A KHSO4 promoted tandem synthesis of 1,3,4-thiadiazoles from thiohydrazides and DMF derivatives

Article abstract of DOI:10.1016/j.tetlet.2020.152195

An efficient, simple and environmentally benign method for the construction of 1,3,4-thiadiazole skeletons via the tandem coupling and cyclization of thiohydrazides with DMF derivatives in the presence of KHSO₄ has been reported. This method re

Full text of DOI:10.1016/j.tetlet.2020.152195

Journal Pre-proofs
A KHSO4 Promoted Tandem Synthesis of 1,3,4-thiadiazoles from Thiohydra‐
zides and DMF Derivatives
Zongjie Gan, Binghua Tian, Jianyong Yuan, Dongzhi Ran, Lin Zhang, Gang
Dong, Tao Pan, Yixin Zeng, Yu Yu
PII:
S0040-4039(20)30660-2
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152195
TETL 152195
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Tetrahedron Letters
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Revised Date:
Accepted Date:
18 February 2020
3 June 2020
28 June 2020
Please cite this article as: Gan, Z., Tian, B., Yuan, J., Ran, D., Zhang, L., Dong, G., Pan, T., Zeng, Y., Yu, Y., A
KHSO4 Promoted Tandem Synthesis of 1,3,4-thiadiazoles from Thiohydrazides and DMF Derivatives,
Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152195
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A KHSO4 Promoted Tandem Synthesis of 1,3,4-thiadiazoles
from Thiohydrazides and DMF Derivatives
Zongjie Gana, b,1, Binghua Tiana,1, Jianyong Yuana,b, Dongzhi Rana,b, Lin Zhanga, Gang
Donga, Tao Pana, Yixin Zenga, Yu Yua*
a Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University,
Chongqing 400016, PR China
b Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical
University, Chongqing 400016, PR China
*Corresponding author
1 These authors contributed equally to this work.
Email: yuyu3519@163.com, gzj@cqmu.edu.cn.
Tel.:86-23-68485161
1

Abstract An efficient, simple and environmentally benign method for the construction of
1,3,4-thiadiazole skeletons via the tandem coupling and cyclization of thiohydrazides with DMF
derivatives in the presence of KHSO4 has been reported. This method reveals good reactivity and
functional group tolerance, and a broad series of 1,3,4-thiadiazoles were obtained in moderate to good
yields.
Keywords 1,3,4-thiadiazoles; KHSO4; Synthesis
Introduction
1,3,4-thiadiazoles represent a prevalent and important class of compounds which exhibit diverse
pharmacological activities such as antibacterial, anticancer, antitubercular and anti-inflammatory.1,2 For
example, acetazolamide,3 which contains the 1,3,4-thiadiazole structure motif has been approved as the
diuretic, whereas cefazedone has shown a broad spectrum of antibacterial activity against various
pathogens.4 In addition, another 1,3,4-thiadiazole derivative BAS0338872 has also been reported as a
potent Src/Abl tyrosine kinase inhibitor for the potential treatment of chronic myeloid leukemia (Figure
1).5 It is worth noting that these important biological effects are mainly attributed to the thiadiazole key
skeleton,6 thus much effort has been devoted to finding out facile and efficient methods for the
synthesis of 1,3,4-thiadiazoles.
H
N
N
N
O
N
O O
S
S
H
N
S
N
O
H3C
S
HN
NH2
N
S
S
I
N N
O
CH3
O
N
N
N
N
BAS0338872
Cefazedone
Acetazolamide
Figure.1 Some bioactive compounds contain 1,3,4-thiadiazole motif.
As of now, several approaches have been developed to synthesize 1,3,4-thiadiazoles, generally
involve the dehydration of thioacylhydrazides or oxidative cyclization of thiohydrazones.7
Thioacylhydrazides prepared from thiohydrazides with carboxylic acids, aryl chlorides, amides or
nitriles are used as crucial intermediates to obtain thiadiazoles with several dehydrated reagents
including p-TsCl/TEA,8 POCl3,9 H2SO4,10 EDCI,7 PPA11 and so on. Alternatively, in situ cyclization of
14
15
thiohydrazones in the presence of some oxidants such as PhI/H2O2,12 Br2,13 FeCl3 or Eosin Y/O2
have also been proposed as a common method to afford 1,3,4-thiadiazoles. Besides the traditional
2

synthesis, some elegant methods have been reported in recent years. Zhu16 and co-workers reported a
novel protocol to produce 1,3,4-thiadiazole from the hydrazides and aryl halide via isocyanide insertion.
In addition, Taha17 presented another method by treating isothiocyanate with hydrazides to form
1,3,4-thiadiazoles under basic condition. However, these existing methodologies are more or less
inconvenient due to the addition of hazardous, corrosive or unavailable regents, and the requirement of
a transition metal or strong acidic catalyst also makes them unattractive. Hence, the development of a
convenient, economical and environmentally benign synthesis procedure to this scaffold is still
valuable.
Recently, transamidation of amides with amines has been recognized as a convenient and
straightforward strategy for amide bond formation.18,19 Various promotors such as concentrated HCl,20
Fe(III),21 B(OCH2CF3),22 [Ni(quin)2]23 and L-Proline24 have been applied for catalyzing the reaction.
Despite significant progress, it is still demanded to deveople novel, green and cost-effective catalysts
due to the drawbacks of these promoting agents. To our delight, we fortunately found that a mild and
inexpensive catalyst KHSO4 can carry out the N-formylation and N-acylation of amines with high yield
and good selectively. More importantly, we also observed that KHSO4 can catalyze the intramolecular
cyclization of thioacylhydrazides as a dehydrating agent under non-stringent conditions. Therefore, in a
continuation of our ongoing research,25 herein, we would like to describe an eco-friendly, facile and
inexpensive method to prepare 1,3,4-thiadiazoles from thiohydrazides and N, N-Dimethylformamide
(DMF) derivativities utilizing KHSO4 both as transamidation and dehydrating agent for the first time.
(Scheme 1).
S
KHSO4
S
R1
R2
NH2
R1
N
O
H3C
H3C
N
N
H
, 100°C, 2-5h
N
R2
Scheme 1. Synthetic procedure for 1,3,4-thiadiazoles
Results and discussion
Based on our previous work,25 The initial investigation of the reaction was focused on the screening
of catalysts by using a model reaction of benzothiohydrazide with N, N-dimethylacetamide (DMA). As
shown in table 1, the screening study revealed that the catalyst played an essential role in this reaction.
3

No desired product 3a was observed when the model reaction was carried out without any other
additives (Table 1, entry 1), whereas acids such as HAc and TsOH could catalyze this reaction (Table 1,
entries 2-3). Notably, when an acidic salt KHSO4 (3 equiv.) was employed, the reaction could also
afford the target product 3a in moderate isolated yield (Table 1, entry 4). This encouraging finding
intrigued us to investigate other inorganic salts including CaCl2, Cu(OAc)2, FeCl3, NaH2PO4 and NH4Cl.
Interestingly, CaCl2 and Cu(OAc)2 failed to promote this reaction, while FeCl3, as well as NaH2PO4 and
NH4Cl provided the desired product in inferior yield (Table 1, entries 5–9), thus KHSO4 was found to
be a suitable catalyst for this reaction. Then, the effect of different amounts of KHSO4 on the reaction
outcome was examined. To our delight, an incremental increase in the yield was observed by
increasing the loading of KHSO4 and 5.0ꢀequiv. of KHSO4 was sufficient for the complete conversion
of 1a and obtained the desired product 3a in 86% yield (Table 1, entries 10–11). Next, the performance
of the reaction under different temperature was also evaluated. Increasing the temperature did not
provide any further positive influence on the yield of 3a, conversely, impurities such as
2,5-diphenyl-1,3,4-thiadiazole derived from the self-condensation of 1a were generated in higher
temperature leading to a lower yield (Table 1, entry 12). Similarly, decreasing the temperature from
100 °C to 80 °C prolonged the reaction time and resulted in the decrease of the yield too (Table 1, entry
13), so the optimal temperature was 100 °C. Finally, the ultimately reaction parameters were selected
as 5 equiv. of KHSO4 in DMA at 100 °C.
Table 1. Optimization of the reaction conditionsa
S
O
Cat
NH2
H3C
S
CH3
N
N
CH3
H
Temp(°C)
CH3
N
N
3a
1a
Entry
Catalyst (equiv.)
Temp (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
-
100
100
100
100
100
100
100
5
5
5
5
5
5
5
NRc
50
HAc (3.0)
TsOH (3.0)
KHSO4 (3.0)
CaCl2 (3.0)
FeCl3 (3.0)
Cu(OAc)2 (3.0)
65
67
trace
45
trace
4

8
NaH2PO4 (5.0)
NH4Cl (5.0)
KHSO4 (4.0)
KHSO4 (5.0)
KHSO4 (5.0)
KHSO4 (5.0)
100
100
100
100
130
80
5
5
5
5
5
8
30
42
75
86
74
60
9
10
11
12
13
a Reaction conditions: benzothiohydrazide (0.1 g, 0.6 mmol, 1.0 equiv.) and DMA (1 mL).
b Isolated yield.
c No reaction
Under the optimized reaction conditions, the substrate scope and versatility of the reaction was
subsequently explored, and the results are summarized in table 2. To our delight, the protocol was
compatible with benzothiohydrazides containing a range of functional groups, little influence of
electronic properties was observed on their reactivity. For example, benzohydrazides with
electron-donating groups on the para-position of benzene ring, such as OCH3 and CH3, yielded the
corresponding products in 77% and 80% yield, respectively (Table 2, entries 2b, 2c). On the other hand,
benzohydrazides bearing electron-withdrawing groups such as F, Cl, also gave the desired product with
a yield ranging from 82% - 85% (Table 2, entries 2d, 2e). Additionally, the position effect of the
substituents on the reaction outcome was not obvious, 3-methyl benzothiohydrazide underwent the
reaction smoothly and provided the corresponding product in 78% yield (Table 2, 2f). Likewise,
dimethyl substituted benzothiohydrazide 1g was found to be reactive too and transformed into the
target compound 2g in lower yield (72%) under the standard reaction conditions. It is important to note
that the steric hindered substrate naphthalene-2-carbothiohydrazide 1h was also well-tolerated and
furnished the reaction with 70% yield (Table 2, 2h). Grippingly, heterocyclic thiohydrazide derivatives
such as thiophene-2-carbothiohydrazide and furan-2-carbothiohydrazide were suitable for the reaction
and resulted in the corresponding products 2i and 2j in good yields.
Table 2. Substrate scope with respect to substituted benzothiohydrazides a
S
KHSO4
O
H
H3C
H3C
S
R
NH2
N
R
N
N N
H
2
1
5

H3CO
H3C
S
S
S
N N
N N
N N
2a, 84%
2b, 77%
2e, 82%
2h, 70%
2c, 80%
Cl
F
S
S
S
H3C
N N
N N
N N
2d, 85%
2f, 78%
S
H3C
S
S
S
H3C
N N
N N
N N
2g, 72%
2i, 82%
O
S
N N
2j, 83%
a Reagents and conditions: benzothiohydrazides (1.2 mmol), KHSO4 (5.0 equiv.) and DMF (2 mL), 100 °C for 2 h,
air, isolated yield.
Inspired by the success synthesis of 2-substitued 1,3,4-thiadiazole derivatives, we then turned our
attention to synthesize 2,5-disubstitued 1,3,4-thiadiazoles. DMA, N, N-Dimethylpropionamide
(DMPA), N, N-dimethylbenzamide (DMBA) and N, N-dimethyl-2-phenylacetamide instead of DMF
were applied to this protocol under the optimized condition (table 3). Similarly, treatment of 1a-j with
DMA produced the corresponding products in moderate to good yields (70 - 86%) (Table 3, 3a-j).
Likewise, when DMF was replaced by DMPA, the reaction also took place efficiently and provided the
desired product 3k with a yield of 75%. However, in the case of DMBA, additional reaction time (12 h)
was required and the desired product was obtained in inferior yield (69%) probably owing to the steric
hinderance (Table 3, 3l-m). Deserved to be noted, for the N, N-dimethyl-2-phenylacetamide and
N,N-dimethyl-2-phenylpropanamide substrates, they can also participate in the same reaction, but
higher temperature (130 °C) was required to accomplish the reaction compared with other derivatives
(Table 3, 3n-q).
6

Table 3. Substrate scope with respect to DMF derivativesa
S
S
KHSO4
O
H3C
H3C
R1
R2
NH2
N
N
R1
N N
H
R2
3
1
H3CO
H3C
S
CH3
S
S
CH3
CH3
N N
N N
N N
3a, 86%
3c, 80%
3b, 77%
Cl
F
S
S
S
CH3
CH3
CH3
H3C
N N
3e, 83%
N N
N N
3d, 81%
3f, 74%
H3C
S
S
S
N N
S
CH3
CH3
CH3
H3C
N N
N N
3g, 77%
3h, 70%
3i, 76%
O
S
S
S
CH3
CH3
N N
N N
N N
3lb, 69%
3j, 78%
3k, 75%
S
S
S
H3C
Cl
H3C
N N
N N
N N
3oc, 55%
3nc, 63%
3mb, 60%
CH3
S
S
N N
N N
3pc, 58%
3qd, 42%
a Reaction conditions: thiohydrazide (1.2 mmol), KHSO4 (5.0 equiv.) and DMA (2 mL), 100 °C, 5 h, air, isolated
yield.
b Reaction conditions: benzothiohydrazide (1.0 mmol), KHSO4 (5.0 equiv.) and DMBA (5.0 mmol), 100 °C, 12 h,
air, isolated yield.
c 130 °C, 3 h
d 130 °C, 6 h
7

Furthermore, in order to investigate the efficiency of this process, the method was extended for a
gram-scale synthesis (Scheme 2). Fortunately, the desired product 2a was isolated by column
chromatograph in 80% yield.
Scheme 2. Gram Scale synthesis experiment
S
KHSO4 (5.0 equiv.)
H3C
H3C
O
H
S
NH2
N
N
,
100 °C 2h
H
N
N
2a, 1.3 g, 80% yield
1a (10 mmol)
Based on the literature20,26 and our previous work, we have proposed a plausible mechanism depicted
in scheme 3. Firstly, amide was activated by H+ afforded by KHSO4 to produce cationic intermediate A,
which was attacked by benzothiohydrazides results in the formation of a tetrahedral intermediate B.
Breakdown of intermediate B lead to the intermediate C. Then, cyclization via nucleophilic attack of
thiol group on the carbonyl group afforded intermediate D and a subsequent dehydration of
intermediate D finally provided the 1,3,4-thiadiazoles.
S
H2N
H
N
S
H
N
H
OH
OH
R
O
N
H
R
N
N
R
O
R
N
HN
C
NH
A
B
S
H
HO
SH
R
N
R
H
N
S
R
S
NH
N
N
O
N
D
Scheme 3. A plausible mechanism for the synthesis of 2,5-disubstituted 1,3,4-thiadiazoles
Conclusion
To sum up, an efficient, simple and economical synthetic protocol for the preparation of
1,3,4-thiadiazoles via the direct coupling and dehydration of thiohydrazides and DMF derivatives has
been developed. This process employing KHSO4 as the only promoter would provide a better synthetic
option for the synthesis of 1,3,4-thiadiazoles.
8

Acknowledgements
We appreciate the finical support from the National Natural Science Foundation of China (No.
21907013) and the Scientific and Technological Research Program of Chongqing Municipal Education
Commission (KJQN20190043)
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Highlights
 Facile synthesis of 1,3,4-thiadiazoles from thiohydrazides with DMF
derivatives.
 KHSO4 promoted the reaction both as coupling and dehydrating
agent.
 Operationally simple catalysis and Solvent-free conditions.
Graphical abstract
S
KHSO4
operational simplicity
inexpensive promotor
solvent-free
S
R1
R2
NH2
R1
N
O
H3C
H3C
N N
H
, 100°C, 2-6h
N
R2
27 examples
42-86% yield
10