Novel, green and sustainable route for synthesis of 5-aryl-4-phenyl-1,2,4-triazolidine-3-thiones

Article abstract of DOI:10.1016/j.tetlet.2020.152015

A highly efficient, one-pot, novel and greener straightforward multi-component approach has been disclosed for the facile synthesis of 5-aryl-4-phenyl-1,2,4-triazolidine-3-thiones from reaction of phenyl isothiocyanate, hydrazine hydrate and diverse aromatic aldehydes/cyclic ketones/isatins in the presence of a novel Lewis acid-surfactant-combined catalyst. High yields, use of ambient temperature and water as a universally accepted green solvent, simple work-up procedure, easy isolation of product, high atom economy makes the present method attractive, sustainable and economical.

Full text of DOI:10.1016/j.tetlet.2020.152015

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Novel, Green and Sustainable Route for Synthesis of 5-Aryl-4-Phenyl-1,2,4-
Triazolidine-3-Thiones
Mayuri Patil, Pradeep Mhaldar, Vrushali Mahadik, Dattaprasad M. Pore
PII:
S0040-4039(20)30458-5
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152015
TETL 152015
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
5 March 2020
29 April 2020
5 May 2020
Please cite this article as: Patil, M., Mhaldar, P., Mahadik, V., Pore, D.M., Novel, Green and Sustainable Route
for Synthesis of 5-Aryl-4-Phenyl-1,2,4-Triazolidine-3-Thiones, Tetrahedron Letters (2020), doi: https://doi.org/
10.1016/j.tetlet.2020.152015
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NOVEL, GREEN AND SUSTAINABLE ROUTE FOR SYNTHESIS OF 5-ARYL-4-PHENYL-1,2,4-
TRIAZOLIDINE-3-THIONES
Mayuri Patil a , Pradeep Mhaldar a, Vrushali Mahadik a and Dattaprasad M. Pore,*a

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Tetrahedron Letters
journal homepage: www.elsevier.com
NOVEL, GREEN AND SUSTAINABLE ROUTE FOR SYNTHESIS OF 5-ARYL-4-PHENYL-1,2,4-
TRIAZOLIDINE-3-THIONES
Mayuri Patil a , Pradeep Mhaldar a, Vrushali Mahadik a and Dattaprasad M. Pore,*a
aDepartment of Chemistry, Shivaji University, Kolhapur- 416004, India *E-mail: p_dattaprasad@rediffmail.com
Abstract
A highly efficient, one-pot, novel and greener straightforward multi-component approach has been disclosed for the facile synthesis of
5-aryl-4-phenyl-1,2,4-triazolidine-3-thiones from reaction of phenyl isothiocyanate, hydrazine hydrate and diverse aromatic aldehydes /
cyclic ketones / isatins in the presence of a novel Lewis acid-surfactant-combined catalyst. High yields, use of ambient temperature and
water as a universally accepted green solvent, easy work-up procedure and isolation of product, high atom economy makes the present
method attractive, sustainable and economical.
Keywords: Surfactant, Lewis acid, Triazole, Phenylisothiocyanate.
1. Introduction
The discovery of environment friendly synthetic track for ‘drug-resembling’ heterocyclic compounds from easily available precursors
in eco-benign solvents is gaining significant interest in the sectors like pharmaceuticals, academic circles and manufacturing.1 In recent
years, the substitution of toxic and explosive organic solvents as reaction medium by green solvent water which is safe, good-natured,
environment friendly, cheap and with unrivaled reactivity and selectiveness that cannot be achieved in traditional organic solvents is the
major driving force behind cleaner processes.2 In contrast to these advantages, the low solubility of several organic compounds in this
media reflects the biggest downside of use of water as a solvent.3 An introduction of the phase transfer catalysts or surfactants is one of
the way to circumvent this problem. Because of non-toxicity, bio-compatibility, bio-degradability, miscibility and reactivity with
aqueous as well as numerous non-aqueous solvents through the creation of micelles with hydrophobic interior and hydrophilic crown in
ambient environment, the utility of surfactant in water is a greener substitute for toxic organic solvents in organic synthesis.4
Due to the unique possible deeds on biological systems, nitrogen-containing scaffolds are imperative motifs in pharmaceutical
products among various heterocycles. Triazole is a well known heterocyclic scaffold that has been very enticing as a consequence of its
broad array of applications in pharmaceuticals, agrochemicals (Fungicide-Prothioconazole Fig. 1a, Insecticide-Triazophos Fig. 1b),5
dyes, photographic material, corrosion inhibition.6 Moreover, they are found to exhibit a variety of biological activities such as
antiviral,7 antiepileptic,8 antiallergic,9 anticancer,10 anti-HIV,11 antimicrobial activities against Gram-positive bacteria and β3-adrenergic
receptor agonist.12 Interestingly, 1,2,4-triazole core has been included in a extensive collection of therapeutically significant drugs
including anti-inflammatory, Sedatives, antianxiety, CNS depressant (Triazolam, Fig. 1c), anticancer agent (Letrozole, Fig. 1d),
antiviral drug (Ribavirin, Fig. 1e). Owing to these multifarious applications, we persuit for investigating a novel synthetic route for the
construction of functionalized triazoles.
N
Cl
N
Cl
OH
N
N
N
N
N
N
O
P
N
H
S
N
O
H5C
O
C2H5
2 S
Cl
c) Triazolam
Cl
a) Prothioconazole
b) Triazophos
NH2
O
N
N
N
N
N
N
HO
O
HO
e) Ribavirin
OH
NC
CN
d) Letrozole
Fig. 1: Therapeutic drugs containing triazole skeleton

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Tetrahedron Letters
The most preferred conventional path to synthesize 1,2,4- triazole-3-thiones is cyclodehydration of acylthiosemicarbazide in presence of
basic reagents.13-19 Our research group investigated two component routes for the synthesis of 1,2,4-triazolidine-3-thiones viz,
[C16MPy]AlCl3Br catalyzed reaction of aldehyde and thiosemicarbazide, synthesis of novel spiro-1,2,4-triazolidine-3-thione from isatin and
thiosemicarbazide in presence of glycine nitrate.20-21 Several research groups reported different catalysts for the synthesis of 1,2,4- triazole-3-
thiones.22-27 Recently, our research group has also investigated multicomponent route for synthesis of 1,2,4- triazole-3-thiones from sulfamic
acid catalyzed reaction of aldehyde, trimethyl silyl isothiocyanate with hydrazine hydrate.28 In continuation with our interest in designing the
new routes for synthesis of 1,2,4- triazole-3-thiones , in present work, we have investigated novel route for synthesis of diverse class of 1,2,4-
triazolidine-3-thiones by carrying [BZT]+ AlCl4- catalyzed multi component reaction of Aldehydes / Isatin / Cyclic ketone, hydrazine hydrate
and PhSNCS in water solvent at room temperature under the umbrella of green chemistry.
Initially, we focused our attention towards designing of catalyst. The most efficient tool in organic synthesis is Lewis acid catalysis.29
Water-labile character of most of the Lewis acids restricts the reactions under anhydrous conditions. Also, most of the organic reactants do not
usually dissolve in water. Hence, to tackle the solubility issue, the catalyst should contain surfactant counterpart that would help reactants to
solubilise in aqueous media. In this perspective, we designed the surfactant catalyst having water-stable Lewis acidic constituent for the acid-
catalyzed reactions in water.30 ‘Lewis acid-surfactant-combined catalyst’ (LASC), would perform both as a catalyst to activate the reactants as
well as a surfactant to increase the solubility in water by forming micellar aggregation.
2. Result and Discussion:
Primarily, our experimentation commenced with the design and synthesis of novel Lewis acid-surfactant-combined catalyst (LASC) which
would construct the micelles in water, enabling its use as a solvent system to solubilise organic reactants and Lewis acidic counter ion helps to
accelerate the rate of reaction with increasing the product yield. (Fig.2)
-
Fig. 2: Lewis acid surfactant combined catalyst [BZT]+ AlCl4
-
The synthesis of LASC, [BZT]+ AlCl4 was carried out by the reaction of AlCl3 and benzethonium chloride [BZT]+[Cl]- in methanol at 40oC
for 4h furnished LASC (Scheme-1) which was characterized by IR, 1H, 13C, 27Al NMR, ESI-MS and TGA analysis.
O
N+
O
O
AlCl3
N+
O
-
MeOH, 40oC
4 h
Cl-
AlCl4
-
Scheme 1: Synthesis of Novel Lewis acidic surfactant, [BZT]+ AlCl4
FTIR spectrum of [BZT]+ [AlCl4]- shows the band at 2952 cm-1 and 2893 cm-1 due to C-H symmetric and asymmetric stretching vibrations in
methylene and methyl group. The stretching bands at 1241cm-1 and 1118 cm-1 correspond to alkyl aryl ether and alkyl ether, respectively. The
absorption band displayed at 1060 cm-1 indicates presence of C-N stretching vibrations.
1
The structure of LASC was also in well accordance with H and 13C NMR. The peak at δ 74.28 ppm in 27Al NMR spectrum of LASC
(Fig.3) confirmed the existence of Al possessing tetrahedral geometry.31-32 Furthermore, in the mass spectrum of LASC, the peak observed at
-
m/z 169 assist the formation of AlCl4 as a counter ion.
Fig. 3: 27Al NMR spectrum of LASC catalyst, [BZT]+ [AlCl4]-
The thermal stability of catalyst was evaluated by thermo gravimetric analysis (TGA) and differential thermo gravimetric analysis (DTA) in
o
o
the temperature range of 25 to 600 C in an air atmosphere at 10 C/min (Fig. 4). Initially, the weight loss of 11.01% was observed in the
temperature range of 25-148.26 oC may be accredited to the loss of physically adsorbed water molecules in the catalyst. The second weight loss
of 14.53% in the range of 148.26-198.97 o C due to the loss and decomposition of AlCl4 anion. The further largest weight loss of 57.67 % is
-