New method of 4,5-disubstituted 1,2,4-triazolo-3-thiones synthesis

Article abstract of DOI:10.1080/104265090508217

A universal method of 4,5-disubstituted S-triazolo-3-thiones synthesis from methyl esters of arylothiocarbazoic acids and some primary amines is presented. Copyright Taylor & Francis Inc.

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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New Method of 4,5-
Disubstituted 1,2,4-triazolo-3-
thiones Synthesis
Henryk Foks a & Barbara Milczarska a
a Department of Organic Chemistry, Medical
University of Gdańsk , Poland
Published online: 01 Feb 2007.
To cite this article: Henryk Foks & Barbara Milczarska (2005) New Method of 4,5-
Disubstituted 1,2,4-triazolo-3-thiones Synthesis, Phosphorus, Sulfur, and Silicon and
the Related Elements, 180:1, 197-204, DOI: 10.1080/104265090508217
To link to this article: http://dx.doi.org/10.1080/104265090508217
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Phosphorus, Sulfur, and Silicon, 180:197–204, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090508217
New Method of 4,5-Disubstituted 1,2,4-triazolo-3-thiones
Synthesis
Barbara Milczarska
Henryk Foks
Department of Organic Chemistry, Medical University of Gdan´sk,
Poland
A universal method of 4,5-disubstituted S-triazolo-3-thiones synthesis from methyl
esters of arylothiocarbazoic acids and some primary amines is presented.
Keywords 1,2,4-Triazole-3-thiones; 4,5-disubstituted-1,2,4-triazolo-3-thiones; new
method synthesis
INTRODUCTION
The 4,5-disubstituted 1,2,4-triazolo-3-thione derivatives have been pro-
duced mainly by two methods: (a) the imidoesters treatment with
thiosemicarbazide and amines,1 (b) the reaction of hydrazides with
isothiocyanates, followed by cyclization of the compounds obtained in
alkaline environment.2,3
Since the 1,2,4-triazolo-3-thione derivatives have shown widespread
pharmacological activity4–6 the efficient method of preparation of these
compounds was worked out.
RESULTS AND DISCUSSION
The method presented herein, foretold by Foks et al.,7 was based on
the primary amines reaction with methyl esters of aryldithiocarbazoic
acids. The majority of 34 derivatives were obtained in very good yields
(Table I).
Received June 1, 2004; in final form June 15, 2004.
Address correspondence to H. Foks, Department of Organic Chemistry, Medical Uni-
versity of Gdan´sk, Al. Gen. J. Hallera 107, 80-416 Gdan´sk, Poland. E-mail: hfoks@amg.
gda.pl
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B. Milczarska and H. Foks
The method presented was the only way of obtaining the triazoloth-
iones when the isothiocyanates were hardly available.
The method failed, however, in the case of amines having their pri-
mary functional group bounded to a secondary carbon atom. These
amines used to give hydrazides and N,Nꢀ-disubstituted thioureas as
the reaction products, e.g. with cyclohexylamine the methyl esters of
dithiocarbazoic acids decomposed, giving the corresponding acid hy-
drazide and N,Nꢀ-dicyclohexylthiourea.
The methyl monoesters of aryldithiocarbazoic acids were obtained
from the corresponding (benzoic, 2-, 3-, and 4-chlorobenzoic, nicotinic
and isonicotinic) hydrazides by means of methylation with dimethyl
sulphate or methyl iodide (Scheme 1).
SCHEME 1
The methylation course was established experimentally with a view
to the highest possible yields, and a minimum dimethyl derivative con-
tent in the ester obtained.
Dimethyl sulphate was used as the methylating agent in the syn-
theses of phenyl-, 2-chloro-, 3-chloro-, and 4-chlorodithiocarbazoic acid
methyl esters, whereas methyl iodide—in the syntheses of 3-pyridilo-
and 4-pyridilodithiocarbazoic acid methyl esters.
For some of the 1,2,4-triazolo-3-thione derivatives, tuberculostatic
activity has been descriebed3,8–10 therefore the newly obtained com-
pounds will be tested for their activity against Mycobacterium tubercu-
losis. The results together with other group of triazoles will be given in
a separate paper.

Triazolo-Thiones
203
EXPERIMENTAL
Melting points were determined with a Boetius apparatus and are un-
corrected. The IR spectra were taken with a Satelite spectrophotometer.
The 1H-NMR spectra were taken with Tesla BS-487 spectrometer at 80
MHz in CDCl3, CD3OD, and DMSO-d6, or with Varian Gem 200 spec-
trometer at 200 MHz in CDCl3 and CD3OD.
The results of elemental analyses (%C, H) for all the compounds
obtained were in good agreement with the data calculated.
Reaction yields and the physical constants of the new compounds are
given in the Table I.
Preparation of Methyl 2-Acylodithiocarbazates (1–6)
Method A (1–4)
To a solution of KOH (0.06 mol) in water (40 cm3) and ethanol
(30 cm3), the corresponding hydrazide (0.03 mol) was added and then,
through a reflux condenser carbon disulfide (0.03 mol) was added with
stirring. After the oily drops of carbon disulfide disappeared, dimethyl
sulfate (0.015 mol) was added portionwise with stirring. After 3 h the
solution was acidified with acetic acid (pH = 3) and the precipitated
esters (1–4) were collected, washed with water and recrystallized.
Method B (5, 6)
To a suspension of the corresponding hydrazide (0.05 mol) in
methanol (25 cm3), triethyloamine (0.05 mol) was added. Then, carbon
disulfide (0.05 mol) was added dropwise through a reflux condenser.
After the reaction mixture cleared, methyl iodide (0.05 mol) was added
drop by drop with stirring.
After 2 h to the solution water (150 cm3) was added and the mixture
was allowed to stand overnight at room temperature. The precipitated
esters (5, 6) were filtered off and recrystallized.
Preparation of 4,5-Disubstituted S-Triazole-3-thione
Derivatives (1a–6c)
Compounds 1–6 (0.005 mol) and the corresponding amines
(0.015 mol) were refluxed for 1–1.5 h. On cooling down, 10 cm3 of water
was added and the solution was acidified with acetic acid (pH 4–6). The
mixture was ice-cooled, the precipitate collected and recrystallized.

204
B. Milczarska and H. Foks
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