylation agents
As we know, the aromatic sulfenamides (Ar-S-NHAr) could transform to the corresponding
asymmetrical thioether via rearrangement according to Davis’s work63,64. Therefore, we
speculated that aromatic sulfenamide obtained with our previous method, could react continuously
to afford the corresponding asymmetrical thioethers via rearrangement65,66, (Scheme 2).

O
NH2
NH2
NH2
H
S
N
HBCat, DMAP
Toluene, N2
80 oC
S
S
+
？
4
1
2
Yield ( 70%)
This work
one-pot synthesis
Our previous work
Scheme 2. Probability of synthesis asymmetrical thioether with in situ formed sulfenamide
Table 1. Optimization of reaction condition for thioethera
NH2
aCondition:HBCat
(0.25
NH2
HBCat.(1.0 eq)
Condition
S
S
O
mmol), 1 (0.25 mmol), 2 (0.3
+
NH2
1
mmol), additive (10 mol%),
3
2
solvent
in
0.125
M
Entry
Solv.
Temp.(℃) Additive
Yield b (%)
b
concentration for 16 h; the
reaction yield was calculated
based on purification with
fast silicon column.
1
toluene
90
90
90
90
DMAP
DMAP
DMAP
DMAP
DMAP
TEA
62
45
30
< 5
54
47
29
25
22
76
68
70
2
benezene
1,4-dioxane
DMSO
3
4
Initially, the reaction
was investigated with
benzenesulfinamide,
5
chlorobenzene 90
6
toluene
toluene
toluene
toluene
toluene
toluene
toluene
90
7
90
DBU
8
90
DABCO
K2CO3
DMAP
DMAP
DMAP
HBCat and aromatic amine
at higher temperature. As
expected, we found the
9
90
10
11
12
100
110
120
target
product
with
moderate yield, (Table 1,
entry 1). Then the reaction solvent as well as the reaction temperature were screened, which
revealed that the reaction yield could be decreased when replacing toluene with other solvents,
(entries 2–5). To our delight, slightly increasing of yield was observed when the reaction
temperature was raised to 100 ℃ (entry 10). However, higher temperatures didn’t improve
reaction yields continuously (entries 10–12). The best additive for this reaction was DMAP
(entries 6–10) which consistent with the method for synthesis of sulfenamide62. Therefore the
optimal reaction condition was considered as: DMAP as additive at 100 °C in toluene.
O
R'
S
HBCat ( 1.0 eq)
S
R
NH2
NH2
R'
+
R
DMAP ( 0.1 eq), toluene
NH2
N2, 100 o
C
1a - 1p
2a - 2e
3a - 3e

NH2
NH2
O
O
NH2
S
O
S
S
O
O
O
O
62 %
77%
3b
NH2
81%
3a
3c
O
O
NH2
S
S
S
O
NH2
72 %
3d
O
O
O
77 %
3f
75 %
3e
NH2
NH2
O
S
S
S
O
NH2
62 %
3h
O
68 %
3g
67 %
3i
NH2
O
S
O
S
S
H2N
O
NH2
O
60 %
3k
60 %
3l
62 %
3j
NH2
NH2
NH2
S
S
S
O
O
Cl
O
O
55 %
3o
75 %
3m
76 %
3n
NH2
CF3
NH2
NH2
NO2
S
S
S
O
O
F
62 %a
not obtained
not obtained
3p
Scheme 3. Investigation of the scope of the aniline and sulfinamides a reaction at120 ℃
With the optimal reaction condition, we explored the substrates scope based on the different
arylamines and sulfinamides with different substituents on the benzene ring. The experimental
results showed that the stronger the electron donating effect of the substituent that aniline
contained, the higher the yield of the target product obtained (3a vs 3c, 3e vs 3g, 3m vs 3n ).
Especially, rearrangement to afford the para-substituted amine thioether was found when 2,5-
dimethoxy-aniline was investigated (3j). However, When 4-nitroaniline and 4-
(trifluoromethyl)aniline was investigated, there were no target product obtained. The results
demonstrated that the electronic effect of substituents on the aromatic ring of aniline has a critical
effects. The electron-donating substituent on the aniline was beneficial to the reaction. We also
tried several heterocyclic amines like 2-aminopyridine and 2-thienylamine but did not get the
product.
Sulfinamides with different substituents on the aromatic ring have also been investigated. From
the results of the experiment, we found either the electron-withdrawing group or the electron-
donating group could obtain target products with moderate yield. When 4-
methylbenzenesulfinamide and 2-methyl-benzenesulfinamide were investigated, the

corresponding diary thioether 3e was obtained with higher yield compared with 3l, which was
ascribed to the steric hindrance effect, (3e vs 3l). Unlike other sulfinamides, 4-
fluorobenzenesulfinamide requires a higher reaction temperature (120℃ ) to obtain the target
product due to the electro withdrawing property of the fluorine substituent, (3p ).
NH2
H
N
HBCat ( 1.0 eq )
DMAP ( 0.1 eq )
S
a )
b )
S
3
Toluene, N2
100 o
C
4
Yield: 90 %
NH2
H
N
HBCat ( 1.0 eq )
DMAP ( 0.1 eq )
S
S
S
Toluene, N2
100-120 o
C
not obtained
NH2
5
H
N
S
DMAP ( 0.1 eq )
Toluene, N2
S
+
c )
d )
S
3
100 o
C
5
4
Yield: 38 %
Yield: 50 %
NH2
H
N
HBCat ( 1.0 eq )
Toluene, N2
S
S
3
100 o
C
trace
4
Scheme 4 Investigation of the reaction mechanism
In order to explore the mechanism of the reaction, corresponding sulfenamide 4 was prepared
with previous method62. As we imagine, the corresponding rearrangement occurred to produce the
diary thioether 3 under the reaction conditions. (Scheme 4, eq. a). However, when alkyl
substituted sulfenamide 5 was investigated, there was no rearrangement product found although
raising the temperature from 100 ℃ to 130 ℃ (Scheme 4, eq. b). These results are consistent
with David's work63,64. What’s more, both DMAP and HBCat played an important role in this
reaction. The optimal reaction condition without adding HBCat, the target product 3 was obtained
in 38% yield with 50 % 1,2-diphenyldisulfane 5 as byproduct (Scheme 4, eq. c). Meanwhile, there
was trace 3 obtained when HBCat was added without DMAP (Scheme 4, eq. d). The results
demonstrated that the aromatic sulfenamides were the significant intermediate formed in the
reaction process. Moreover, DMAP and HBCat were indispensable for the rearrangement process.
Based on the above experiments, we proposed the possible reaction mechanism (Scheme 5).
Firstly, compound B was formed through the following procedure: coordination of sulfenamide
with catechol borane promoting by DMAP67 and release of hydrogen gas, which is the same as
reported by Du68. Then the aromatic amine reacts with compound B to form intermediate 1, which

is consistent with what we have reported previously62. After that, the intermediate 1 was
decomposed into the sulfenamide and organic boron compound C, which can be regarded as a
Lewis acid for the following rearrangement process. Then intermediate 2 was formed at the higher
temperature, which was transformed to the final product by the cooperate catalytic effect of
DMAP and organic boron compound C. DMAP removes hydrogen from intermediate 2 and
compound C acts as a Lewis acid to activate the imine, which together promotes this
rearrangement. The existence of C after the finish of the reaction was proved with 11B NMR
experiment (see supplementary information).
N
DMAP
Lewis acid
NH
N
Ar2
H
H
S
Ar1
O
O
B
NH
Ar1
S
H
O
intermediate 2
DMAP
A
H2
HBCat.
O
NH2
S
O
O
O
Ar2
S
Ar2
Ar1
S
NH2
B
S
Ar1
N
Ar1
N
H
Ar1
H
Sulfenamide
unsymmetric aryl sulfide
B
OH
NH
O
O
Ar2NH2
B
C
O
O
O
Ar1
Lewis acid
B
S
NH2
Ar2
N
H
intermediate 1
Scheme 5. Possible mechanism of the reaction
Conclusion
In summary, we have developed an efficient method for preparation of asymmetrical thioethers
with odorless sulfinamides as sulfenylation agent. This method was efficient for transforming
kinds of benzenesulfinamide to asymmetrical thioethers. Especially, the method was easy to
control and avoided the use of metals. What's more, no external oxidants were needed in the
process.
Acknowledgements

This work was supported financially by the Natural Science Foundation of Sichuan
province, China (2017JY0055), the Youth Innovation Promotion Association CAS
(2018402).
Supplementary data
Supplementary data (detailed experimental procedure and spectroscopic data) associated
with this article can be found, in the online version.
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Easy to control
New sulfenylation agent without odor
No oxidant required

Sulfinamides as sulfenylation agent
NH2
S
HBCat( 1.0 eq)
DMAP ( 0.10eq)
NH2
NH2
O
R
R
+
Ar
Ar
Toluene, N2
100 oC
S
no malodorous mercaptan
metal-free and ligand-free
no oxidant required
asymmetric thioether with amino in ortho position