Solvent-Free Green Synthesis of Azines and Their Conversion to 2,5-Disubstituted-1,3,4-thiadiazoles

Article abstract of DOI:10.1080/00397911.2015.1113297

A solvent-free, clean, and efficient method has been developed for the synthesis of 2,5-disubstituted-1,3,4-thiadiazoles via azines. This approach exploits the synthetic potential of clean reactions and offers many advantages such as excellent product yie

Full text of DOI:10.1080/00397911.2015.1113297

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
Solvent Free Green Synthesis of Azines and Their
Conversion to 2,5-Disubstituted-1,3,4-thiadiazoles
D Doddramappa Shridevi, Srikantamurthy Ningaiah, Narayan U Kuduva,
Raad K Yhya & Kuduva M Lokanatha Rai
To cite this article: D Doddramappa Shridevi, Srikantamurthy Ningaiah, Narayan U Kuduva,
Raad K Yhya & Kuduva M Lokanatha Rai (2015): Solvent Free Green Synthesis of Azines and
Their Conversion to 2,5-Disubstituted-1,3,4-thiadiazoles, Synthetic Communications, DOI:
10.1080/00397911.2015.1113297
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1113297
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Date: 11 November 2015, At: 04:06

Solvent Free Green Synthesis of Azines and Their Conversion to 2,5-Disubstituted-
1,3,4-thiadiazoles
D Doddramappa Shridevi1,, Srikantamurthy Ningaiah2, Narayan U Kuduva1, Raad K
Yhya1, Kuduva M Lokanatha Rai1
1Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore,
2Department of Chemistry, Vidyavardhaka College of Engineering, Mysore
Corresponding author, E-mail: shridevi20@gmail.com
Abstract
A solvent-free, clean and efficient method has been developed for the synthesis of
2,5 disubstituted 1,3,4 thiadiazoles via azines. This approach exploits the synthetic
potential of clean reaction and offers many advantages such as excellent product yields,
easy isolation of products and eco-friendly benign reaction conditions. The newly
synthesized compounds were analyzed by IR, 1H NMR, 13C NMR and elemental
analysis.
KEYWORDS: azine, 1,3,4 thiadiazole, solvent free, green synthesis, autoclave
1

1. INTRODUCTION
Due to the amplifying concern for the adverse influence of organic solvents on the
environment, solvent-free organic reactions have attracted the attention of organic
chemists.1 Green chemistry has been widely used in the current chemical research to
develop new protocol that is less hazardous to human health and to the environment has
received extensive attention.2,3 The tremendous increase in Environmental (E)-factor4 in
pharmaceutical industry than in other industry sector is mainly due to the use of solvents5
in many batch process.6 Therefore, it is essential to contrive solvent-free methodologies7
for the eco-friendly, greener8 synthesis of drugs.
1,3,4 Thiadiazoles are important heterocycles with “N C S” linkage which can work as
the active center, chelate certain metal ions in vivo, and show good tissue permeability.
The lower toxicity and in vivo stability of thiadiazole nucleus is attributed to its
aromaticity.9 Thiadiazoles have exhibited potential antiviral,10 anticancer,11 anti-
inflammatory,12 antibacterial,13 analgesic,14 antiglaucoma15 and fungicidal activities.16
Recently in our lab Rai et al., have developed the solvothermal method for the synthesis
of thioesters and thioamides,17 isoxazoles and pyrazoles,18 for the conversion of
oxadiazoles to thiadiazoles19 and aldehyde semicarbazones to bishydrazones.20
The different synthetic pathways employed to prepare azines21 and 1,3,4 thiadiazoles
have been reported. The most common procedure for the synthesis of 1,3,4 thiadiazoles
involves the cyclization of 1,2 diacylhydrazines or its thia analogues in presence of
2

SOCl2 or POCl3.22 Symmetrical 2,5 disubstituted 1,3,4 thiadiazoles were synthesized
by condensation of various aldehydes and hydrazine under the pressure of H2S using
microwave irradiation. The major drawback of the above said method was, it needs
additional purification step for the removal of H2S obtained as byproduct and extra care
must be taken for the controlled release of H2S.23 The 1,3,4 thiadiazoles were also
synthesized from the corresponding 1,4 dicarbonyl or acyl precursors using P2S5 and
Lawesson’s reagent,24 from pentafluorophenyl esters,25 acid hydrazides and
triethylorthoalkanoates26 and by the oxidation of in situ generated thiosemicarbazones.27
The antecedent techniques though afford multitude of choices to conspire substituted
1,3,4 thiadiazoles, suffer from longer reaction time, exhaustive work-up, low yield and
multistep procedures, which has restricted the exertion of these methods in high
throughput synthesis. Thus an improved, economical, swift and solvent free access to
substituted 1,3,4 thiadiazoles is of current interest to organic chemists.
2. RESULTS AND DISCUSSION
Owing to the competence and continuation of our interest in autoclave reactions, here we
communicate the novel method for the synthesis of azines starting from semicarbazones
(Scheme 1) and their conversion to 2,5 disubstituted 1,3,4 thiadiazole via sulfuration of
substituted azines under solvent free condition in high yield Scheme 3.
The formation of azines (iv) from semicarbazones (i) presumably occur via the
elimination of bisurea (v) from the two semicarbazone molecule20 Scheme 2. Finally the
3

azines were treated with elemental sulphur under solvothermal conditions to get
1,3,4 thiadiazoles in 85 95% yield as shown in Scheme 3.
The probable mechanism for the formation of 2,5 disubstituted 1,3,4 thiadiazole (3)
from azine (a) involves following steps. Initially the azine (a) attacks the sulfur in the S8
(α sulphur) form which results in the ring opening of α sulphur yields the intermediate
(b). Later the in situ generated intermediate (b) cyclizes to give intermediate (c). The
intermediate (c) undergoes dehydrogenation by sulphur to yield
2,5 disubstituted 1,3,4 thiadiazole (3). The reason for the dehydrogenation may be
attributed to the presence of high temperature and pressure in autoclave reactions and
acquisition of aromaticity in the final product Scheme 4.
The structural assignments to newly synthesized compounds 2(a h) and 3(a h) was
based on their elemental analysis and spectral (IR, 1H NMR, 13C NMR and Mass) data.
The IR spectra of the compound 2a showed the absence of amide carbonyl absorption
1
1
1
1
band at 1650 cm to 1750 cm and NH peak at 3400 cm to 3200 cm and showed
1
new peak due to C═N at 1645 cm . In the 1H NMR spectra the signals of the newly
synthesized compounds were verified on the basis of their chemical shifts, multiplicities,
and coupling constants. The formation of compound 2a was confirmed by the
disappearance of peak at δ 6.7 and 7.9 due to –NH and –NH2. In 13C NMR spectra,
appearance of a doublet at 161.0 ppm due to C═N substantiated the formation of
compound 2a.
4

1
The IR spectra of the compound 3a showed the appearance of a new peak at 670 cm
due to C S stretching. The IR spectra of all other synthesized compounds showed
1
1
characteristic signals at 1640 1595 cm for (C═N) and 1570 1460 cm for (C═C). In
1H NMR spectra, disappearance of peak at δ 8.9 due to –CH═N and in 13C NMR
appearance of peaks at δ 174.1 ppm due to C S linkage confirms the formation of
cyclized heterocycle 3a. The aryl moiety exhibited characteristic signals in the aromatic
region of the spectrum. The mass spectrum of all the compounds showed molecular ion
peak at M+1 corresponding to its molecular formula, which confirmed its chemical
structure.
3. EXPERIMENTAL SECTION
General Procedure For The Synthesis Of Bishydrazones (1E, 2E)-1,2-
Dibenzylidenehydrazine (2a)
(E)-2-benzylidenehydrazinecarboxamide (1a, 1g, 6.13 mmol) was taken in a autoclave
reaction container (Teflon Liner). The lid was placed and was lowered into the autoclave,
the plates were kept over it and the autoclave was closed and tightened. It was kept in the
oven at 160-180 C for 4-6hr. The products after cooling, were extracted into diethyl ether
(20 mL), washed thoroughly with water. TLC of the solution shows single spot, which
was different from the starting material. The organic layer was dried over anhydrous
Na2SO4, solvent was evaporated under reduced pressure and the product obtained as
yellow crystalline solid in 90% yield (1.15 g), mp 89-92°C (lit 88-89°C).27 IR cm-1
5

(Nujol): 1645 cm-1 (C=N); 1H NMR (400 MHz, CDCl3), δ ppm (J, Hz): 7.48-7.54 (m,
6H), 7.88-7.91 (d, 4H, J = 7.2), 8.72 (s, 2H); 13C NMR (100MHz CDCl3): δ (ppm) 129.1,
129.7, 132.4, 137.3, 161.0; MS (relative intensity): m/z for C14H12N2; 209.2 [M+H]+
(100) Anal. % Calc: C, 80.74; H, 5.81; N, 13.45. Found: C, 80.68; H, 5.85; N, 13.49.
The same procedure was followed in all the case.
General Procedure For The Synthesis Of 2,5-Disubstituted-1,3,4-Thiadiazole (3a)
(1E, 2E)-1,2-dibenzylidenehydrazine (2a, 1g, 4.80 mmol) and sulphur (0.08g, 2.40
mmol) was taken in an autoclave reaction container (Teflon Liner). The lid was placed
and was lowered into the autoclave, the plates were kept over it and the autoclave was
closed and tightened. It was kept in the oven at 160 -180 C for 4-6hr. The products
obtained after cooling, were extracted into diethyl ether (20mL), washed thoroughly with
water. TLC of the solution shows single spot, which was different from the starting
material. The organic layer was dried over anhydrous sodium sulphate; solvent was
evaporated under reduced pressure and the product obtained as yellow crystalline solid in
90% yield (1.03g), mp 144-146 °C (lit mp = 143-144°C). IR cm-1 (Nujol): 1648 cm-1
(C=N) and 670 cm-1 (C-S); 1H NMR (400 MHz, CDCl3), ppm (J, Hz): 7.50-7.56 (m,
6H), 7.89-7.95 (d, 4H, J = 8.8); 13C NMR (100 MHz CDCl3): (ppm) 128.7, 129.2,
130.9, 133.5, 174.1; MS (relative intensity): m/z for C14H10N2S; 238.9 [M+H]+ (100);
Anal. % Calc: C, 70.56; H, 4.23; N, 11.76; Found: C, 70.53; H, 4.25; N, 11.77.
The same procedure was followed in all the case.
6

4. CONCLUSIONS
In conclusion we have developed a novel protocol for the synthesis of azines and their
conversion to 2,5 disubstituted 1,3,4 thiadiazoles. The benefit of the described reaction
is the atom efficiency. It only requires theoretical amount (0.5 eq) of elemental sulfur,
and H2 gas is the only waste that is produced during the reaction. Also the present method
offers many advantages such as excellent product yields, easy isolation of products and
eco-friendly benign reaction conditions.
ACKNOWLEDGMENTS
One of the authors (D.S.D) is grateful to Rajiv Gandhi National Fellowship
(DV5/130(6)/RGNF/2011-2012 dated 08-08-2011) UGC, New Delhi, for providing the
necessary fund to carry out the research at University of Mysore.
SUPPLEMENTAL MATERIAL
Supplementary data (Experimental details, NMR, MS and elementary analysis) for this
article can be accessed on the publisher’s website.
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Scheme 1 Synthesis of azines
11

Scheme 2 The possible mechanism for the conversion of semicarbazone to azine.
12

Scheme 3 Synthesis of 2,5 disubstituted 1,3,4 thiadiazole.
13

Scheme 4 The possible mechanism for the conversion of azine to 2,5-disubstituted-1,3,4-
thiadiazole.
14