Studies on pyrazine derivatives, XLVI: The synthesis of new pyrazine derivatives with N′-(pyrazine-2-carbonyl)-hydrazinecarbodithioic acid methyl ester usage

Article abstract of DOI:10.1080/10426500500272327

4-Ω-alkylsubstituted derivatives of 1,2,4-triazole-2-thiones 2-7 were obtained using the high reactivity of N′-(pyrazine-2-carbonyl)- hydrazinecarbodithioic acid methyl ester 1 towards amines. In the reaction with cysteamine 1,3-thiazaethylene-1,2,4-triazole 8 formed. Aromatic amines and N-aminocycloalkylamines gave thiosemicarbazide derivatives 9-12 under the same conditions. The solution of sodium hydroxide caused the decomposition of compounds 11 and 12 and resulted in 4-piperidino- and 4-morpholino- thiosemicarbazides 13 and 14. Compounds 11 and 12 were cyclized to appropriate 4-substituted 1,2,4-triazole-2-thiones 16 and 17 under the influence of DBU or potassium carbonate solution. The heating of derivative 12 with sulfuric acid led to disubstituted 1,3,4-thiadiazole 18. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500500272327

Phosphorus, Sulfur, and Silicon, 181:977–986, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500272327
Studies on Pyrazine Derivatives, XLVI:
The Synthesis of New Pyrazine Derivatives with
N ꢀ-(Pyrazine-2-carbonyl)-hydrazinecarbodithioic
Acid Methyl Ester Usage
Katarzyna Gobis
Henryk Foks
Joanna Francuz
Department of Organic Chemistry, Medical University of Gdan´sk,
Gdan´sk, Poland
Zofia Zwolska
Ewa Augustynowicz-Kopec
´
Department of Microbiology, Institute of Tuberculosis and Pulmonary
Diseases, Warsaw, Poland
4-ꢀ-alkylsubstituted derivatives of 1,2,4-triazole-2-thiones 2–7 were obtained using
the high reactivity of Nꢀ-(pyrazine-2-carbonyl)-hydrazinecarbodithioic acid methyl
ester 1 towards amines. In the reaction with cysteamine 1,3-thiazaethylene-1,2,4-
triazole 8 formed. Aromatic amines and N-aminocycloalkylamines gave thiosemi-
carbazide derivatives 9–12 under the same conditions. The solution of sodium
hydroxide caused the decomposition of compounds 11 and 12 and resulted in 4-
piperidino- and 4-morpholino-thiosemicarbazides 13 and 14. Compounds 11 and
12 were cyclized to appropriate 4-substituted 1,2,4-triazole-2-thiones 16 and 17 un-
der the influence of DBU or potassium carbonate solution. The heating of derivative
12 with sulfuric acid led to disubstituted 1,3,4-thiadiazole 18.
Keywords 1,2,4-triazoles; 4-N-cycloakylamino-thiosemicarbazides; dithiocarboxylic
acid esters; pyrazine derivatives; tuberculostatic activity
INTRODUCTION
Our previous research has shown that Nꢀ-(pyrazine-2-carbonyl)-
hydrazinecarbodithioic acid methyl ester 1 is a perfect substrate
for the synthesis of heterocyclic systems like 1,3,4-oxadiazole and
Received April 12, 2005; accepted April 26, 2005.
Address correspondence to Katarzyna Gobis, Medical University of Gdan´sk, De-
partment of Organic Chemistry, Al. Gen. Hallera 107, Gdan´sk 80-416, Poland. E-mail:
katarzyna.gobis@wp.pl
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K. Gobis et al.
1,2,4-triazole with substituents of an arrangement that has a diffi-
cult access or is unattainable.1,2 The example of that synthesis is
the reaction of pyrazinoylcarbodithioic acid methyl ester with the
ethanolamine, which forms 4-(2-hydroxyethyl)-[1,2,4]triazole-2-thione
with the pyrazine moiety in the 5-position.2
The subject of this work was the study of the reactivity of 1
in reactions with primary aliphatic and aromatic amines and N-
aminocycloalkylamines.
RESULTS AND DISCUSSION
The starting Nꢀ-(pyrazine-2-carbonyl)-hydrazinecarbodithioic acid
methyl ester 1 was obtained in the reaction of pyrazine-2-caboxylic acid
hydrazide with carbon disulfide and dimethyl sulfate in a solution al-
kalized with potassium hydroxide.
Compound 1 and the amines 2-piperidinoethylamine, 4-(2-amino-
ethyl)morpholine, 4-(3-aminopropyl)morpholine, 3-ethoxypropylamine,
1-(3-aminopropyl)imidazole, and tryptamine reacted during heating in
pyridine to 4-substituted 1,2,4-triazole-2-thiones 2–7.
In the reaction with cysteamine, the cyclization occurred and the con-
densed system of triazole with thiazoline formed as 1,3-thiazaethylene-
[1,2,4]triazole 8. Its structure was confirmed by the additional synthesis
by the heating of 4-β-hydroxyethylene-5-pyrazin-2-yl-[1,2,4]-triazole-
2-thiol in hydrochloric acid solution, which is the method described
earlier.3
Under the same condition reaction with aromatic amines, p-methyl-
and p-chloroaniline did not lead to the cyclization to triazole, and the
products are thiosemicarbazide derivatives. The treatment of hydrazide
with isothiocyanates confirmed the structure of the obtained products
as we reported previously4 (Scheme 1).
An unexpected result was acquired in the reaction of compound
1 with 1-aminopiperidine and 4-aminomorpholine. The first step
of that reaction occured according to our expectation, and com-
pounds 11 and 12 were obtained as a result of the thiomethyl
group substitution. The probe of their cyclization in 10% sodium
hydroxide solution to 4-N-cycloalkyl-triazole-thiones of compound
16 type was unsuccessful because the molecule decomposed, and
finally 4-N-piperidinethiosemicarbazide 13 and 4-(4ꢀ-morpholine)-
thiosemicarbazide 14 were obtained. 1H NMR spectra and an additional
MS spectrum for derivative 14 corroborated that course of the reaction.
The product of the condensation of 14 with p-chlorobenzaldehyde gave
15. The structure of derivative 14 was also confirmed by its synthesis

Studies of Pyrazine Derivatives, XLVI
979
SCHEME 1
according to a simplified method of Podgornaya:5 Ammonium gas was
replaced with triethylamine.
Compound 11 in water-alkaline solution decomposed to product 13,
and only the cyclization in an anhydride medium in the presence of
DBU led to 4-piperidin-1-yl-5-pyrazin-2-yl-2,4-dihydro[1,2,4]triazole-
3-thione 16. The structure of that product was confirmed by IR,1H
NMR, and MS spectra.1H NMR spectrum determined for that com-
pound indicated an equilibrium state between thione–thiol tautomeric
forms existing in DMSO-d6 solution. The similar reaction performed for
derivative 12 resulted in compound 17.
Compounds 16 and 17 were also obtained by the cyclization of the
appropriate substrate 11 and 12 under the influence of 25% potassium
carbonate solution. Derivative 12 also underwent cyclization in con-
centrated sulfuric acid, but the reaction led to a completely different
product: morpholine-4-yl-(5-pyrazin-2-yl-[1,3,4]-thiadiazol-2-yl)-amine
18 (Scheme 2).
MICROBIOLOGY
The tuberculostatic properties of the newly synthesized derivatives
were examined towards the Mycobacterium tuberculosis H37Rv strain
and two “wild” strains isolated from tuberculotic patients: one (Spec.
210) resistant to p-aminosalicic acid (PAS), isonicotinic acid hydrazide

980
K. Gobis et al.
SCHEME 2
(INH), and etambutol (ETB) and rifampicine (RFP), another (Spec. 192)
fully sensitive to the administrated drugs. In vitro investigations were
performed by a classical test-tube method of successive dilution with
Youman’s liquid medium containing 10% of bovine serum.6 The deter-
mined Minimum Concentrations (MIC) inhibiting the growth of tuber-
culous strains for all the tested compounds were within the limits of
25–50 µg/mL, which indicates low antituberculosis activity.
EXPERIMENTAL
All materials and solvents were of analytical reagent grade. Thin-layer
chromatography was performed on Merck Kieselgel 60F254 plates and
visualized with UV. The results of elemental analyses (% C, H, N) for all
the compounds obtained were in good agreement with the data calcu-
lated. 1H NMR spectra in CDCl3 or DMSO-d6 were recorded on Varian
Gemini (200 MHz) and Varian Unity Plus (500 MHz) instruments. IR
Spectra (KBr) were determined as KBr pellets of the solids on a Satellite
FT-IR spectrophotometer. Mass spectra for compounds 14 and 16 were
taken on Finngan MAT 95 (70 eV). Melting points were determined on
a BOETIUS apparatus and were uncorrected. Reaction yields, physical
constants, and spectral data of the compounds are given in Table I.

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K. Gobis et al.
4-Substituted 5-pyrazin-2-yl-2,4-dihydro-[1,2,4]triazole-3-
thiones (2–7)
General Method
N ꢀ -(Pyrazine-2-carbonyl)-hydrazinecarbodithioic acid methyl ester
1 (5 mmol) and appropriate amine (6 mmol) were heated under reflux
in 2 mL of pyridine for 1.5 h. Then the solvent was evaporated, 5 mL
of water were added, and the mixture was acidified with glacial acetic
acid. The precipitate was filtered after cooling and recrystallized.
3-Pyrazin-2-yl-5,6-dihydro-thiazolo[2,3-c][1,2,4]triazole (8)
A quantity of 5 mmol of compound 1 was refluxed with 6 mmol of cys-
teamine in 2 mL of pyridine for 1.5 h. Pyridine was evaporated, and
5 mL of water was added. The solid in an amount of 1 mmol was fil-
tered and recrystallized.
Pyrazinoylthiosemicarbazide Derivatives (9, 10)
General Methods
A. Compound 1 (5 mmol) was heated under reflux with an appropri-
ate amine (6 mmol) in 2 mL of pyridine for 1.5 h. Pyridine was evapo-
rated in vacuum. The oily residue was dissolved in 3 mL of methanol,
and the product was precipitated from the solution by water addition.
Then water was decanted, and the crude product was treated with chlo-
roform and filtered.
B. Pyrazine-2-carboxylic acid hydrazide (1 mmol) was dissolved
in 5 mL of ethanol and treated with an appropriate isothiocyanate
(1 mmol). The mixture was refluxed for 15 min, and the product was
filtered after cooling (m.p. was in agreement with literature data5).
Pyrazinoylthiosemicarbazide Derivatives (11, 12)
A quantity of 5 mmol of 1 was heated under reflux with 6 mmol of
1-aminopyridine or 1-aminomorpholine in 2 mL of pyridine. After the
removal of pyridine, 10 mL of water was added, and the mixture was
acidified with acetic acid. The precipitate was filtered after cooling and
recrystallized.
4-N-Cycloalkylaminothiosemicarbazides (13, 14)
A. Derivative 11 or 12 (1 g) was refluxed for 2 h in 10 mL of 10%
solution of sodium hydroxide. After cooling, if the solution was not clear,

Studies of Pyrazine Derivatives, XLVI
985
then it was filtered and acidified with acetic acid. The solid was filtered
and recrystallized.
B (for compound 14). 4-Aminomorpholine (2.55 mL, 25 mmol) was
added to 10 mL of ethanol then treated with triethylamine (4 mL, 30
mmol) and carbon disulfide (1.6 mL, 25 mmol). The reaction mixture
was stirred for 15 min, and about 5 mL of water was added to dis-
solve the precipitate. Then methyl iodide (1.55 mL, 25 mmol) was added
dropwise, and the product precipitated immediately. The mixture was
stirred for about 15 min, and the solid of S-methyl derivative (4 g, 83%)
was filtered after cooling. That compound was next dissolved in 50 mL
of ethanol, and 3 mL of 100% hydrazine hydrate was added. The re-
action mixture was refluxed for 1.5 h and cooled, and the precipitate
was filtered and recrystallized (m.p. was in agreement with literature
data4).
1-(4-Chlorobenzylidene)-4-N-morpholinothiosemicarbazone
(15)
Equimolecular amounts of compound 14 and p-chlorobenzaldehyde
were refluxed in 10 mL of ethanol for 30 min. Then the mixture was
cooled in an ice bath, and the product was filtered and recrystallized.
4-Piperidin-1-yl-5-pyrazin-2-yl-2,4-dihydro-[1,2,4]triazole-3-
thione (16)
A. Compound 11 (0.7 g, 2.5 mmol) and DBU (1 mL) were heated un-
der reflux in 5 mL of n-butanol for 2 h. Then the mixture was condensed,
ice was added, and the solution was acidified with acetic acid.
B. Compound 11 (1.5 g, 5 mmol) was dissolved in 20 mL of 25%
potassium carbonate water solution. The mixture was refluxed for 4 h
and then cooled. The precipitate was dissolved by an addition of a small
amount of water. The clear solution was acidified with acetic acid, and
the product was filtered and recrystallized. Yield 72% (0.53 g).
4-Morpholin-4-yl-5-pyrazin-2-yl-2,4-dihydro-[1,2,4]triazole-3-
thione (17)
A. Compound 12 (0.2 g, 0.7 mmol) was refluxed with 1 mL of DBU
in 2 mL of pyridine for 4 h. Then 15 g of ice was added, and the mixture
was acidified with hydrochloric acid. The precipitate was filtered and
recrystallized.

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K. Gobis et al.
B. The synthesis was performed according to Method B described for
compound 16 from (0.55 g, 2 mmol) of 12.Yield 75% (0.39 g).
2-Aminomorpholin-4-yl-5-pyrazin-2-yl-[1,3,4]thiadiazole (18)
A quantity of 0.22 g (0.78 mmol) of compound 12 was heated in 2 mL
of concentrated sulfuric acid at 90◦C for 30 min. Then the mixture was
poured onto ice and alkalized with ammonium hydroxide. The precipi-
tate was filtered and recrystallized.
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[3] H. Foks, M. Janowiec, Z. Zwolska, and E. Augustynowicz-Kopec´, Phosphorus, Sulfur,
and Silicon, 179, 2519 (2004).
[4] W. Rudnicka, H. Foks, M. Janowiec, and Z. Zwolska-Kwiek, Acta Polon. Pharm., 43,
523 (1986).
[5] I. V. Podgovnaya and I. Ya. Postovskii, Zh. Obskch. Khim., 34, 33 (1964); J. Gen.
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