A copper-catalyzed approach for the synthesis of asymmetrical disubstituted 1,2,4-thiadiazoles via elemental sulfur-mediated decarboxylative redox cyclization

Article abstract of DOI:10.1016/j.tetlet.2020.152744

The variety of asymmetrical disubstituted 1,2,4-thiadiazoles are smoothly prepared by copper-catalyzed approach, which employed arylacetic acids and amidines as substrates, and elemental sulfur to mediate decarboxylative redox cyclization. The advantages of this method are simple, efficient, and ligand-free. In addition, this method can provide products in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2020.152744

Tetrahedron Letters 65 (2021) 152744
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A copper-catalyzed approach for the synthesis of asymmetrical
disubstituted 1,2,4-thiadiazoles via elemental sulfur-mediated
decarboxylative redox cyclization
Yafei Liu a, Yurong Zhang a, Jun Zhang a, Liang Hu a, Shiqing Han a,b,
⇑
a College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, CAS, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The variety of asymmetrical disubstituted 1,2,4-thiadiazoles are smoothly prepared by copper-catalyzed
approach, which employed arylacetic acids and amidines as substrates, and elemental sulfur to mediate
decarboxylative redox cyclization. The advantages of this method are simple, efficient, and ligand-free. In
addition, this method can provide products in moderate to good yields.
Received 3 September 2020
Revised 2 December 2020
Accepted 7 December 2020
Available online 29 December 2020
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
1,2,4-Thiadiazoles
Elemental sulfur
Arylacetic acids
Redox reaction
Copper-catalyzed
Five-membered heterocyclic compounds, as pivotal roles in
medicinal chemistry, have unique chemical properties [1]. 1,2,4-
Thiadiazoles are broad existed in natural products, drug molecules,
and functional materials. In particular, they have more extensive
applications in pharmaceuticals industry owing to the improve-
ment of liposolubility of medicine by sulfur atom [2]. The nucleus
of 1,2,4-thiadiazoles is a fundamental constituent of synthetic
products with biological activities, such as agonists [3], antibiotic
[4] (Fig. 1), anticancer [5], analgesic [6], and inhibitor [7]. It is
reported that 1,2,4-thiadiazoles possess hypoglycemic activity,
and inhibition of Beta-secretase activity that can be used in treat-
ing Alzheimer’s disease as a lead candidate [8].
According to these properties, many researchers focus on find-
ing a simple, convenient, and efficient approach to obtain 1,2,4-
thiadiazoles. The general synthetic ways of 1,2,4-thiadiazoles were
to use thioamides as the starting material via oxidative dimeriza-
tion, which use iodine reagents [9], dimethyl sulfoxide [10], oxone
[11], oxygen [12] etc. as oxidant (Scheme 1a). Noei et al. have
introduced a new synthetic method with aryl nitriles to produce
1,2,4-thiadiazoles, which main steps were activation of nitrile
group and obtaining the thioamides by nucleophilic addition [13]
(Scheme 1b). Later, a novel one-pot synthesis of asymmetrical dis-
ubstituted 1,2,4-thiadiazoles has been disclosed by Deng’s group
using amidines, elemental sulfur, and 2-methylquinolines or alde-
hydes as starting materials under transition-metal-free conditions
[14] (Scheme 1c and d). Recently, Ling et al. used thioamides and
nitriles as substrates to acquire asymmetrical disubstituted 1,2,4-
thiadiazoles [15] (Scheme 1e). Though a large amount of synthetic
researches about 1,2,4-thiadiazoles have been discovered, there
were few reports for synthesis of asymmetrical disubstituted
1,2,4-thiadiazoles. Hence, it is crucial to explore a simple and effi-
cient method to produce asymmetrical disubstituted 1,2,4-
thiadiazoles.
Oxidative decarboxylation is a significant chemical reaction,
which contribute to Heck reaction, forming carbon-heteroatom
bonds, redox neutral cross-coupling reactions, and direct arylation
processes [16,17]. In addition, the properties of arylacetic acids are
easily available, low-cost, stable, and nontoxic. Previously, our
group reported strategies constructing carbon-heteroatom bonds
through decarboxylative redox cyclization of arylacetic acids
[18,19], which laid the foundation for our new research. Based
on previous research [14,20b], a synthetic method of asymmetrical
3,5-disubstituted 1,2,4-thiadiazoles was developed by using ben-
zamidine hydrochloride and phenylacetic acid as starting materials
(Scheme 1f).
Originally, our efforts were to explore the optimized reaction
conditions using phenylacetic acid, benzamidine hydrochloride,
and element sulfur as model reactants by varying diverse
⇑
Corresponding author at: College of Biotechnology and Pharmaceutical Engi-
neering, Nanjing Tech University, Nanjing 211816, China.
E-mail address: hanshiqing@njtech.edu.cn (S. Han).
https://doi.org/10.1016/j.tetlet.2020.152744
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

Y. Liu, Y. Zhang, J. Zhang et al.
Tetrahedron Letters 65 (2021) 152744
parameters that include catalyst, base, temperature, solvent, reac-
tion time, and equivalent (Table 1). As shown in Table 1, the best
catalyst was CuI, which provided desired product 3,5-diphenyl-
1,2,4-thiadiazole (3aa) in 51% yield (entries 1–5). Among the vari-
ous bases tested, Na2CO3 was optimal choice, and few product was
found using NaOH and KOH (entry 1 VS entries 6–9). Decreasing
and increasing reaction time, the yields were not increased, respec-
tively (entry 1 VS entries 10–11). With the study of solvent, DMF,
PEG-400, and NMP were inferior to DMSO (entry 1 VS entries
12–14). Temperature also had influence in yields (entries 15–16).
Delightfully, the yield was improved to 60% under nitrogen atmo-
sphere (entry 17). Finally, the effect of sulfur equivalent on yields
was tested (entries18-21). When the equivalent of sulfur was
increased to 6.0, the yield was improved to 72%. Continuing to
add the amount of sulfur, there was no increment in the yield. In
addition, the target product is only 32% yield without CuI catalyst.
Therefore, it was inferred the optimized reaction conditions:
phenylacetic acid 1a (2.0 equiv, 1.0 mmol), benzamidine
hydrochloride 2a (1.0 equiv), element sulfur (6.0 equiv), CuI
(20 mmol%), and Na2CO3 (2.0 equiv) in DMSO (2.0 mL) at 130 °C
for 24 h under a nitrogen atmosphere (entry 20).
Fig. 1. Antibiotic drug: cefozopran.
With the optimized reaction conditions in hand, various aryl
acetic acids were used to investigate the adaptability of reaction
(Table 2). Phenylacetic acids with electron donating group, such
as methyl and methoxy, were provided moderate to good yields
(3ca–3ea, 3ia–3ka) except o-methyl (3ba). The yields of halogen
substituents were poor (3fa–3ga). And there is no target product
when using o-halophenylacetic acids as substrates, possibly since
o-halophenylacetic acids are prone to substitution reaction. The
strong electron withdrawing group (-CF3) probably had beneficial
effects on the reaction that the isolated yield of 3ha was improved
to 82%. Then, 2-thiopheneacetic acid, 2-naphthaleneacetic acid and
2-biphenylacetic acid reacted with benzamidine hydrochloride
respectively led to moderate and good yields (3la–3na). There is
Scheme 1. Synthetic methods of 1,2,4-thiadiazoles.
Table 1
Optimization of 3,5-diphenyl-1,2,4-thiadiazole synthesis.a
Entry
Catalyst
Base
S8 (equiv)
Solvent
Temp (oC)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
CuI
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaOH
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
3.0
5.0
6.0
7.0
6.0
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
130
130
130
130
130
130
130
130
130
130
130
130
130
130
120
140
130
130
130
130
130
130
24
24
24
24
24
24
24
24
24
18
30
24
24
24
24
24
24
24
24
24
24
24
51
40
41
47
42
Trace
26
Trace
21
33
25
11
14
20
27
45
60
37
Cu(OAc)2ÁH2O
CuO
Cu(OAc)2
Cu
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
K2CO3
KOH
9
NaHCO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
10
11
12
13
14
15
16
17c
18c
19c
20c
21c
22c
PEG-400
NMP
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
64
72
68
32
CuI
CuI
–
a
b
c
Reaction conditions: 1a (2.0 equiv, 1.0 mmol), 2a (1.0 equiv), sulfur powder, base (2.0 equiv), catalyst (20 mmol%) and solvent (2.0 mL) under air.
Isolated yields.
Under nitrogen atmosphere.
2

Y. Liu, Y. Zhang, J. Zhang et al.
Tetrahedron Letters 65 (2021) 152744
Table 2
Substrate scopes with various aryl acetic acids.a
a
Reaction conditions: 1 (2.0 equiv, 1.0 mmol), 2 (1.0 equiv), S (6.0 equiv), Na2CO3 (2.0 equiv), CuI (20 mmol%) and DMSO (2.0 mL)
under N2 at 130 oC for 24 h.
Table 3
Substrate scopes with various benzamidine hydrochlorides.a
a
Reaction conditions: 1 (2.0 equiv, 1.0 mmol), 2 (1.0 equiv), S (6.0 equiv), Na2CO3 (2.0 equiv), CuI (20 mmol%) and DMSO (2.0 mL)
under N2 at 130 oC for 24 h.
3

Y. Liu, Y. Zhang, J. Zhang et al.
Tetrahedron Letters 65 (2021) 152744
no product in the reaction with 2-bromoacetic acid and pivalic acid
as substrates (3oa–3pa). What’s more, the scopes of benzamidine
hydrochloride were also tested (Table 3). Methyl, trifluoromethyl,
and phenyl benzamidine hydrochloride all have moderate to good
yields (3ab, 3ac, 3ae), except methoxy benzamidine hydro-chlo-
ride (3ad).
In order to study proposed mechanism, the following control
experiments were performed (Scheme 2). There is no product in
absence of sulfur under the standard conditions (Scheme 2, Eq.
1). The sulfur is pivotal for the reaction and may play a key role
in the beginning. The addition of 2,2,4,4-tetramethyl-1-piperidiny-
loxy (TEMPO) had no obvious differences in the yield of target pro-
duct (Scheme 2, Eq. 2). It was concluded that the proposed reaction
mechanism may exclude the radical pathway.
Based on the control experiments and consulting literatures
[20], the proposed mechanism was disclosed in Scheme 3. First,
under alkaline conditions, phenylacetic acid 1a was transformed
to 3 which reacted with sulfur to form sulfide 4, and another
Scheme 2. Control experiments.
Scheme 3. Proposed Mechanism.
4

Y. Liu, Y. Zhang, J. Zhang et al.
Tetrahedron Letters 65 (2021) 152744
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Declaration of Competing Interest
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We thank to Major National Science and Technology Program of
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