Transition-Metal-Free Synthesis of Thiosulfonates through Radical Coupling Reaction

Article abstract of DOI:10.1055/s-0037-1610649

An efficient and practical transition-metal-free radical coupling reaction of sulfonyl hydrazides mediated by NIS/K ₂ S ₂ O ₈ has been developed to afford a variety of biological activity thiosulfonates in moderate to excellent yields. Compared to a known approach for the synthesis of thiosulfonates from sulfonyl hydrazides, this strategy features high yields, mild reaction conditions, and broad substrate scope. The mechanistic studies revealed that the procedure undergoes via a radical cross-coupling process for the construction of S-S bonds.

Full text of DOI:10.1055/s-0037-1610649

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©
Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
Synlett
G. Zhou et al.
Letter
Transition-Metal-Free Synthesis of Thiosulfonates through Radical
Coupling Reaction
Guodong Zhoua◊
NIS (20 mol%)
Xu-Dong Xua◊
K S O (1.2 equiv)
O
2
2
8
S
RSO2NNH2
S
R
Gan-Ping Chena
Wen-Ting Wei*a,b
Zhiyong Guo*a
R
THF, 70 °C
O
Transition-metal-free
S–S bond formation
Mild conditions
R = aryl, alkyl, pyridyl
14 examples
6
1–88% yield
a
School of Materials Science and Chemical Engineering,
Ningbo University, Ningbo 315211, P. R. of China
weiwenting@nbu.edu.cn
guozhiyong@nbu.edu.cn
State Key Laboratory of Chemo/Biosensing and
b
Chemometrics, Hunan University, Changsha 410082,
P. R. of China
◊
These authors contributed equally to this work
Received: 03.06.2018
Accepted after revision: 03.07.2018
Published online: 02.08.2018
Previous work:
O
SO2NHNH2
S
Pd/ZrO2 (3 wt%)
S
DOI: 10.1055/s-0037-1610649; Art ID: st-2018-w0336-l
R
R
(a)
(b)
R
O
EtOH, O2, 45 °C
visible light
Abstract An efficient and practical transition-metal-free radical
coupling reaction of sulfonyl hydrazides mediated by NIS/K S O has
O
SO2NHNH2
S
CuBr (10 mol%)
R2
2
2
8
S
R1
2
+
R SH
been developed to afford a variety of biological activity thiosulfonates
in moderate to excellent yields. Compared to a known approach for the
synthesis of thiosulfonates from sulfonyl hydrazides, this strategy fea-
tures high yields, mild reaction conditions, and broad substrate scope.
The mechanistic studies revealed that the procedure undergoes via a
radical cross-coupling process for the construction of S–S bonds.
R1
O
TBHP (7.5 equiv)
MeCN, 80 °C
This work:
NIS (20 mol%)
K2S2O8 (1.2 equiv)
O
S
RSO2NNH2
S
R
(c)
R
THF, 70 °C
O
Scheme 1 Synthesis of thiosulfonates using sulfonyl hydrazides
Keywords transition-metal-free, radical coupling reaction, S–S bonds,
thiosulfonates
9
Thiosulfonates constitute the pivotal core of a wide
variety of pharmaceutical molecules that exhibit anti-
microbial and antiviral activities. On the other hand, they
transformations. Recently, we have reported the C–hetero
bonds formation under transition-metal-free conditions via
radical coupling reaction. As part of our continuous efforts
1
10
are also important synthetic building blocks in organic syn-
thesis. The most common methods for building the thio-
in this strategy, we report a radical coupling reaction of sul-
fonyl hydrazides mediated by N-iodosuccinimide (NIS) with
K S O as the oxidant for the synthesis of thiosulfonates
(Scheme 1, c). The most important features of the present
method are the mild reaction conditions, high efficiency,
and broad substrate scope.
We commenced our studies with the reaction of 4-
methylbenzenesulfonohydrazide (1a) in the presence of
tetrabutylammonium iodide (TBAI, 20 mol%), and TBHP
(1.2 equiv) in tetrahydrofuran (THF) under air at 70 °C for
8 h. Gratifyingly, the desired radical coupling product S-(p-
tolyl) 4-methylbenzenesulfonothioate (2a) was obtained in
53% yield (Table 1, entry 1).
When the reaction was performed at 60 °C, only 36%
yield of 2a was generated from the reaction, and a homo-
coupling product 1,2-di-p-tolyldisulfane (3a) was obtained
in 15% yield (Table 1, entry 2). Further increasing the tem-
perature to 80 °C gave an identical yield to that of 70 °C
2
sulfonates framework generally rely on the direct oxidation
2
2
8
3
4
of disulfides or mercaptans and the sulfuration of sulfinic
5
acid salts. In 2017, Guo and co-workers used sulfonyl
hydrazides as reagent for the preparation of thiosulfonates
6
under Pd/ZrO /O /visible light conditions (Scheme 1, a). In
2
2
the same year, the Zou group described a copper-catalyzed
tert-butyl hydroperoxide (TBHP) mediated cross-coupling
of sulfonyl hydrazides with thiols for the synthesis of thio-
7
sulfonates (Scheme 1, b). In spite of these advances, further
exploration of more efficient and greener approach to en-
rich the synthesis of thiosulfonates is still highly desirable.
As an ideal alternative to transition-metal-catalytic oxi-
dation system, the [I]/K S O system has been increasingly
2
2
8
8
explored. Iodine sources (e.g., iodine, N-iodosuccinimide,
tetrabutylammonium iodide, and potassium iodide) are
low cost, nontoxic, and they can apply to a wide variety of
(Table 1, entry 3). The controlled experiments showed that
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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Synlett
G. Zhou et al.
Letter
Table 1 Optimization of Reaction Conditionsa
entries 8–12). It is worth noting that the PhI(OAc)2 and
H O nearly have no reactivity for this radical coupling.
2
2
O
Several solvents including 1,4-dioxane, toluene, and N,N-di-
methylformamide (DMF) were then examined but were in-
ferior to THF (Table 1, entry 10 vs entries 13–15). Therefore,
the optimal reaction conditions are as follows: 4-methyl-
benzenesulfonohydrazide (0.3 mmol), NIS (20 mol%),
K S O (1.2 equiv), and THF (2 mL) under air at 70 °C for 8 h.
SO2NHNH2
S
additive, oxidant
S
O
solvent, 70 °C
Me
Me
Me
1
a
2a
Entry
1
Additive (mol%) Oxidant (equiv)
Solvent
Yield (%)
2
2
8
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
–
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
–
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
53
36
55
0
Using the optimal conditions described in Table 1, we
next explored the scope of this transformation.11 This reac-
tion displayed high functional group tolerance and proved
to be an efficient methodology for the preparation of thio-
sulfonates. Sulfonyl hydrazides with para-substituted elec-
tron-donating groups on aryl rings, such as methyl, tert-
butyl, and methoxy, all gave the corresponding radical cou-
pling product in 84–88% yields (Table 2, 2a–c). Benzenesul-
fonohydrazide (1d) was also applied to this reaction and
furnished the desired product in 80% yield (2d). In compari-
son, slightly lower yields (70–76%) were observed having
sulfonyl hydrazides with para-substituted electron-with-
drawing groups (fluoro, chloro, bromo, and nitro) on aryl
rings (2e–h). It was worth mentioning that the ortho- or
meta-chloro-substituted sulfonyl hydrazides still exhibited
high reactivity, affording the corresponding products in 72%
and 73% yields, respectively (2i,j). In addition, polysubsti-
tuted sulfonyl hydrazide 2,4,6-trimethylbenzenesulfonohy-
drazide (1k) also proceeded smoothly to give the desired
product in 88% yield (2k).
2b
3c
4
5
6
7
8
9
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
DTBP (1.2)
0
I
2
(20)
50
10
81
82
87
trace
0
KI (20)
NIS (20)
NIS (20)
NIS (20)
NIS (20)
NIS (20)
NIS (20)
NIS (20)
NIS (20)
1
1
1
1
1
0d
K
2
S
2
O
8
(1.2)
1
PhI(OAc) (1.2)
2
2
2 2
H O
3
K
K
K
2
S
2
O
O
O
8
8
8
(1.2)
(1.2)
(1.2)
1,4-dioxane
toluene
DMF
43
12
7
4
2
2
S
2
2
15
S
a
Reaction conditions: 1a (0.3 mmol), additive (0.06 mmol, 20 mol%), oxi-
dant (0.36 mmol, 1.2 equiv), and solvent (2 mL) open in air at 70 °C for 8 h.
b
At 60 °C, and 1,2-di-p-tolyldisulfane (3a) was obtained in 15% yield.
At 80 °C.
c
Polycyclic aromatic sulfonyl hydrazide (1l) also reacted
efficiently and produced the corresponding thiosulfonate in
good yield (2l). However, no reaction occurred when
heteroaromatic sulfonyl hydrazide that contain pyridine
(1m) was used as the substrate (2m). To our satisfaction,
alkyl-substituted sulfonyl hydrazide methanesulfonohydra-
zide (1n), successfully went through this protocol, giving
the corresponding product in 61% yield (2n). The known
d
1,2-Di-p-tolyldisulfane (3a) was obtained in 5% yield.
the reaction did not take place in the absence of either an
oxidant or an additive (Table 1, entries 4 and 5). Different
additives, such as I , KI, and NIS, were further tested for the
reaction (Table 1, entries 6–8), and the best yield was
obtained with NIS (81%, Table 1, entry 8). Subsequently, fur-
ther optimization was done with the oxidants di-tert-butyl
peroxide (DTBP), K S O , PhI(OAc) or H O , and K S O was
2
methodology that require Pd/ZrO nanocomposite catalyst
2
is not compatible with such type of substrate.6
2
2
8
2
2
2
2
2
8
proved to be most effective for this transformation (Table 1,
NIS (20 mol%)
K2S2O8 (1.2 equiv)
O
S
SO2NHNH2
S
(a)
O
THF, 70 °C
Me
Me
1a
Me
2a
Additive
Yield of 2a
TEMPO (2.0 equiv)
BHT (2.0 equiv)
0
8%
Me NIS (20 mol%)
K2S2O8 (1.2 equiv)
O
S
S
S
(
b)
S
O
THF, 70 °C
Me
Me
Me
3
a
2
a, <5%
Scheme 2 Control experiments
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Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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G. Zhou et al.
Letter
Table 2 Scope of Sulfonyl Hydrazidesa
NIS (20 mol%)
K2S2O8 (1.2 equiv)
O
S
RSO2NNH2
S
R
R
THF, 70 °C
O
1
2
Entry
1
Substrate 1
Product 2
Yield (%)
87
O
SO2NHNH2
SO2NHNH2
SO2NHNH2
S
S
O
Me
Me
Me
1
a
2
a
O
S
S
2
O
84
t-Bu
t-Bu
t-Bu
1
b
2
b
O
S
S
3
4
5
O
88
80
76
MeO
OMe
MeO
1
c
2
c
O
SO2NHNH2
S
S
O
1
1
d
2
2
d
O
SO2NHNH2
S
S
O
F
F
F
e
e
O
SO2NHNH2
SO2NHNH2
SO2NHNH2
S
S
6
7
8
O
71
73
70
Cl
Cl
Cl
1
f
2
f
O
S
S
O
Br
Br
Br
1
g
2
g
O
S
S
O
O2N
NO2
O2N
1
h
2
h
Cl
SO2NHNH2
O
S
S
9
72
O
Cl
Cl
1
i
2
i
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G. Zhou et al.
Letter
Table 2 (continued)
Entry
Substrate 1
Product 2
Yield (%)
73
O
SO2NHNH2
S
S
O
1
0
1
2
Cl
Cl
Cl
1
j
2
j
Me
Me
Me
O
S
SO2NHNH2
S
1
88
84
O
Me
Me
Me
Me
Me
Me
1
k
2
k
O
S
SO2NHNH2
S
O
1
1
1
l
2
2
l
O
S
SO2NHNH2
S
N
N
N
1
3
4
O
trace
61
m
m
O
S
MeSO
1
2
NHNH
2
S
Me
1
Me
n
O
2
n
a
2 2 8
Reaction conditions: 1 (0.3 mmol), NIS (0.06 mmol, 20 mol%), K S O (0.36 mmol, 1.2 equiv), and THF (2 mL) open in air at 70 °C for 8 h.
To gain insight into the reaction mechanism, two con-
In conclusion, we have demonstrated a novel and envi-
ronmentally benign method for the efficient synthesis of
thiosulfonates via NIS/K S O -promoted radical coupling
reaction of sulfonyl hydrazides. The reaction proceeds
through a radical cross-coupling process, in which one new
S–S bond was formed. A possible reaction mechanism was
trol experiments were performed under the standard con-
ditions (Scheme 2). We found that radical scavengers, such
as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-
di-tert-butyl-4-methylphenol (BHT), significantly sup-
pressed the reaction progress, indicating that the transfor-
mation occurred via a radical process (Scheme 2, a). Moti-
vated by the result in Table 1, entry 2 and the literature
2
2
8
12
precedents, we speculated that the 1,2-di-p-tolyldisulfane
3a) might be an intermediate for this reaction. However,
O
O
+
O
I
N
I
O
N
(
K2SO4
I
K2S2O8
the designed reaction was inert under the standard condi-
tions (Scheme 2, b).
Lastly, a hypothetical mechanism for the radical cou-
pling reaction is outlined in Scheme 3 on the basis of the
O
HI
S
O
NHNH2
N2
6
,13,14
Me
above results and previously reports.
At first, the
O
S
O
I
1
3
iodine radical was generated from NIS. Subsequently, sul-
fonyl hydrazide 1a can transfer to sulfonyl radical I and II
with the aid of iodine radical under the oxidative condi-
cross-coupling
K2SO4
I
K2S2O8
HI
2a
S
13,14
Me
tions.
The generation of sulfonyl radical II is supported
1a
by the isolation of 3a. Finally, the cross-coupling reaction
HOI, N2
Me
between radical I and II forms the desired thiosulfonate 2a.6
II
homocoupling
3a
Scheme 3 Plausible reaction mechanism
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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Synlett
G. Zhou et al.
Letter
proposed to explain the product formation. Further studies
of this strategy, focusing on the synthesis of other S-hetero-
cyclic compounds via a radical coupling process, is under-
way in our laboratory.
(7) Zhang, G.-Y.; Lv, S.-S.; Shoberu, A.; Zou, J.-P. J. Org. Chem. 2017,
82, 9801.
(
8) For selected papers, see: (a) Liu, Y.-W.; Badsara, S. S.; Liu, Y.-C.;
Lee, C.-F. RSC Adv. 2015, 5, 44299. (b) Zhang, X.-S.; Jiao, J.-Y.;
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Liu, Y.-F.; Guo, C.-C. J. Org. Chem. 2016, 81, 5181. (e) Sen, C.;
Sahoo, T.; Ghosh, S. C. ChemistrySelect 2017, 2, 2745. (f) Wu,
Y.-D.; Huang, B.; Zhang, Y.-X.; Wang, X.-X.; Dai, J.-J.; Xu, J.; Xu,
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Funding Information
This research is sponsored by the Natural Science Foundation of Zhejiang
Province (No. LQ18B020002), State Key Laboratory of Analytical
Chemistry for Life Science (No. SKLACLS1804), the Open Subject of
State Key Laboratory of Chemo/Biosensing and Chemometrics
(
9) Finkbeiner, P.; Nachtsheim, B. J. Synthesis 2013, 45, 979.
10) (a) Wei, W.-T.; Zhu, W.-M.; Shao, Q. J.; Bao, W.-H.; Chen, W.-T.;
(
(2017016), Education Foundation of Zhejiang Province (No.
Chen, G.-P.; Luo, Y.-J.; Liang, H. Z. ACS Sustainable Chem. Eng.
Y201737123), and the K. C. Wong Magna Fund in Ningbo University.
Prof. Z.Y. Guo also thank the Natural Science Foundation of China
2018, 6, 8029. (b) Wei, W.-T.; Zhu, W.-M.; Ying, W.-W.; Wang,
Y.-N.; Bao, W.-H.; Gao, L.-H.; Luo, Y.-J.; Liang, H. Z. Adv. Synth.
Catal. 2017, 359, 3551. (c) Wei, W.-T.; Zhu, W.-M.; Ying, W.-W.;
Wu, Y.; Huang, Y.-L.; Liang, H. Z. Org. Biomol. Chem. 2017, 15,
(Grants 41576098, 81773483).
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ut ra
l
Secince
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o
u
n
d
oaitn
of
Z
hanie
j
g
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orvn
i
ce
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8
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0
2
0
0
0
2
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ut arl
Secince
F
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n
d
oaitn
of
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i
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1
5
7
6
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8
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a
utarl
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n
d
oaitn
of
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n
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8(
1
7
7
3
4
8
3)
5
254. (d) Wei, W.-T.; Zhu, W.-M.; Liang, W. D.; Wu, Y.; Huang,
Supporting Information
H.-Y.; Huang, Y.-L.; Luo, F.-J.; Liang, H. Z. Synlett 2017, 28, 2153.
(e) Ying, W.-W.; Zhu, W.-M.; Gao, Z.-H.; Liang, H. Z.; Wei, W.-T.
Synlett 2018, 29, 663.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610649.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(11) General Procedure
To a Schlenk tube were added sulfonyl hydrazides (0.3 mmol),
NIS (0.06 mmol), K S O (0.36 mmol), and THF (2 mL). Then the
References and Notes
2
2
8
tube was stirred open in air at 70 °C for the indicated time until
complete consumption of starting material as monitored by TLC
analysis. After the reaction was finished, the solution was con-
centrated under reduced pressure, and the mixture was purified
by flash column chromatography over silica gel (hexane/ethyl
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1
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13
NMR and C NMR spectroscopy (see Supporting Information).
Typical Data for Representative Compound: S-(p-Tolyl)4-
methylbenzenesulfonothioate (2a)
1
Yellow oil (36.3 mg, 87% yield). H NMR (400 MHz, DMSO-d ):
6
δ = 7.45 (d, J = 7.6 Hz, 2 H), 7.38 (d, J = 7.6 Hz, 2 H), 7.26–7.20
13
(
m, 4 H), 2.40 (s, 3 H), 2.34 (s, 3 H). C NMR (100 MHz, DMSO-
d6): δ = 145.6, 142.6, 140.1, 136.5, 130.9, 130.3, 127.6, 124.2,
1.6, 21.4.
2
(
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©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E