Reactivity of N1-dithioester substituted pyridinand pyrazincarboxamidrazones

Article abstract of DOI:10.1080/10426500500270065

The N¹-dithioester substituted pyridin- and pyrazincarboxamidrazones underwent cyclocondensation to 5-methylsulfanyl-1,3,4- thiadiazole or 1,2,4-triazole derivatives, depending on the reaction conditions. With an excess of secondary amines, pyrazincarboxamidrazone dithioester gave 5-amino-1,3,4-thiadiazoles and with an ethanoloamine a 1,2,4-triazole derivative. Prepared compounds were evaluated as potential tuberculostatic agents, but the minimum inhibitory concentrations values indicated no significant activity. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500500270065

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Reactivity of N 1-Dithioester
Substituted Pyridinand
Pyrazincarboxamidrazones
Czeslawa Orlewska a , Danuta Pancechowska-
Ksepko a , Henryk Foks a , Zofia Zwolska b & Ewa
Augustynowicz-Kopec b
a Department of Organic Chemistry , Medical
University of Gdansk , Poland
b Department of Microbiology , Institute of
Tuberculosis, Institute of Pulmonary Diseases ,
Warsaw, Poland
Published online: 15 Aug 2006.
To cite this article: Czeslawa Orlewska , Danuta Pancechowska-Ksepko , Henryk
Foks , Zofia Zwolska & Ewa Augustynowicz-Kopec (2006) Reactivity of N 1-Dithioester
Substituted Pyridinand Pyrazincarboxamidrazones, Phosphorus, Sulfur, and Silicon and
the Related Elements, 181:4, 737-744, DOI: 10.1080/10426500500270065
To link to this article: http://dx.doi.org/10.1080/10426500500270065
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Phosphorus, Sulfur, and Silicon, 181:737–744, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500270065
1
Reactivity of N -Dithioester Substituted Pyridin-
and Pyrazincarboxamidrazones
Czeslawa Orlewska
Danuta Pancechowska-Ksepko
Henryk Foks
Department of Organic Chemistry, Medical University
of Gdansk, Poland
Zofia Zwolska
Ewa Augustynowicz-Kopec
Department of Microbiology, Institute of Tuberculosis, Institute
of Pulmonary Diseases, Warsaw, Poland
1
The N -dithioester substituted pyridin- and pyrazincarboxamidrazones underwent
cyclocondensation to 5-methylsulfanyl-1,3,4-thiadiazole or 1,2,4-triazole deriva-
tives, depending on the reaction conditions. With an excess of secondary amines,
pyrazincarboxamidrazone dithioester gave 5-amino-1,3,4-thiadiazoles and with an
ethanoloamine a 1,2,4-triazole derivative. Prepared compounds were evaluated as
potential tuberculostatic agents, but the minimum inhibitory concentrations values
indicated no significant activity.
Keywords 1,2,4-triazoles; 1,3,4-thiadiazoles; amidrazones; hydrazinecarbodithioic acid
esters; tuberculostatics
INTRODUCTION
Many compounds having an amidrazone moiety have been de-
scribed for their in vitro tuberculostatic activity, particularly 4-
pyridin- and pyrazincarboxamidrazones1 as well as their N1-arylidene
derivatives,2,3 showed promising results. Recently, the antimycobac-
terial activity of N1-hetarylmethylene-substituted pyridin- and pyraz-
incarboxamidrazones was investigated.4,5 We found that a thioamide
Received May 24, 2005; accepted May 24, 2005.
We are grateful to Dr. P. Sowinski, Technical University of Gdansk, for recording and
discussing 2D-NMR spectra.
Address correspondence to Czeslawa Orlewska, Medical University of Gdansk,
Department of Organic Chemistry, J. Hallera 107, Gdansk 80-416, Poland. E-mail:
corl@amg.gda.pl
737

738
C. Orlewska et al.
or dithioester group directly linked to the N1 nitrogen atom also
yielded compounds with considerable activity.6,7 On the other hand,
certain related 1,3,4-thiadiazole, 1,3,4-oxadiazole, and 1,2,4-triazole
derivatives have already been tested and have shown activity as
antimycobacterial,8,9 antifungal,10 and anticonlvusant11 agents. These
findings encouraged us to investigate more systematically products of
cyclondensations of the amidrazone derivatives.
RESULTS AND DISCUSSION
Chemistry
The reactivity of dithioesters 16 resembled that reported of N1-thioacy-
lamidrazones,12 N1-thioamidrazones,13 and acylthiosemicarbazides.14
They rapidly eliminated ammonia when treated with diluted hydrochlo-
ric acid to form 5-methysulphanyl-1,3,4-thiadiazoles (2a–d) (Scheme 1).
The cyclocondensation of compounds 1 under basic conditions proceeded
much more slowly, requiring that the reaction be carried out in reflux-
ing alcoholic potassium hydroxide, and it led to 1,2,4-triazoles 3a–d. By
heating dithioesters 1 in excess of cyclic amines, the 1,3,4-thiadiazoles
4a–d bearing an amine group on C-5 were produced. In order to get some
information on the influence of the amine type on the reactivity of com-
pounds 1, we carried out a similar reaction of 1e with ethanoloamine;
SCHEME 1

N1-Dithioester Substituted Pyridin- and Pyrazincarboxamidrazones
739
in this case, the formation of triazole derivative 5 was observed. The
latter product was clearly different from the isomeric thiadiazole 4e
obtained by acid promoted cyclocondensation reaction of thiosemicar-
bazide 66 reaction, which generally gave amino-thiadiazoles.15 The
methylation of 5 under basic conditions yielded an S-alkylated product
7.16 The physical data of the obtained compounds are given in Table I.
For compound 5, the 1H NMR spectrum showed differences with that
obtained for 4e, confirming the unambigous assignment of the struc-
1
ture. The pattern of long-range proton-carbon correlations in H-13C
HMBC spectrum of 5 showed a correlation between C-3 of the triazole
ring and H-1 of the 2-ethanole fragment. In the case of 5, the thione
1
form was demonstrated by H NMR (in DMSO-d6) with δNH14.24 as
a broad singlet, whereas for 4e, the exocyclic NH signal (triplet) was
present at δ 8.30.
In all cases, the cyclocondensation reactions of 1a–d were regioselec-
tive and led to a thiadiazole or triazole system isolated after a simple
work-up.
Microbiology
The tuberculostatic activity of the new compounds was tested in vitro.
The following three bacterial strains were used: Mycobacterium tuber-
culosis H37RV, the strain isolated from patients and resistant against
isonicotinhydrazide, ethambutol and rifampicine, as well as the bac-
terial strain isolated from patients and susceptible to isonicotinhy-
drazide, ethambutol and rifampicine. The determination was performed
in Youmans fluid medium containing 10% of bovine serum.17 The mini-
mal inhibitory concentration for the compounds studied was in a range
of 50–500 µg/mL, thus indicating that cyclization led to compounds with
much lowered tuberculostatic activity in comparison with the open-
chain substrates studied previously.6,7
EXPERIMENTAL
Melting points were determined on a Reichert hot microscope and are
uncorrected. IR spectra were measured with a Specord IR-75 spec-
trophotometer using potassium bromide and are given as cm−1 1H
.
NMR spectra were recorded on, either a Tesla Brno BS-478c (80 MHz),
Tesla Brno BS-567A (100 MHz), or Varian Gemini 200 (200 MHz) at r.t.
The 1H−13C HMBC NMR spectra were recorded with a Varian Unity 500
Plus (500 MHz). The chemical shifts (δ) are reported in parts per mil-
ion (ppm) relative to tetramethylsilane as internal standard. Coupling
constants (J ) values are given in Hz. EI mass spectra were obtained on

740

741

742
C. Orlewska et al.
a LKB 2090 GCM instrument at 70 eV. Reaction courses and product
purity were routinely monitored by TLC on silica gel precoated 60 F254
Merck plates. Elemental analyses (C, H, and N) were within 0,4% of
the theoretical value.
General Procedure for the Synthesis of 2-Substituted
5-Methylsulfanyl-1,3,4-thiadiazole (2a–d)
A mixture of S-ester 1 (2 mmol) in 10 mL of diluted (1:1) hydrochloric
acid was refluxed for 5 min. and cooled, and the acid was neutralized
with a solution of potassium carbonate. The precipitate was filtered and
washed with water, and the crude product recrystallized to give 2.
Compound 2b; MS m/z (%): 211 (8, M+ + 2), 210 (11, M+ + 1), 209
(100, M+) 122 (47), 105 (34), 104 (19).
General Procedure for the Synthesis of 3-Substituted
1,2,4-Triazolo-5-thiones (3a–d)
A mixture of S-ester 1 (2 mmol) and 0.25 g (4 mmol) potassium hydrox-
ide in 10 mL of methanol was refluxed for 4 h. After cooling, the mixture
was acidified with acetic acid, and the precipitate was filtered, washed
with water, and recrystallized to give 3a–d.
Compound 3b; MS m/z (%): 180 (4, M+ + 2), 179 (9, M+ + 1), 178
(100, M+), 119 (26), 105 (33).
General Procedure for the Synthesis of 2-Substituted
5-Amino-1,3,4-thiadiazoles (4a–d)
A mixture of S-ester 1 (5 mmol) and appropriate amine (pyrrolidine,
morpholine, and N-fenylopiperazine) was refluxed for 3–6 h. After cool-
ing, methanol was added to the mixture, and the precipitate was filtered
and recystallized to give 4.
5-(2-Ethanoloamino)-2-pyrazin-2-yl-[1,3,4]-thiadiazole (4e)
A mixture of thiosemicarbazone 6 (0.48 g, 2 mmol) and 10 mL of diluted
(1:1) hydrochloric acid was refluxed for half an hour, cooled and neu-
tralized with potassium carbonate solution. The precipitate was filtered
and recrystallized from water to give 0.13 g (29%) of compound 4e; m.p.
1
192–194◦C. H NMR (DMSO-d6, 500 MHz) δ (ppm): 3.44 (q, 2H, CH2,
J = 5.4 Hz); 3.61 (q, 2H, CH2, J = 5.4 Hz); 4.87 (t, 1H, OH, J = 5.4 Hz);
8.30 (br.t, 1H, NH, 5.4 Hz); 8.67 (m, 2H pyrazine); 9.27 (d, 1H pyrazine,
J = 1.5 Hz).

N1-Dithioester Substituted Pyridin- and Pyrazincarboxamidrazones
743
4-(2-Ethanolo)-3-pyrazin-2-yl-2,4-dihydro-[1,2,4]-triazole-5-
thione (5)
A mixture of S-ester 1e (3 mmol) and 2-ethanoloamine (2 mL) was
refluxed for 2 h. After cooling, the mixture was acidified with 2 mL of
acetic acid, and the precipitate was filtered, washed with a small volume
of cooled water, and recrystallized from methanol to give 0.60 g (87%)
of thione 5.
4-(2-Ethanolo)-5-methylsulfanyl-3-pyrazine-2-yl-[1,2,4]-
triazole (7)
To a solution of potassium hydroxide (0.12 g, 2 mmol) in 10 mL of
methanol thione 5 (0.45 g, 2 mmol) and methyl iodide (0.13 mL, 2 mmol)
were added. This solution was stirred at r.t. for 1 h. After cooling, the
precipitate was filtered and washed with water to afford compound 7
(0.40 g, 84%); m.p. 178–179◦C (MeOH), lit. 159–160◦C (MeOH/H2O).16
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