Metal-free synthesis of 2-aminothiadiazoles via TBHP-Mediated oxidative C-S bond formation

Article abstract of DOI:10.1080/00397911.2017.1398330

An efficient one-pot synthesis of 2-amino-1,3,4-thiadiazoles from easily available aldehydes and thiosemicarbazide using TBHP as an oxidant has been described. Notably, these reactions were carried out at room temperature using ethanol as solvent. This is the first example for one-pot synthesis of 2-amino-1,3,4-thiadiazole derivatives from aldehydes. This new synthetic methodology provides a simple procedure utilizing a safer oxidizing system that affords the target products in mild reaction condition with satisfactory yields and wide substrate scope.

Full text of DOI:10.1080/00397911.2017.1398330

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Metal-free synthesis of 2-aminothiadiazoles via
TBHP-Mediated oxidative C-S bond formation
Navnath T. Hatvate, Shrikant M. Ghodse & Vikas N. Telvekar
To cite this article: Navnath T. Hatvate, Shrikant M. Ghodse & Vikas N. Telvekar (2018): Metal-
free synthesis of 2-aminothiadiazoles via TBHP-Mediated oxidative C-S bond formation, Synthetic
Communications, DOI: 10.1080/00397911.2017.1398330
To link to this article: https://doi.org/10.1080/00397911.2017.1398330
View supplementary material
Published online: 03 Jan 2018.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [University of New England]
Date: 03 January 2018, At: 22:07

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1398330
Metal-free synthesis of 2-aminothiadiazoles via
TBHP-Mediated oxidative C-S bond formation
Navnath T. Hatvate , Shrikant M. Ghodse, and Vikas N. Telvekar
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga,
Mumbai, India
ABSTRACT
ARTICLE HISTORY
Received 26 August 2017
An efficient one-pot synthesis of 2-amino-1,3,4-thiadiazoles from
easily available aldehydes and thiosemicarbazide using TBHP as an
oxidant has been described. Notably, these reactions were carried out
at room temperature using ethanol as solvent. This is the first example
for one-pot synthesis of 2-amino-1,3,4-thiadiazole derivatives from
aldehydes. This new synthetic methodology provides a simple
procedure utilizing a safer oxidizing system that affords the target
products in mild reaction condition with satisfactory yields and wide
substrate scope.
KEYWORDS
1
,3,4-Thiadiazole; aldehydes;
c-s bond formation; metal
free; TBHP
GRAPHICAL ABSTRACT
Introduction
Thiadiazole is an important heterocycle in agricultural, material science, and medicinal
[
1]
chemistry. Mainly, the 2-amino-1,3,4-thiadiazole scaffold is very important in drug
design and development due to its mesoionic nature which imparts the compound to cross
the cellular membrane and interact with receptors. The sulfur atom of this compound is
also improving the lipophilicity and its aromaticity makes it lower toxic and in vivo
[
2]
durabile. Megazole (antiparasitic), Furidiazine (antimicrobial), Acetazolamide (to treat
glaucoma), Butazolamide (diuretics) are the present marketed 1,3,4-thiadiazole drugs.
[
3]
(
Figure 1). Similarly, it shows diverse bioactivity such as antitubercular, antidiabetics,
[
4–10]
anti-inflammatory, antidepressant, anticancer, anticonvulsants, and antiviral.
Hence,
the development of new methodologies to access 2-amino-1,3,4-thiadiazole synthesis is
very important in medicinal chemistry predominantly in drug discovery and developments.
As of now, there are several methods have been reported for the synthesis of 2-amino-
1
,3,4-thiadiazoles derivatives. The common method for the synthesis of 1,3,4-thiadiazoles
CONTACT Vikas N. Telvekar
vikastelvekar@rediffmail.com
Department of Pharmaceutical Sciences and Technology,
Institute of Chemical Technology, Matunga, Mumbai 400 019, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
©
2017 Taylor & Francis

2
N. T. HATVATE ET AL.
Figure 1. 1,3,4-thiadiazole containing pharmaceuticals.
involves dehydrative cyclization of N’-(acyl)thiohydrazide or thiosemicarbazides in the
[
11]
presence of POCl , FeCl , H SO , and Iodine.
Drawback of above reagents is the use
3
3
2
4
of hazardous materials, forcing reaction conditions such as high reaction temperature,
longer reaction time, problems in the purification, and limited substrate scope. Among
them FeCl , there is metal-based reaction, which having again additional drawbacks such
3
as low yield and tedious workup procedure. Recently, there are several reports published
which have milder cyclization methods for the synthesis of 1,3,4-thiadiazole using
trimethylsilyl chloride, triphenylphosphine, diphenyl phosphoryl chloride, Lawesson’s
[
12]
[13]
reagent
and p-TsCl/TEA.
but those reagents are moisture sensitive, unstable, and
also Hazardous in nature. 1,3,4-thiadiazole is also synthesized from acid hydrazides with
thioethyl ortho alkanoates, dithiocarbamate and trimethyl silyl isothiocyanate (TMSNCS)
[
14]
using P S /Al O , triethylamine in water and sulfuric acid, respectively.
4
10
2 3
In our previous work, we used aldehydes and thiosemicarbazide for the synthesis of
triazolidines and triazole in the presence of base like DMAP.[15] It is found in the literature
that, the same substrates were used for the synthesis of 2-amino-1,3,4-thiadiazole, by
[
11]
activating sulfur instead of amide using oxidizing agents such as FeCl and Iodine. Thus,
3
we thought that 1,3,4-thiadiazole is possible to synthesize by using common available start-
ing materials such as aldehydes and thiosemicarbazide, using a novel strategy of C-S bond
formation via oxidative C-H bond activation, rather than common methods. Herein, we
report a highly efficient metal-free protocol for the synthesis of 2-amino-1,3,4-thiadiazoles
derivatives from easily available aldehydes and thiosemicarbazide in EtOH in the presence
of tert-Butylhydroperoxide (TBHP) as an oxidizing agent.
Result and discussion
We initiated the present study with benzaldehyde (1a) and thiosemicarbazide (2) as a
model substrate using various oxidizing agents in DMSO as a solvent, but reaction does
not go to completion even after long reaction time (Table 1, entries 1–6). The effort was
put to increase the yield of the reaction using different solvents such as DMF, ACN,
MeOH, and EtOH. Out of these solvents, MeOH and EtOH gave a maximum yield of
the desired product. Hence, ethanol was chosen as a solvent for further studies as is
more ecofriendly and also nontoxic as compared with methanol. Finally to optimize
the reaction conditions, we have used different oxidizing agents such as hydrogen
peroxide, oxone, O , and tert-butyl hydroperoxide (TBHP, 70% aqueous solution). It
2
was observed that TBHP as an oxidant gave the best outcome as compared with other
oxidizing agents.

SYNTHETIC COMMUNICATIONS®
3
a,b
Table 1. Optimization of reaction conditions.
Entry
Oxidizing agents
Equiv.
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
O
2
–
DMSO
DMSO
DMSO
DMSO
DMF
24
24
24
24
24
8
NR
25
26
49
46
56
85
85
Oxone
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.5
2.0
2 2
H O
TBHP
TBHP
TBHP
TBHP
TBHP
ACN
MeOH
EtOH
EtOH
EtOH
EtOH
4
4
9
TBHP
TBHP
TBHP
4
68
86
85
1
1
0
1
4
4
a
b
Reaction conditions: 1a (1 mmol), 2 (1 mmol), oxidizing agent (1 mmol), and solvent (5 mL) at room temperature.
Isolated yield after column chromatography.
a,b
Table 2. Synthesis of various 5-substituted-2-amino-1,3,4-thiadiazoles compound using TBHP.
Compound
R (1a-1n)
Product
Yield (%)
85
3a
3
3
b
c
75
75
3d
75
3
3
e
f
70
70
(Continued)

4
N. T. HATVATE ET AL.
Table 2. Continued.
Compound
R (1a-1n)
Product
Yield (%)
80
3g
3h
80
3
3
3
i
75
82
80
j
k
3
3
3
l
83
83
76
b
m
n
a
Reaction conditions: 1 mmol of aldehydes (1a-1n), 1 mmol of thiosemicarbazide (2), 1 mmol of TBHP in EtOH at r.t. Isolated
yields after column chromatography.
Next, we studied the concentration of the TBHP and observed that 1 equivalent of
TBHP was sufficient to obtain a good yield, whereas decrease in mole equivalents ratios
resulted in lower yield (Table 1, entry 9), and no further improvements in the yield of
the product was observed with higher mole equivalents of TBHP as an oxidant (Table 1,
entries 10–11)
Optimized reaction conditions are suitable for aromatic aldehydes having electron
donating groups, for example, p-methyl benzaldehyde and p-hydroxybenzaldehyde
(Table 2, entries 3g and 3h) and electron withdrawing groups such as 2 and 4-nitrobenzal-
dehyde, 2 and 4-chlorobenzaldehyde and 4-fluorobenzaldehyde (Table 2, entries 3b–3f)
give good to excellent yield of desired product. The unsaturated double bond of cinnamal-
dehyde is stable and also gives a good yield of desired product (Table 2, entry 3i). Hetero-
aryl aldehydes such as thiophene-2-carboxyaldehyde and pyrrole-2-carboxyaldehyde
(
Table 2, entries 3j and 3k) and the alkyl aldehydes such as acetaldehyde, Trifluoroacetal-
dehyde, and n-butyraldehyde (Table 2, entries 3l–3n) are also tolerated.

SYNTHETIC COMMUNICATIONS®
5
Scheme 1. Plausible reaction pathway.
Based on the literature, a plausible reaction mechanism for the reaction is illustrated in
[
10]
Scheme 1.
In the first step, respective thiosemicarbazones are formed in situ from
aldehydes and thiosemicarbazide, and then ring closure occurs via oxidative cyclization
in the presence of tert-butyl hydroperoxide (TBHP), as an oxidizing agent to get the final
compound.
Conclusion
We have successfully developed an efficient, mild, and metal-free one-pot synthesis of
2
-amino-1,3,4-thiadiazole derivatives from easily available starting materials by the use
of tert-butyl hydroperoxide (TBHP). Various functional groups are well tolerated under
this reaction system and gave moderate to good yields.
Experimental section
General procedure for the preparation of 2-amino-1,3,4-thiadiazoles
A mixture of aldehydes (1 mmol), thiosemicarbazide (1 mmol) in ethanol (10 mL) and
tert-butyl hydroperoxide (TBHP, 70% aqueous solution) (1 mmol) was stirred at room
temperature for 4h. The progress of the reaction was monitored by TLC using hexane/
EtOAc as the mobile phase. After the completion of the reaction, ethanol was evaporated
under vacuum to obtain a solid residue. To this solid residue, ethyl acetate (10 ml) and

6
N. T. HATVATE ET AL.
water (10 ml) were added followed by saturated sodium bicarbonate solution (10 mL).
Separated organic layer was dried over anhydrous sodium sulfate and evaporated under
vacuum to obtain the product, which was further purified using silica gel column chroma-
tography (hexane/ethyl acetate).
5
-Phenyl-1,3,4-thiadiazol-2-amine (3a): White solid; Mp. 222–224 °C. 1H NMR
(
400 MHz, DMSO): δ ¼ 7.72–7.70 (d, J ¼ 8.00 Hz, 2H), 7.45–7.38 (m, 3H), 7.36 (bs, 2H);
1
3
C NMR (100 MHz, DMSO): δ ¼ 168.57, 156.42, 130.99, 129.59, 129.14, 126.31. GC/
MS: m/z, 177, 135, 121, 104, 74, 51.1.
Acknowledgments
VNT thanks to University Grant Commission, New Delhi, India for providing financial support
under UGC-Major research scheme. NTH and SMG thank to University Grant Commission, New
Delhi, India for providing fellowship under basic science research (UGC-BSR).
ORCID
Navnath T. Hatvate
http://orcid.org/0000-0002-3388-3247
References
[
1] Li, C. Y.; Wang, X. M.; Yang, Y. H.; Zhu, H. L. Chem. Rev. 2014, 114, 5572.
2] (a) Gur, M.; Muglu, H.; Cavus, M. S.; Guder, A.; Sayıner, H. S.; Kandemirli, F. J. Mol. Struct.
[
2
017, 1134, 40. (b) Altıntop, M. D.; Sever, B.; Ozdemir, A.; Kucukoglu, K.; Onem, H.; Nadar-
oglu, H.; Kaplancıkli, Z. A. Bioorg. Med. Chem. 2017, 25, 3547.
[
[
[
3] Haider, S.; Alam, M. S.; Hamid, H. Eur. J. Med. Chem. 2015, 92, 156.
4] Oruc, E. E.; Rollas, S.; Kandemirli, F.; Shvets, N.; Dimoglo, A. S. J. Med. Chem. 2004, 47, 6760.
5] Lee, J.; Lee, S. H.; Seo, H. J.; Son, E. J.; Lee, S. H.; Jung, M. E.; Lee, M.; Han, H. K.; Kim, J.; Kang,
J.; Lee, J. Bioorg. Med. Chem. 2010, 18, 2178.
[
6] (a) Ragab, F. A.; Heiba, H. I.; El-Gazzar, M. G.; Abou-Seri, S. M.; El Sabbagh, W. A.; El-Hazek,
R. M. J. Photochem. Photobiol. B. 2016, 166, 285. (b) Schenone, S.; Brullo, C.; Bruno, O.;
Bondavalli, F.; Ranise, A.; Filippelli, W.; Rinaldi, B.; Capuano, A.; Falcone, G. Bioorg. Med.
Chem. 2006, 14, 1698.
[7] Yusuf, M.; Khan, R. A.; Ahmed, B. Bioorg. Med. Chem. 2008, 16, 8029.
[8] Rzeski, W.; Matysiak, J.; Kandefer-Szerszen, M. Bioorg. Med. Chem. 2007, 15, 3201.
[9] Jatav, V.; Mishra, P.; Kashaw, S.; Stables, J. P. Eur. J. Med. Chem. 2008, 43, 135.
[
10] Cakir, G.; Kucukguzel, I.; Guhamazumder, R.; Tatar, E.; Manvar, D.; Basu, A.; Patel, B. A.; Zia,
J.; Talele, T. T.; Kaushik-Basu, N. Arch. Pharm. 2015, 348, 10.
[
11] (a) Ramprasad, J.; Nayak, N.; Dalimba, U.; Yogeeswari, P.; Sriram, D.; Peethambar, S. K.;
Achur, R.; Kumar, H. S. Eur. J. Med. Chem. 2015, 95, 49. (b) Siddiqui, S. M.; Salahuddin,
A.; Azam, A. Med. Chem. Res. 2013, 22, 1305. (c) Pandit, N.; Shah, K.; Agrawal, N.; Upmanyu,
N.; Shrivastava, S. K.; Mishra, P. Med. Chem. Res. 2016, 25, 843. (d) Niu, P.; Kang, J.; Tian, X.;
Song, L.; Liu, H.; Wu, J.; Yu, W.; Chang, J. J. Org. Chem. 2015, 80, 1018.
[
12] (a) Hwang, J. Y.; Choi, H. S.; Lee, D. H.; Gong, Y. D. J. Comb. Chem. 2005, 7, 816. (b) Kaleta, Z.;
Makowski, B. T.; Soos, T.; Dembinski, R. Org. Lett. 2006, 8, 1625.
[
[
13] Yang, S. J.; Lee, S. H.; Kwak, H. J.; Gong, Y. D. J. Org. Chem. 2013, 78, 438.
14] (a) Aryanasaba, F.; Halimehjani, A. Z.; Saidi, M. R. Tetrahedron Lett. 2010, 51, 790. (b) Polshet-
tiwar, V.; Varma, R. S. Tetrahedron Lett. 2008, 49, 879. (c) Guda, D. R.; Cho, H. M.; Lee, M. E.
RSC Adv. 2013, 3, 6813.
[15] Mali, D. A.; Telvekar, V. N. Synth. Commun. 2016, 47, 324.