Straightforward synthesis of novel substituted 1,3,4-thiadiazole derivatives in choline chloride-based deep eutectic solvent

Article abstract of DOI:10.1016/j.tetlet.2017.01.057

A one-pot, three-component route for the synthesis of novel 1,3,4-thiadiazole derivatives using a ketene S,S-acetal, a carbonyl compound and thiocarbohydrazide is described. The main advantages of this approach are high yields, short reaction times, simple reaction conditions and a green reaction medium. The 1,3,4-thiadiazole core has been substituted with biologically active groups such as arylhydrazones, coumarin, isatin, Meldrum's acid and barbituric acid. Structures of the thiadiazoles were elucidated from spectroscopic data.

Full text of DOI:10.1016/j.tetlet.2017.01.057

Accepted Manuscript
Straightforward Synthesis of Novel Substituted 1,3,4-Thiadiazole Derivatives
in Choline Chloride-Based Deep Eutectic Solvent
Seyyed Mohammad Shahcheragh, Azizollah Habibi, Sahar Khosravi
PII:
S0040-4039(17)30079-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.057
TETL 48560
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 October 2016
2 January 2017
17 January 2017
Please cite this article as: Mohammad Shahcheragh, S., Habibi, A., Khosravi, S., Straightforward Synthesis of Novel
Substituted 1,3,4-Thiadiazole Derivatives in Choline Chloride-Based Deep Eutectic Solvent, Tetrahedron Letters
(2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.057
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Tetrahedron Letters
Straightforward Synthesis of Novel Substituted 1,3,4-Thiadiazole Derivatives in
Choline Chloride-Based Deep Eutectic Solvent
Seyyed Mohammad Shahcheragh, Azizollah Habibi and Sahar Khosravi
Faculty of Chemistry, Kharazmi University, No. 43, P. Code 15719-14911, Mofatteh Street, Enghelab Ave., Tehran, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A one-pot, three-component route for the synthesis of novel 1,3,4-thiadiazole derivatives using a
ketene S,S-acetal, a carbonyl compound and thiocarbohydrazide is described. The main
advantages of this approach are high yields, short reaction times, simple reaction conditions and
a green reaction medium. The 1,3,4-thiadiazole core has been substituted with biologically
active groups such as arylhydrazones, coumarin, isatin, Meldrum’s acid and barbituric acid.
Structures of the thiadiazoles were elucidated from spectroscopic data.
Available online
Keywords:
2016 Elsevier Ltd. All rights reserved.
1,3,4-thiadiazole
Thiocarbohydrazide
Ketene S,S-acetal
Deep Eutectic Solvent
Meldrum’s acid
Barbituric acid
Amongst heterocyclic compounds, those containing five-
membered rings are the most commonly encountered building
blocks, with a large number possessing interesting biological
activities.1 Thiadiazoles consist of four isomers; 1,2,3-
thiadiazoles, 1,2,4-thiadiazoles, 1,2,5-thiadiazoles, and 1,3,4-
thiadiazoles (Fig. 1a), of which 1,3,4-thiadiazoles have seen
special interest in recent years demonstrating biological
properties including antimicrobial,2 antiviral,3 antitubercular,4
antiparasitic,5 anticonvulsant,6 antidepressant, anxiolytic,7 and
anticancer8 activities. They are also key intermediates in the
synthesis of commercially available drugs such as megazol,9
acetazolamide, and furidiazine (Fig. 1b).10
reagent, or a combination of reagents to form the thiadiazole ring.
Additionally, commonly reported methods often suffer from
harsh reaction conditions, multi-step procedures, or
stoichiometric formation of intractable by-products.17
A one-pot or one-step synthesis via simple and efficient
procedures would be interesting for both laboratory and industrial
purposes.18 Herein, a one-pot approach for the synthesis of novel
substituted 1,3,4-thiadiazoles using thiocarbohydrazide,
a
carbonyl compound and a ketene S,S-acetal in a deep eutectic
solvent (DES) was developed (Scheme 1).
DESs are commonly prepared from a eutectic mixture of
Lewis or Brønsted acids and bases, which may contain a variety
of anionic or cationic species, and possess a melting point much
lower than either of the individual components.12 Compared to
ionic liquids, DESs are generally cheaper to make, are less toxic
and are often biodegradable. Thus, DESs can be used as low–
cost, safe and efficient solvents.13. Herein, the choline chloride
and urea based DES (ChCl-urea) was used.
Our investigation started with the one-pot, three-component
model reaction of thiocarbohydrazide 1, Meldrum’s acid based
ketene-S,S-acetal 3a or barbituric acid based ketene-S,S-acetal 3b
and 4-methoxybenzaldehyde in order to optimize the reaction
conditions. First, the effects of various solvents on reaction times
and yields were evaluated. Moderate to high yields of 4a and 5a
were obtained in both protic and aprotic solvents (Table 1,
Entries 1-5 and 14-18). Since DESs have many advantages
including ready availability, non-toxicity, biodegradability,
recyclability, and low price in comparison with organic
Figure 1. (a) Isomers of thiadiazole. (b) Commercially available
1,3,4-thiadiazole based drugs.
Commonly reported methods for the synthesis of 1,3,4-
thiadiazoles include those starting from acylhydrazines, including
monoacylhydrazines
and
N,N′-diacylhydrazines,11
or
thiosemicarbazides,12
thiocarbazides,13
dithiocarbazates,14
thiohydrazides and bithioureas,15 as well as the transformation of
1,3,4-oxadiazoles.16 These methods usually require a sulfuration
reagent to introduce the sulfur atom to the ring, a cyclization
———
 Corresponding author; Tel./fax: +98 21 88848949. E-mail address: habibi@khu.ac.ir (A. Habibi).

2
solvents,19 the synthesis of the model compounds were also
investigated in ChCl-urea.
Thus, heating thiocarbohydrazide 1 (0.4 mmol), carbonyl
compound 2 (0.4 mmol) and ketene-S,S-acetal 3a or 3b (0.4
mmol) in ChCl-urea at 80 °C was considered as the optimum
conditions for the synthesis of products 4 and 5.20
The scope of the reaction was then examined using various
carbonyl compounds (Table 2). Using this method, 24 derivatives
were synthesized in moderate to high yields. Aromatic aldehydes
containing electron-withdrawing groups such as 4-chloro-3-
nitrobenzaldehyde,
2,6-dichlorobenzaldehyde,
2,4-
dichlorobenzaldehyde and 3-nitrobenzaldehyde proceeded with
high yields (Entries 3–6 and 15-17). Aromatic aldehydes
containing
methoxybenzaldehyde,
electron-donating
groups
such
as
3-
4-
4-methoxybenzaldehyde,
(dimethylamino) benzaldehyde and 2-hydroxybenzaldehyde also
afforded comparative yields (Entries 1, 2, 7, 10, 12, 13, 14, 19
and 22). Furthermore, 5-membered heterocyclic aldehydes such
as furan-2-carbaldehyde and thiophen-2-carbaldehyde were
suitable substrates (Entries 8, 9, 20 and 21). Due to the
considerable biological significance of the isatin and coumarin
motifs, 3-acetylcoumarin and isatin were applied as carbonyl
compounds to give the desired products in high yields (Entries
11, 12, 23 and 24).
Scheme 1. One-pot synthesis of 1,3,4-thiadiazoles
Although poor yields were obtained at room temperature
(Entries 6 and 19), increasing the temperature to 80 °C resulted in
increased yields (Entries 7-9 and 20-22). Further increasing the
reaction temperature to 95 °C resulted in decreased yields
(Entries 10 and 23). Finally, the synthesis of 4a and 5a in
mixtures of EtOH or MeOH and ChCl-urea were examined.
Although the yields increased upon increasing the amount of
ChCl-urea in the reaction medium, the yields were lower
compared to those using only ChCl-urea as the reaction medium.
The proposed mechanism for the synthesis of compounds 4
and 5 is exemplified for compound 5k (Scheme 2). The reaction
begins with the reaction of thiocarbohydrazide with 3-acetyl-
coumarin to give the corresponding thiocarbohydrazone A. Then,
condensation of thiocarbohydrazone A with ketene-S,S-acetal 3b
occurs over two sequential steps; first, aza-Michael addition of
the thiocarbohydrazone nitrogen to the ketene-S,S-acetal,
followed by elimination of methanethiol to provide intermediate
B, which undergoes intramolecular cyclization and elimination of
the second methanethiol group to afford 5k. 21
Table 1. Reaction conditions optimization for the synthesis of 4a and
5a.
Entry
Product
Solvent/Co-solventb
Temp. (°C)
Time (h)
Yielda (%)
1
2
EtOH
MeOH
Reflux
Reflux
Reflux
100
Reflux
rt
5
5
5
5
5
5
5
5
5
5
5
65
45
35
50
50
-
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
3
CH3CN
4
DMF
5
CH2Cl2
6
ChCl-urea
ChCl-urea
ChCl-urea
ChCl-urea
ChCl-urea
EtOH/ChCl-urea
(10 mol%)
EtOH/ChCl-urea
(20 mol%)
EtOH/ChCl-urea
(30 mol%)
EtOH
7
45
35
50
85
65
45
8
65
9
80
10
11
95
80
12
13
80
80
5
5
55
65
4a
4a
14
15
16
17
18
19
20
21
22
23
24
Reflux
Reflux
Reflux
100
Reflux
rt
5
5
5
5
5
5
5
5
5
5
5
40
70
40
50
45
-
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
MeOH
Scheme 2. Proposed mechanism for the synthesis of 1,3,4-
thiadiazoles
CH3CN
DMF
CH2Cl2
ChCl-urea
ChCl-urea
ChCl-urea
ChCl-urea
ChCl-urea
MeOH/ChCl-urea
(10 mol%)
MeOH/ChCl-urea
(20 mol%)
MeOH/ChCl-urea
(30 mol%)
In conclusion, a simple and efficient method has been
developed for the synthesis of novel molecules containing the
1,3,4-thiadiazole ring using a one-pot, three-component reaction
of a carbonyl compound, thiocarbohydrazide, and a ketene-S,S-
acetal. The products were obtained in high yields in suitable
times using ChCl-urea as a green reaction medium. This protocol
provides a straightforward route for the synthesis of complex
molecules containing biologically active motifs such as 1,3,4-
thiadiazole, Meldrum’s acid or barbituric acid, and coumarin,
isatin or substituted benzenes in a single molecule which may
find interest for the construction of novel pharmaceuticals.
45
43
50
80
60
48
65
80
95
65
25
26
65
65
5
5
52
67
5a
5a
a Isolated yield
b Solvent volume (10 mL)

Table 2. Diversity in the synthesis of 1,3,4-thiadiazole derivatives 4a–l and 5a-la
Yield
Yield
(%)b
Entry
Product
Time (h)
Entry
Product
Time (h)
5
(%)b
1
5
85
13
80
85
65
4a
4b
4c
5a
5b
5c
2
3
4
5
80
67
14
15
4.5
5
4
6
55
16
5.5
68
4d
5d
5
6
4.5
60
67
80
65
70
80
6.5
5.5
5
70
65
83
70
65
80
17
18
4e
4f
5e
5f
6
7
5.5
19
20
21
22
4g
5g
8
4
6
4h
5h
9
4.5
5.5
4.5
4i
4j
5i
5j
10
5
11
4
65
23
6
75
4k
5k
12
6
70
24
5.5
65
4l
Reagents and conditions: Meldrum’s acid based ketene-S,S-acetal 3a or barbituric acid based ketene-S,S-acetal 3b (1 mmol), thiocarbohydrazide 1 (1 mmol), carbonyl 2 (1 mmol),
5l
a
ChCl-urea (20 mL), 80 °C.
b Isolated yields.
Acknowledgments
Iran. Also, we thank Dr. Azim Ziyaei Halimehjani for comments
which improved the manuscript.
We are grateful for the continuing financial support of this
research project by Faculty of Chemistry, Kharazmi University,
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20. Typical procedure for the synthesis of compound 4a: 4-
Methoxybenzaldehyde (0.4 mmol) was added to a stirred
solution of thiocarbohydrazide 1 (0.4 mmol) in ChCl-urea (10
mL) over 30 min and stirring continued at room temperature for
1 h. Then, 5-[bis(methylthio)methylene] Meldrum’s acid 3a (0.4
mmol) was added and the reaction mixture heated at 80 °C for

Straightforward Synthesis of Novel
Substituted 1,3,4-Thiadiazole
Derivatives in Choline Chloride-Based
Deep Eutectic Solvent
Seyyed Mohammad Shahcheragh, Azizollah
Habibi and Sahar Khosravi
———

6
HIGHLIGHTS
 One-pot, three-component route for the
synthesis of novel 1,3,4-thiadiazoles.
 Choline Chloride-Based Deep Eutectic Solvent
used as a green reaction medium.
 Advantages of this work include high yields and
simple reaction condition.
 Products contain biologically active motifs.