Synthesis of symmetrical / unsymmetrical thiosulfonates through the disproportionate coupling reaction of sulfonyl hydrazide mediated by phosphomolybdic acid

Article abstract of DOI:10.1016/j.tetlet.2020.152757

Phosphomolybdic acid (H₃PMo₁₂O₄₀) is reported as a green low-cost catalyst for the synthesis of symmetrical / unsymmetrical thiosulfonates via the disproportionate coupling reaction of sulfonyl hydrazide. The attributes of this reported catalytic system include low catalyst loadings (1 mol%), efficient turnover, and high yields (up to 94%). Additionally, this reaction mechanism involves the formation of a thiyl radical and sulfonyl radical via sulfinyl radical disproportionation.

Full text of DOI:10.1016/j.tetlet.2020.152757

Tetrahedron Letters 65 (2021) 152757
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of symmetrical / unsymmetrical thiosulfonates through
the disproportionate coupling reaction of sulfonyl hydrazide
mediated by phosphomolybdic acid
⇑
Mengting Lv, Yufeng Liu, Ke Li, Guoping Yang
Jiangxi Key Laboratory for Mass Spectrometry and Instrumentation, East China University of Technology, Nanchang 330013, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Phosphomolybdic acid (H3PMo12O40) is reported as a green low-cost catalyst for the synthesis of symmet-
rical / unsymmetrical thiosulfonates via the disproportionate coupling reaction of sulfonyl hydrazide. The
attributes of this reported catalytic system include low catalyst loadings (1 mol%), efficient turnover, and
high yields (up to 94%). Additionally, this reaction mechanism involves the formation of a thiyl radical
and sulfonyl radical via sulfinyl radical disproportionation.
Received 16 September 2020
Revised 8 December 2020
Accepted 11 December 2020
Available online 5 January 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Polyoxometalates
Sulfonyl hydrazide
Disproportionate coupling
Symmetrical / unsymmetrical
thiosulfonates
Introduction
in organic synthesis owing to their high corrosion resistance, low
cost and several other advantages [18–21]. In particular, Keggin-
Thiosulfate derivatives are commonly used in various pharma-
ceuticals that have fungicidal, antiviral, antimicrobial and bacteri-
cidal properties [1–6]. Besides, thiosulfate derivatives are also
important synthetic building blocks in organic synthesis [7–10].
Significant efforts have been devoted to the development of meth-
ods for the synthesis of thiosulfate derivatives [11]. As shown in
Scheme 1, traditional methods for the synthesis of thiosulfates
are mainly based on the direct oxidation of disulfides or mercap-
tans (Scheme 1a) [12]. In recent years, many alternative methods
have been developed, such as the cross-coupling reaction of sul-
fonyl hydrazides with thiols (Scheme 1b) [13,14], disproportionate
coupling reaction of sodium sulfinates (Scheme 1c) [15] and sul-
fonyl hydrazides (Scheme 1d) [16,17]. The commonly reported
methods for the synthesis of thiosulfate derivatives are constrained
to the use of toxic reactants, volatile solvents, expensive catalysts,
halogen reagents, large catalyst amounts, long synthesis time, poor
specificity and low yield. These urge further research on the devel-
opment of more efficient and more environment-friendly reaction
systems for the preparation of thiosulfate derivatives.
type POMs display an excellent catalytic effect for the oxidative
coupling, dehydration coupling, condensation and cycloaddition
[22–29]. As part of our ongoing research on POMs chemistry, we
envisioned that Keggin-type POMs could be applied as catalysts
for the synthesis of thiosulfate derivatives. We herein report an
efficient and environmentally-friendly protocol for the synthesis
of symmetrical / unsymmetrical thiosulfonates through dispropor-
tionate coupling reaction of sulfonyl hydrazide by H3PMo12O40
(1 mol%) as the catalyst.
Results and discussion
In order to optimize the reaction conditions, p-Toluenesulfonyl
hydrazide 1a was chosen as substrate for the model reaction in
EtOH solvent at 70 °C and catalyzed by POMs for 2 h. As shown
in Table 1, the control experiment without catalyst cannot obtain
the desired product 2a (entry 1). 4-methylbenzenesulfonohy-
drazide 1a was catalyzed by 1 mol% Keggin-type POMs (i.e.,
H3PW12O40, H4SiW12O40 and H3PMo12O40) in EtOH at 70 °C for
2 h. Neither H3PW12O40 nor H4SiW12O40 showed catalytic activity,
while H3PMo12O40 showed a certain catalytic activity, and the
desired product 2a could be obtained with 28% yield (entry 2–4).
Subsequently, various reaction solvents were screened, including
H2O, 1,4-dioxane, acetone, CH3CN, 1,2-dichloroethane (DCE), THF,
Polyoxometalates (POMs) are a class of metal oxygen cluster
compounds with special structure that are widely used as catalysts
⇑
Corresponding author.
E-mail address: erick@ecut.edu.cn (G. Yang).
https://doi.org/10.1016/j.tetlet.2020.152757
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

M. Lv, Y. Liu, K. Li et al.
Tetrahedron Letters 65 (2021) 152757
Scheme 1. Different methods for the synthesis of symmetrical/unsymmetrical
thiosulfate derivatives.
Scheme 2. Synthesis of symmetrical thiosulfonates from sulfonyl hydrazide 1. [a, b]
Table 1
reaction time was increased to 3 h, the yield increased to 94% (en-
try 15). Therefore, the optimal reaction conditions are as follows:
p-Toluenesulfonyl hydrazide 1a (0.3 mmol), H3PMo12O40 (1 mol
%), and CH3NO2 (1 mL) under air at 90 °C for 3 h.
Effects of various catalysts and solvents on the yield of disproportionate coupling
reaction.a
Having established a standard set of reaction conditions, the
disproportionate coupling reaction of various sulfonyl hydrazides
was carried out to establish the scope and generality of this proto-
col. As listed in Scheme 2, both electron-withdrawing and electron-
donating substituents can be transformed into the corresponding
symmetrical thiosulfonates (2a-l) in moderate to excellent yields.
Thus, substrates bearing Me, MeO, CF3, NO2 and CN at the benzene
ring served well in this reaction. The halo-substituted products like
2d, 2e, 2f and 2g could also be readily prepared by using the cur-
rent strategy. To our delight, we found that polycyclic substituted
sulfonyl hydrazide can be also transformed into the corresponding
product with good yield (2k). Although 2,4,6-trimethylbenzenesul-
fonyl hydrazide is also suitable for this reaction system, the corre-
sponding reaction product (2l) has a yield of only 73%, with the
27% yield of a by-product (2m). It is worth noting that the pro-
pane-2-sulfonohydrazide was also converted to the corresponding
thiosulfate (2n) under the standard conditions.
In order to further explore the versatility of this protocol and
the reaction competitiveness of different functional groups,
p-methoxybenzenesulfonyl hydrazide 1b and other benzenesul-
fonyl hydrazides were used to react under optimal conditions to
prepare the unsymmetrical thiosulfonates by disproportionate
coupling. The results are summarized in Scheme 3. As expected,
both p-methoxybenzenesulfonyl hydrazide 1b and another
reaction substrate 1d-1f, 1h and 1k will mainly afford the homo-
coupling products. In addition, two corresponding unsymmetrical
thiosulfonates can be generated by disproportionate coupling,
and the main products in the four products are mainly generated
by the sulfonyl bond of p-methoxybenzenesulfonyl hydrazide
(3a-e). By further comparison, we found that the reaction between
p-methoxybenzenesulfonyl hydrazide and halogen-substituted
Entry
Solvent
Temp (oC)
Yield[b][%]
1[c]
2[d]
3[e]
4
5
6
7
8
9
10
11
12
13
14
15[f]
EtOH
EtOH
EtOH
EtOH
70
70
70
70
70
70
70
70
70
70
70
70
80
90
90
0
0
0
28
18
23
0
24
19
8
67
23
79
87
94
H2O
1,4-dioxane
Acetone
CH3CN
DCE
THF
CH3NO2
i-PrOH
CH3NO2
CH3NO2
CH3NO2
[a] Reaction conditions: p-Toluenesulfonyl hydrazide (0.3 mmol), H3PMo12O40
(1 mol%), solvent (1 mL), air, 70 °C, 2 h.
[b] Isolated yield.
[c] Without catalyst.
[d] H3PW12O40 (1 mol%) as catalyst.
[e] H4SiW12O40 (1 mol%) as catalyst.
[f] Reaction time: 3 h.
CH3NO2, and i-PrOH. According to the results, CH3NO2 is the best
solvent for this reaction (entries 5–12), and the desired product
2a was obtained with the yield of 67% (entry 11). An increase in
the temperature of reaction to 80 °C brought about a reasonable
rise in the yield (entry 13), and a further incremental increase in
the temperature to 90 °C enhanced the yield to 87% (entry 14,
for details, see Fig. S1 in the Supporting Information). When the
2

M. Lv, Y. Liu, K. Li et al.
Tetrahedron Letters 65 (2021) 152757
Scheme 5. The proposed reaction mechanism. (HPMo12O40 = HPMoO).
Scheme 3. Synthesis of unsymmetrical thiosulfonates from sulfonyl hydrazide 1b
[a, b]
and 10.
benzenesulfonyl hydrazides decrease the yield of the desired prod-
ucts as the electron-withdrawing capacity of halogen increases.
It is well known that thiosulfate derivatives are important
synthetic building blocks in organic synthesis [30–35]. Hence, it
is very important to develop approaches for the synthesis of sym-
metrical/unsymmetrical thiosulfonates through disproportionate
coupling reaction. Moreover, Keggin-type POMs (i.e., H3PW12O40
,
Scheme 6. Gram-scale synthesis.
H4SiW12O40 and H3PMo12O40) are commonly used as Bronsted acid
with high activity in various coupling reactions, H3PMo12O40 being
particularly efficient catalyst. The synthesis of symmetrical /
unsymmetrical thiosulfonates through disproportionate coupling
reaction of sulfonyl hydrazide mediated by H3PMo12O40 was
reported here for the first time. Therefore, it is necessary to design
a series of control experiments to explore the mechanism of the
reaction.
Initially, we conducted the radical trapping experiments by
adding 2,2,6,6-tetramethyl-1- piperidinyloxy (TEMPO) into the
model reaction under the standard conditions. As expected, the
reaction is completely suppressed (Eq. (1) in Scheme 4). The results
of control experiment also indicate that H3PMo12O40 is essential for
this transformation (Eq. (2) in Scheme 4). In addition, the results
indicate that N2 atmosphere is unfavorable for the reaction, but
the effect is rather minor (Eq. (3) in Scheme 4). The highest yield
of 94% is obtained in the air atmosphere (Eq. (4) in Scheme 4).
On the basis of the above experimental results and previous
reports [15–17,36,37], a possible reaction pathway is proposed,
as shown in Scheme 5. First, sulfonyl hydrazide 1 is heated and oxi-
dized into activated oxygen-centered radical B in the air atmo-
sphere, and radical B can be resonance stable with the sulfonyl
radical A. Then, radical B is converted to intermediate sulfinic acid
C. Subsequently, C can be catalyzed by H3PMo12O40 to form the
corresponding disulfoxide D. Finally, the homolytic cleavage of
unstable intermediate D takes place under heating, and the gener-
ated radical E may easily disproportionate into radical F and radi-
cal G, which can be combined into the desired thiosulfonate 2.
To demonstrate the practical use of this protocol, a scaled-up
experiment was performed with p-Toluenesulfonyl hydrazide 1a.
As shown in Scheme 6, the disproportionate coupling reaction of
1a on gram-scale can give thiosulfonate 2a in a yield 91%. And 4-
chlorobenzenesulfonyl hydrazide 1d as substrate also produced
the corresponding product 2d in 85% of isolated yield. These results
indicated that this method is operationally simple, scalable, and
efficient.
Conclusion
In summary, we reported an efficient and green H3PMo12O40
catalyst for the disproportionate coupling reaction of benzenesul-
fonyl hydrazides for the first time. This approach proceeds with
extremely low catalyst loadings, utilizes air as the only oxidant,
and affords good-to-excellent yields. Furthermore, this reported
method provides straightforward procedures that could be scaled
up to a gram scale with consistent yields, which provides an effi-
cient and quick access to many critical thiosulfonates derivatives.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Scheme 4. Control experiment.
3

M. Lv, Y. Liu, K. Li et al.
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