Synthesis of novel 4-substituted 1,2,3-thiadiazoles via iodine-catalyzed cyclization reactions

Article abstract of DOI:10.1016/j.tetlet.2021.152824

Iodine-catalyzed the reaction of substituted methyl ketone N-tosylhydrazones with elemental sulfur has been developed. The cyclizations of the ester-substituted N-tosylhydrazone substrates proceeded smoothly under optimal reaction conditions, and the corr

Full text of DOI:10.1016/j.tetlet.2021.152824

Tetrahedron Letters 66 (2021) 152824
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Tetrahedron Letters
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Synthesis of novel 4-substituted 1,2,3-thiadiazoles via iodine-catalyzed
cyclization reactions
a,
b
Weiwei Li a, Xuezhen Li a, Yijiao Feng a, Ping Liu a, , Xiaowei Ma , Jixing Zhao
⇑
⇑
a School of Chemistry and Chemical Engineering, The Key Laboratory for Green Processing of Chemical Engineering of Xinjiang, Bingtuan Shihezi University, Shihezi City 832003, China
b Analysis and Testing, Center of Shihezi University, Shihezi City 832004, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Iodine-catalyzed the reaction of substituted methyl ketone N-tosylhydrazones with elemental sulfur has
been developed. The cyclizations of the ester-substituted N-tosylhydrazone substrates proceeded
smoothly under optimal reaction conditions, and the corresponding products 4-alkyl-1, 2, 3-thiadiazoles
are obtained. For the reaction of 4-arylbutan-2-one of N-tosylhydrazone substrates, (E)-4-styryl-1, 2, 3-
thiadiazole derivatives were obtained with high selectivity through the control of reaction conditions.
In addition, gram-scale synthesis and further transformation of the product were also investigated.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 24 October 2020
Revised 27 December 2020
Accepted 29 December 2020
Available online 19 January 2021
Keywords:
Cyclization
Iodine-catalyzed
1,2,3-thiadiazole
Selective
Synthesis
Introduction
p-toluenesulfonyl hydrazide, and KSCN (Scheme 1c) [10]. With
our continued interest in the development of N-tosylhydrazones
Substituted 1, 2, 3-thiadiazoles are important heterocyclic com-
pounds that frequently occur in pharmaceuticals and synthetic
agrochemicals due to their unique bio-activities [1,2]. In addition,
1, 2, 3-thiadiazoles as versatile intermediates had been used
widely in organic synthesis [3]. Therefore, the development of
effective methods for constructing 1, 2, 3-thiadiazole backbones
has received extensive attention. The classical methods mainly
included Hurd-Mori reaction, Wolff synthesis, Pechmann synthe-
sis, and so on [4–7]. However, these methods often suffer from lim-
itations, such as the use of highly reactive reagents (the diazo
compounds or azide), air-sensitive sulfur sources (SCl2 or SOCl2),
and prefunctionalized substrates. To overcome these shortcom-
ings, direct cyclization of readily available N-tosylhydrazones and
various sulfur sources into 4-aryl-1, 2, 3-thiadiazoles under the
action of iodine-catalysis, photo-catalysis or electrochemical-catal-
ysis has been developed (Scheme 1a) [8]. But so far, there are few
reports on the synthesis of alkyl-substituted thiadiazoles. Recently,
Zhou et al. described I2/DMSO-mediated one-pot cyclization reac-
tion of enaminones, tosylhydrazine, and elemental sulfur for the
synthesis of 5-acyl-1, 2, 3-thiadiazoles (Scheme 1b) [9]. Wu et al.
reported I2/CuCl2-promoted one-pot synthesis of aliphatic or
aromatic substituted 1, 2, 3-thiadiazoles from ketones,
[11], herein we developed a novel synthesis of aliphatic substituted
1, 2, 3-thiadiazoles functionalized with ester groups from ethyl 3-
(2-tosylhydrazono)butanoate and elemental sulfur (Scheme 1d).
Notable features of our findings include (i) the use of catalytic
amount of elemental iodine, (ii) a novel 4-alkyl-1, 2, 3-thiadiazole
skeleton was constructed, (iii) mild reaction conditions, and (iv)
good reaction selectivity for different types of substrates.
Results and discussion
Our investigation of the 4-aliphatic-1, 2, 3-thiadiazoles began
with ethyl (E)-2-benzyl-3-(2-tosylhydrazono)butanoate (1a) and
elemental sulfur (2a) as model substrates to optimized the reaction
conditions (Table 1). First, we investigated the effects of various
iodine sources (20 mol%) such as NH4I, KI, TBAI (tetrabutylammo-
nium iodide), I2, HI, and CuI in the presence of DMSO as solvent at
100 °C for 8 h. The results showed that the reaction could proceed
smoothly, and the desired product ethyl 2-phenyl-2-(1, 2, 3-thiadi-
azol-4-yl)acetate 3a was obtained in 47–54% yield (entries 1–6).
Considering comprehensively, we chose elemental iodine as the
catalyst for the next exploration. Unfortunately, increasing the
amount of iodine did not promote the reaction (entries 7–9). Other
solvents such as 1, 4-dioxane, DMA, DMF, MeCN, or toluene signif-
icantly inhibited the reaction (entries 10–14). Extending the reac-
tion time to 18 h, the reaction yield did not increase significantly
⇑
Corresponding authors.
E-mail addresses: liuping@shzu.edu.cn (P. Liu), mxw_tea@shzu.edu.cn (X. Ma).
https://doi.org/10.1016/j.tetlet.2021.152824
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

W. Li, X. Li, Y. Feng et al.
Tetrahedron Letters 66 (2021) 152824
Table 2
The scope of the reaction.a
Scheme 1. The synthesis of various substituted 1, 2, 3-thiadiazoles.
(entry 15). To our delight, by adjusting the reaction temperature,
the reaction yield was increased to 61% at 80 °C (entry 17 vs entries
16 and 18). Furthermore, increasing the amount of 2a did not lead
to a better yield (entry 19). On the contrary, when the amount of
2a was reduced to 1.2 equivalents, the yield of 3a could be
increased to 68% (entry 20).
a
Reaction conditions: 1a (0.30 mmol), 2a (1.2 equiv.), I2 (20 mol%), and solvent
(2 mL) at 80 °C for 8 h under air, isolated yield. bReaction time 12 h.
With the optimized conditions in hand (Table 1, entry 20), we
next explored the substrate scope of a-ester ketone N-tosylhydra-
zones 1 (Table 2). The methyl (2-Me, 3-Me, and 4-Me) in different
positions at the aryl ring were suitable for this protocol and pro-
vided the corresponding products 3b, 3j, and 3k in good yields,
but the yield of the product 3c decreased to 47% when the elec-
tron-donating group 4-OMe was employed. In addition, a variety
of electron withdrawing group substituted N-tosylhydrazones 1
reacted with S8 smoothly to provide the corresponding products
3d-3i in 47–74% yields. The structure of 3i was further confirmed
by single crystal X-ray diffraction (Fig. 1, CCDC: 2036307). It is
worth mentioning that the halogen groups (-F, -Cl, and -Br) at
the para-positions of the aryl ring were well tolerated, furnishing
the desired products 3e-3g in 62–74% yields. Furthermore, biphe-
nyl and naphthyl substituted N-tosylhydrazones were also suitable
substrate, delivering the desired products 3l-3n in 52–75% yields.
Moreover, the structure of the ester groups (–COOR, R = Me, i-Pr,
and t-Bu) on the N-tosylhydrazones had no significant effect on
the reactivity, and the desired products 3o-3q were obtained in
63–75% yields. In contrast, the N-tosylhydrazones derived from
acetoacetate esters can also react with S8, affording the corre-
sponding products 3r-3u albeit with lower yields. To our delight,
ethyl (Z)-2-ethyl-3-(2-tosylhydrazono)butanoate was utilized as
a partner to furnish the desired product 3v was obtained in 76%
yield.
Interestingly, when the N-tosylhydrazones derived from 4-
arylbutan-2-ones were used as reactants, the substituted (E)-4-
styryl-1,2,3-thiadiazole 4aa and 4ba were obtained in 73% and
71% 1H NMR of yields with high selectivity, accompanied by lower
yields of the products substituted 4-phenethyl-1,2,3-thiadiazole
4ab and 4bb (Scheme 2a). The above results indicated that the
ester group had a significant influence on the selectivity of the
reaction. This speculation was further confirmed by the reaction
of 4c as a substrate with S8, and the products 4ca and 4cb were
obtained in 33% and 32% isolated yields, respectively
(Scheme 2b). In addition, we found that the selectivity of the
resulting product 4ab was improved in the presence of 20 mol%
NH4I as catalyst and TBHP as oxidant (Scheme 2c). Next, the reac-
tion of the mixture of 4aa and 4ab (the ratio of 1H NMR = 5:1) was
performed in the presence of I2, the 4aa and 4ab ratio of 1H
NMR = 5:1 were increased to 8 : 1. The result showed that the pro-
duct 4ab can be further transformed into 4aa under standard con-
dition (Scheme 2d).
Table 1
Optimization of the reaction conditions.a
Entry
Catalyst/mol%
Solvent/mL
T/°C
Yield (%)b
1
2
3
4
5
6
7
8
NH4I (20)
KI (20)
TBAI (20)
I2 (20)
HI (20)
CuI (20)
I2 (50)
I2 (100)
I2 (200)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
1,4-dioxane (2)
DMF (2)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
130
80
52
52
48
54
48
47
47
38
9
16
trace
8
10
11
12
13
14
15c
16
17
18
19d
20e
DMA (2)
13
MeCN (2)
toluene (2)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
trace
trace
55
45
61
31
62
68
60
80
80
a
Reaction conditions: 1a (0.30 mmol), 2a (2 equiv.), catalyst (20 mol%), and
solvent (2 mL) at 100 °C under air for 8 h. bIsolated yield. cReaction time 18 h. d2a (3
equiv.). e2a (1.2 equiv.).
2

W. Li, X. Li, Y. Feng et al.
Tetrahedron Letters 66 (2021) 152824
Fig. 1. The crystal structure of compound 3i.
Scheme 3. Gram-scale experiments and further conversion of 3 g.
Scheme 4. Proposed reaction mechanism.
Scheme 2. The reactions of other N-tosylhydrazones with S8.
Conclusion
In conclusion, we have developed an iodine-catalyzed the reac-
tion of the ester-substituted N-tosylhydrazones, the desired prod-
ucts 4-alkyl-1, 2, 3-thiadiazoles were obtained with good
functional group tolerance. When the N-tosylhydrazones of 4-
arylbutan-2-one were used as reactants, the (E)-4-styryl-1, 2, 3-
thiadiazole derivatives were provided with high selectivity by
adjusting the reaction conditions. The merits of this method
include the use of catalytic amount of I2, broad substrate scope,
gram-scale synthesis, and further transformations.
To demonstrate the practicality of this method, a gram-scale
reaction was conducted under standard conditions. As shown in
Scheme 3, the reaction could be easily scaled up with 6.0 mmol
of 1g, affording the product 3g in 65% (1.33 g) yield. Importantly,
the synthetic versatilities of 3g as the substrate were demonstrated
by the corresponding transformations. The compound 3g and
phenylboronic acid underwent the Suzuki À Miyaura reaction in
the presence of Pd(PPh3)4 (0.2 mol%) and PCy3ꢀHBF4 (0.4 mol%),
affording the desired product 3l in 67% yield. Under the action of
10% NaOH, the hydrolysis reaction of the compound 3g could be
carried out to give the corresponding product 3ga in 81% yield.
In addition, under the catalysis of the Pd2(dba)3 (2 mol%) and
Xphos (4 mol%), the CAN coupling reaction could proceed
smoothly, providing the corresponding product 3gb in 35% yield.
Based on the previous reports [8], a plausible mechanism was
proposed (Scheme 4). First, elemental iodine reacts with 1 to form
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.
a-iodation of tosylhydrazone (I), and the elimination of HI pro-
Acknowledgements
vided azoalkene intermediate (II). Subsequently, the reaction of
azoalkene intermediate (II) with S8 affords zwitterionic intermedi-
ate (III), which underwent cyclization that furnished intermediate
(IV). Furthermore, the elimination of S7 and TsH led to the forma-
tion of the product 3a. In addition, for non-ester substituted pro-
duct 3, the iodination will continue to form intermediate (V)
under the action of I2. Finally, this intermediate (V) loses one mole-
cule of HI to obtain the product 4aa. In the whole process, the
released HI is oxidized by DMSO to I2 for the next cycle of the
reaction.
We gratefully acknowledge financial support of this work by
the National Natural Science Foundation of China (No. 21563025)
and the Shihezi University (No. CXRC201602).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152824.
3

W. Li, X. Li, Y. Feng et al.
Tetrahedron Letters 66 (2021) 152824
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