Metal-free three-component synthesis of thioamides from β-nitrostyrenes, amines and elemental sulfur

Article abstract of DOI:10.1016/j.tetlet.2021.153092

A metal-free C[dbnd]C bond cleavage reaction of β-nitrostyrenes in the presence of elemental sulfur and secondary amines/amides is described. Elemental sulfur serves as both a raw material and an oxidant for C[dbnd]C bond cleavage, and secondary amines or amides are both feasible nitrogen sources. Besides mild reaction condition and simple work-up procedure, the method provided thioamides with good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2021.153092

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal-free three-component synthesis of thioamides from
b-nitrostyrenes, amines and elemental sulfur
b,c,
Ling Peng a, Li Ma a, Ying Ran b, Yunfeng Chen a, , Zhigang Zeng
⇑
⇑
a School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, 206 Optics Valley 1st Road, Wuhan, Hubei 430205, China
b School of Nuclear Technology and Chemistry & Biology, Hubei University of Science and Technology, 88 Xianning Avenue, Xianning, Hubei 437100, China
c Hubei Key Laboratory of Radiation Chemistry and Functional Materials, 88 Xianning Avenue, Xianning, Hubei 437100, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A metal-free C@C bond cleavage reaction of b-nitrostyrenes in the presence of elemental sulfur and sec-
ondary amines/amides is described. Elemental sulfur serves as both a raw material and an oxidant for
C@C bond cleavage, and secondary amines or amides are both feasible nitrogen sources. Besides mild
reaction condition and simple work-up procedure, the method provided thioamides with good to excel-
lent yields.
Received 10 March 2021
Revised 9 April 2021
Accepted 14 April 2021
Available online xxxx
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
C@C bond cleavage
Metal-free
Three-component reaction
Thioamides
Introduction
[7]. In recent years, organic skeletons which are cleaved by CAC
bonds to form new C-X bonds have attracted considerable atten-
As one of the characteristic molecular fragments containing
C@S bond, thioamides are useful intermediates for the synthesis
of various compounds, including some heterocycles and ligands
[1]. Furthermore, thioamides showed wide applications in medici-
nal chemistry [2]. So far, many approaches have been developed
for the preparation of thioamides. The popular method is direct
addition of H2S or other sulfide surrogates to the cyanide group
under pressure condition [3]. Another traditional synthetic method
is to convert the carbonyl group to a thiocarbonyl group using
Lawesson’s reagent and its analogs, but this sulphur phosphorus
reagent produces phosphorus waste [4]. Currently, due to its rich
resource, eco-friendliness and high atomic utilization, elemental
sulfur is often used as an alternative and preferred sulfur reagent
to build sulfur-containing compounds [5]. The Willger-Kindler
reaction uses arylmethyl ketones, amines and elemental sulfur to
synthesize thioamides, with the disadvantage of requiring harsh
reaction conditions [6]. Moreover, the coupling reaction of amides
and elemental sulfur with alkynes, amines, and aldehydes has been
reported to be an effective method for the synthesis of thioamides
tion in the field of organic synthesis [8], and some methods for
constructing thioamides by means of CAC bonds cleavage have
been gradually established [9]. Such as decarboxylation/thioami-
dation of aryl acetic acid and cinnamic acid [9a], decyanation/
thioamidation of arylacetonitriles [9b], cleavage of C@C bond of
aryl ethylene with elemental sulfur and amide [9c], and cleavage
of carbon–carbon triple bond of aryl acetylenes with elemental
sulfur and amide [9d]. We recently reported a novel process
involving a CAN bond cleavage and CAH bond thionation of
a-
azido ketones to construct a thioamide functional motif in the
presence of elemental sulfur [10], at the same time, the research
interests of our group focus on the development of new reactivities
of nitroalkenes. [11,13] Herein, we report a base-promoted metal-
free C@C bond cleavage reaction of b-nitrostyrenes in the presence
of elemental sulfur and secondary amines/amides. This three-com-
ponent reaction has proven to be a beneficial method for achieving
substituted thioamides.
Results and discussion
⇑
Corresponding authors at: School of Nuclear Technology and Chemistry &
To commence our study, b-nitrostyrene (1a), elemental sulfur
and morpholine (2a) were chosen as model substrates for the
three-component reaction, and the detail are summarized in
(Table 1). Firstly, the reaction cannot be carried out without any
additives (entry 1). Then some copper(II) salts were introduced
Biology, Hubei University of Science and Technology, 88 Xianning Avenue,
Xianning, Hubei 437100, China (Z. Zeng). School of Chemistry and Environmental
Engineering, Wuhan Institute of Technology, 206 Optics Valley 1st Road, Wuhan,
Hubei, 430205, China (Y. Chen)
E-mail addresses: yfchen@wit.edu.cn (Y. Chen), zzgang@hbust.edu.cn (Z. Zeng).
https://doi.org/10.1016/j.tetlet.2021.153092
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: L. Peng, L. Ma, Y. Ran et al., Metal-free three-component synthesis of thioamides from b-nitrostyrenes, amines and elemental
sulfur, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153092

L. Peng, L. Ma, Y. Ran et al.
Tetrahedron Letters xxx (xxxx) xxx
Table 1
Optimization of reaction conditions.a
Entry
Cat.
Base
Temp (°C)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
–
–
–
–
–
110
110
110
110
110
110
110
110
110
110
110
110
110
100
80
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1,4-Dioxane
DMF
n.d.
n.d.
n.d.
n.d.
60
43
48
75
55
63
80
72
23
88
31
77
trace
85
Cu(acac)2
CuBr2
Cu(OAc)2
–
–
–
–
–
–
–
–
–
–
–
–
–
–
K2CO3
Na2CO3
NaHCO3
Cs2CO3
NaOH
NaOAc
t-BuOK
DBU
9
10
11
12
13
14
15
16
17
18c
Et3N
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
100
100
100
DMSO
a
Reaction conditions: 1a (0.13 mmol, 1.0 equiv), 2a (0.39 mmol, 3.0 equiv), catalyst (10 mol %), base (0.26 mmol, 2.0 equiv), Sulfur (0.26 mmol, 2.0 equiv), solvent (0.5 mL),
under air, 2 h.
b
Isolated yields.
Under Ar atmosphere.
c
to the reaction, but this attempt was proved to be invalid (entries
2–4). To our delight, when K2CO3 was introduced to this reaction,
the desired product 3a (4-morpholinylphenylmethanethione)
was obtained in 60% yield (entry 5). Based on this attractive result,
a series of different bases, namely Na2CO3, NaHCO3, Cs2CO3, NaOH,
NaOAc and t-BuOK were tested. It was found that t-BuOK exhibited
the best promotion effect on the reaction, producing product 3a in
80% yield (entries 6–11). The other two organic bases (DBU and
Et3N) were not as effective as t-BuOK in this reaction (entries 12
and 13). Further lowering the reaction temperature to 100 °C, the
yield of 3a was increased to 88% (entry 14). When the temperature
was continued to lower to 80 °C, the yield of 3a was dropped to
31% (entry 15). Screening of solvent showed that 1,4-dioxane or
DMF were not as effective as DMSO (entries 14, 16 and 17). Sur-
prisingly, when DMF was used as a solvent, the N, N-dimethylben-
zene was obtained in 70% yield as a major product and only trace
amount of 3a was obtained (entry 17). This means that amide
could also be used as an amine source. Finally, the reaction was
conducted under Ar atmosphere, the yield of the target product
could not be improved significantly (entry 18). Thus, the t-BuOK/
DMSO at 100 °C was chosen as the optimal reaction condition.
Once the optimized reaction conditions were established, the
scope of substrates was studied (Scheme 1). Overall, the reaction
of morpholine as the amine source could produce the correspond-
ing products in high yields ranging from 70% to 95% (3a, 3b, 3c, 3d,
3e). Amines such as piperidine and pyrrolidine were suitable for
this reaction and they could also produce corresponding products
in moderate yields ranging from 45% to 65% (3g, 3h, 3i, 3j, 3k).
The scope of the substrate was extended to the heterocyclic
b-nitrostyrene to produce the 3f with a yield of 72%. Obviously,
electron-donating group displayed higher reactivity than the elec-
tron-withdrawing group b-nitrostyrene, and the secondary amine
with strong basicity was more beneficial to the reaction.
presence of t-BuOK, the corresponding thioamides could be
acquired with moderate to high yield (Scheme 2). It was found that
nitroolefins with electron-donating group (4b, 4c) gave a higher
yield than electron-withdrawing group (4d). Further studies were
secondary amine and elemental sulfur in DMSO.
According to the unexpected discovery of Table 1, we found that
DMF could be severed as amine source for the formation of thioa-
mides. When nitroolefins and sulfur was stirring in DMF in the
Scheme 1. Reactions of different b-nitrostyrenes with secondary amine and
elemental sulfur in DMSO.
2

L. Peng, L. Ma, Y. Ran et al.
Tetrahedron Letters xxx (xxxx) xxx
Scheme 4. Control experiments.
Scheme 2. Reactions of different a-nitrostyrenes with DMF and elemental sulfur.
one equivalent of elemental sulfur cannot give full conversion of
nitroolefin. Moreover, the b-disubstituted nitrostyrene did not pro-
duce the corresponding product, which indicated that the reaction
process involved a C@C bond cleavage (Scheme 4c). While isomeric
devoted towards the meta-substituted b-nitrostyrene gave the cor-
responding products in 70% and 66% yields respectively (4e, 4f).
Finally, b-nitrostyrene with aromatic heterocycle also yielded cor-
responding products in considerable yields (4g, 4h), which further
expanded the scope of the reaction.
In order to explore the practicability of this reaction, 1 g of 1a
was reacted under the optimum conditions for 2 h. As a result,
1.14 g of 3a was obtained, and the yield was up to 82%. It showed
that the method had strong practicability in preparing thioamides
(Scheme 3).
To further understand this three-component reaction in depth
and explored the reaction process, some control experiments were
carried out (Scheme 4). Firstly, the reaction gave satisfied yield in
the presence of radical inhibitor TEMPO, which revealed that this
reaction might not involve a radical process. Secondly, it was found
that the equivalent of elemental sulfur was crucial to this reaction,
a-methyl-b-nitrostyrene exhibited poor reactivity and only gave
trace product (Scheme 4d).
Based on these observations, a possible mechanism is proposed
in Scheme 5. 9a First, b-nitrostyrene was reacted with S8 to form
the cyclization product A. Then, the proton on the ring of A was
captured by t-BuOK to drive the CAC bond cleavage to form the
thioaldehyde B, accompany with nitrothioformaldehyde and S6.
At the same time, the secondary amine was deprotonated with
the aid of alkali to form the amino anion C. During this process,
if the amine source is DMF, the carbonyl group will be removed
as CO [11,12]. Subsequently, the intermediate B suffered oxidation
by S8 was nucleophilic attacked by the amino anion C to yield the
intermediate D. Finally, the desired product was obtained by the
elimination of sulfhydryl ion.
Scheme 3. Large-scale synthesis.
3

L. Peng, L. Ma, Y. Ran et al.
Tetrahedron Letters xxx (xxxx) xxx
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In summary, we have developed a novel method to synthesize
thioamides through a three-component reaction based on the
metal-free C@C bond cleavage method, by using b-nitroolefins as
raw materials, secondary amines/amides as the amine source.
The elemental sulfur serves as both a raw material and an oxidant
for C@C bond cleavage. This method has a wide range of substrates,
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Declaration of Competing Interest
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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.
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Acknowledgments
We are grateful to the National Natural Science Foundation of
China (31601675), the PhD Start-up Fund of Hubei University of
Science and Technology (BK201821), the High-level Talents Project
of Xianning City (2019) and the Graduate Innovative Fund of
Wuhan Institute of Technology.
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Supplementary data to this article can be found online at
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