Synthesis of 2-aminoaryl-5-substituted-1,3,4-thiadiazoles in a thermal 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1080/104265090930399

The preparation of a series of new 2-aminoaryl-1,3,4-thiadiazoles substituted with methylsulfanyl, methansulfinyl, or amine in the 5-position is described in this article. The compounds were obtained from N-hydroxyimidoyl chlorides and methyl dithiocarbazinate or 4-substituted thiosemicarbazides in a thermal 1,3-dipolar cycloaddition reaction. The new derivatives were tested for their activity against Mycobacterium tuberculosis. Copyright Taylor & Francis Inc.

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Phosphorus, Sulfur, and Silicon
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Synthesis of 2-Aminoaryl-5-
Substituted-1,3,4- Thiadiazoles
in a Thermal 1,3-Dipolar
Cycloaddition Reaction
a
a
b
Katarzyna Gobis , Henryk Foks , Zofia Zwolska
&
b
Ewa Augustynowicz-Kopeć
a
Department of Organic Chemistry, Medical
University of Gdansk, Gdansk, Poland
b
Department of Microbiology, Institute of
Tuberculosis and Pulmonary Diseases, Warsaw,
Poland
Published online: 19 Aug 2006.
To cite this article: Katarzyna Gobis , Henryk Foks , Zofia Zwolska & Ewa
Augustynowicz-Kope (2005) Synthesis of 2-Aminoaryl-5-Substituted-1,3,4- Thiadiazoles
in a Thermal 1,3-Dipolar Cycloaddition Reaction, Phosphorus, Sulfur, and Silicon and
the Related Elements, 180:12, 2653-2666, DOI: 10.1080/104265090930399
To link to this article: http://dx.doi.org/10.1080/104265090930399
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Phosphorus, Sulfur, and Silicon, 180:2653–2666, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090930399
Synthesis of 2-Aminoaryl-5-Substituted-1,3,4-
Thiadiazoles in a Thermal 1,3-Dipolar
Cycloaddition Reaction
Katarzyna Gobis
Henryk Foks
Department of Organic Chemistry, Medical University of Gdansk,
Gdansk, Poland
Zofia Zwolska
Ewa Augustynowicz-Kopec´
Department of Microbiology, Institute of Tuberculosis and Pulmonary
Diseases, Warsaw, Poland
The preparation of a series of new 2-aminoaryl-1,3,4-thiadiazoles substituted with
methylsulfanyl, methansulfinyl, or amine in the 5-position is described in this arti-
cle. The compounds were obtained from N-hydroxyimidoyl chlorides and methyl
dithiocarbazinate or 4-substituted thiosemicarbazides in a thermal 1,3-dipolar
cycloaddition reaction. The new derivatives were tested for their activity against
Mycobacterium tuberculosis.
Keywords 1,3-Dipolar cycloaddition; 1,3,4-thiadiazoles; 4-substituted thiosemicar-
bazides; antituberculosis activity; hydroxamoyl chlorides; methyl dithiocarbazinate
INTRODUCTION
Many 1,3,4-thiadiazole derivatives show various pharmacological ac-
1
2
tivities, including antibacterial, antifungal, and antituberculosis
3
activity. It is also well documented that some agents possessing a
pyrazine or pyridine ring, such as pyrazinamide and isoniazide, are
very effective antituberculosis drugs.
These facts prompted us to synthesize 1,3,4-thiadiazoles substi-
tuted with pyrazine or a pyridine moiety in the 2-position. The
2-amino-5-aryl-1,3,4-thiadiazoles already have been obtained from
Received November 30, 2004; in final form December 14, 2004.
Address correspondence to Katarzyna Gobis, Medical University of Gdansk, De-
partment of Organic Chemistry, Al. Gen. Hallera 107, 80-416 Gda n´ sk, Poland. E-mail:
katarzyna.gobis@wp.pl
2653

2
654
K. Gobis et al.
4
arylthiosemicarbazones or by direct cyclization of carboxylic acid and
5
thiosemicarbazide in phosphorus oxychloride. Reaction of the aro-
matic hydroxamoyl chlorides with methyl dithiocarbazinate also was
6
,7
described as a method of 2-aminoaryl-1,3,4-thiadiazole obtainment.
However, the cyclization reactions of hydroxamoyl chlorides with 4-
amino-substituted thiosemicarbazides have not been reported yet.
In this work, a series of 2-aminopyrazinyl-, 2-pyridin-2-, 3- or
4-yl- and 1-oxy-isonicotin-1,3,4-thiadiazole-5-sulfides, sulfoxides, and
amines were synthesized and evaluated for in vitro antituberculosis
activity.
RESULTS AND DISCUSSION
The required compounds were obtained according to the reaction
sequences outlined in Scheme 1. Hydroxamoyl chlorides were used
as starting material. N-hydroxypyrazinecarboximidoyl, N-hydroxy-
pyridinecarboximidoyl, and 1-oxy-isonicotincarboximidoyl chlorides
were prepared from the corresponding amidoximes on treatment with
◦
sodium nitrite in hydrochloric acid solution at 0 C. That method has
been published by Ko cˇ evar and colleagues as a simple procedure for
8
the synthesis of pyridinecarbohydroximoyl chlorides.
Hydroxamoyl chlorides were refluxed in ethanol with two equiv-
alent amounts of methyl dithiocarbazinate, giving 2-aminoaryl-5-
methylsulfanyl-1,3,4-thiadiazoles 1–5. Methyl dithiocarbazinate was
9
obtained by the method of Kleyman and colleagues from hydrazine,
potassium hydroxide, carbon disulfide, and methyl iodide in water-
isopropanol solution. The products of condensation reactions formed
with moderated yields. Similar syntheses were described by Dornow
6
and Fischer. The products that were obtained suggest that this kind
of reaction is a thermal 1,3-cycloaddition (Scheme 2(a)). That mech-
anism is typical for all hydroxamoyl chlorides. However, Sasaki and
7
Yoshioka reported that some of these compounds can give 2-aryl-5-
methylsulfanyl-1,3,4-thiadiazole as a second product, which is a result
of a simple substitution reaction followed by hydroxylamine elimination
(
Scheme 2(b)). We did not obtain the second kind of products.
Subsequent oxidation of sulfides 1–5 using an excess of 30% hydro-
gen peroxide and glacial acetic acid gave sulfoxides 6–10. The yields
of these reactions were rather good, and sulfoxides isolation was very
easy. Further oxidation resulted in sulfones, which were formed next to
other products, and finally their synthesis was given up.
4
-substituted thiosemicarbazides 11–17, the intermediates em-
ployed for the syntheses of corresponding 2-amino-5-aminoaryl-1,3,

2
-Aminoaryl-5-Substituted-1,3,4-Thiadiazoles
2655
SCHEME 1
4
-thiadiazoles 18–34, were prepared by the procedure of Agrawal
10
and colleagues. The various amines, such as pyrrolidine, piperi-
dine, hexamethyleneimine, morpholine, 1-phenylpiperazine, 1-
benzylpiperazine, and 1-(2-pyridyl)piperazine, that were used for the
nucleophilic substitution of methyl dithiocarbazinate were commer-
cially obtained. For more basic amines, water was a suitable solvent,
but for 1-phenylpiperazine and its derivatives, reactions were carried

2
656
K. Gobis et al.
SCHEME 2
out in ethanol. The yields of the reactions were not very high, although
amines were used in large excess to methyl dithiocarbazinate (3:1).
This fact prompted us to work out another method for these syntheses,
which will be a subject of a future article.
The reactions of N-hydroxyimidoyl chlorides with two equivalent
amounts of 4-(1-phenylpiperazino)thiosemicarbazide 15 gave the de-
sired 2-aminoaryl-5-phenylpiperazino-1,3,4-thiadiazoles 22, 29, and
3
2–34. The syntheses were performed in refluxing DMF and the reac-
tion yields presented similar tendency as obtained for the appropriate
sulfides 1–5. The structures of the products led us to conclude that these
reactions also follow the thermal 1,3-dipolar cycloaddition mechanism,
as maintained for the sulfides 1–5 obtainment.
Treatment of N-hydroxypyrazine and N-hydroxy-2-pyridinecar-
boximidoyl chlorides with 6 other 4-substituted thiosemicarbazides

2
-Aminoaryl-5-Substituted-1,3,4-Thiadiazoles
2657
1
1–14, 16, and 17 under similar reaction conditions resulted in the
formation of 2-amino-5-aminopyrazin-2-yl- or 5-aminopyridin-2-yl-1,3,
4-thiadiazoles 18–21, 23–28, 30, and 31.
The synthesized 1,3,4-thiadiazoles were examined for their tubercu-
lostatic activity towards the Mycobacterium tuberculosis H37Rv strain
and two “wild” strains isolated from tuberculotic patients: one (Spec.
210) was resistant to p-aminosalicic acid, isonicotinic acid hydrazide,
etambutol and rifampicine, another (Spec. 192) was fully sensitive to the
administrated drugs. The determined minimum concentrations inhibit-
ing the growth of tuberculous strains for all of the tested compounds
were within the limits 50–100 µg/mL, which indicates low antituber-
culosis activity.
EXPERIMENTAL
All materials and solvents were of an 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, S)
for all the compounds obtained were in good agreement with the data
that was calculated. Reaction yields and the physical constants of the
1
compounds are given in Tables I and II. H NMR spectra in DMSO-
d6 were recorded on Varian Unity Plus (500 MHz) and Varian Gemini
(
200 MHz) instruments. IR Spectra (KBr) were determined as KBr pel-
lets of the solids on a Satellite FT-IR spectrophotometer (Table III).
Mass spectra for compounds 1, 6, and 22 were taken on Finnigan MAT
95 by a chemical ionization method with isobutane. Melting points were
determined on a BOETIUS apparatus and were uncorrected.
2-Aminoaryl-5-Methylsulfanyl-1,3,4-Thiadiazoles (1–5)
A solution of 5 mmol of appropriate hydroxamoyl chloride and 11 mmol
of methyl dithiocarbazinate in 30 mL of ethanol was refluxed for 12 h.
After cooling, the precipitate was filtered, washed with cold ethanol,
and recrystallized. For compound 1, a mass spectrum was taken. MS:
+
(
m/z) = 226 (100 MH ), 227 (11), and 268 (4).
2
-Aminoaryl-5-Methansulfinyl-1,3,4-Thiadiazoles (6–10)
A quantity of 1 mmol of appropriate 5-methylsulfanylthiadiazole (1–
) was suspended in 3 mL of glacial acetic acid. Next, 3 mL of 30% of
5
H2O2was added dropwise. The reaction mixture was heated for 2.5–
◦
7
h at 50 C with stirring. The reaction progress was controlled by TLC
method. Then the mixture was neutralized with a saturated NaHCO3

2
658
K. Gobis et al.
TABLE I Physical Constants of
◦
Compound
Yield
[%]
M.p.[ C] solvent
Formula
MW
no.
Het
R
for crystallization
1
2
3
4
5
6
7
SCH3
47
38
34
20
54
91
88
250–251
Pyridine-ethanol
C7H7N5S2
225.29
SCH3
SCH3
236–237
Pyridine-ethanol
C8H8N4S2
224.29
215–216
Ethanol
C8H8N4S2
224.29
SCH3
213–214
Ethanol
C8H8N4S2
224.29
SCH3
236–237
DMF
C8H8N4OS2
240.29
SOCH3
SOCH3
249–250
Pyridine-ethanol
C7H7N5OS2
241.29
235–236
Pyridine-ethanol
C8H8N4OS2
240.29
8
9
SOCH3
SOCH3
63
35
210–211
Ethanol
C8H8N4OS2
240.29
218–219
Ethanol-water
C8H8N4OS2
240.29
1
1
1
2
0
8
9
0
SOCH3
61
28
44
37
150–151
DMF
C8H8N4O2S2
256.29
225–226
DMF
C10H12N6S
248.31
216–217
DMF
C11H14N6S
262.33
230–231
DMF-water
C12H16N6S
276.36

2
-Aminoaryl-5-Substituted-1,3,4-Thiadiazoles
2659
TABLE I Physical Constants of
(Continued)
◦
Compound
no.
Yield M.p.[ C] solvent
Formula
MW
Het
R
[%] for crystallization
2
2
2
2
2
2
1
40
47
23
36
30
26
230–231
Pyridine-ethanol
C10H12N6OS
264.31
2
3
4
5
6
302–303
Pyridine-ethanol
C16H17N7S
339.41
226–228
Pyridine-ethanol
C17H19N7S
353.43
223–224
Pyridine-ethanol
C15H16N8S
340.40
240–241
DMF/water
C11H13N5S
247.31
252–253
Ethanol
C12H15N5S
261.34
2
2
2
3
7
8
9
0
20
29
14
25
201–202
DMF
C13H17N5S
275.37
208–209
DMF-water
C11H13N5OS
263.31
230–231
Pyridine-ethanol
C17H18N6S
338.42
205–206
DMF
C18H20N6S
352.45
3
3
3
3
1
2
3
4
26
19
18
28
214–215
DMF-water
C16H17N7S
339.41
215–216
Ethyl acetate
C17H18N6S
338.42
235–236
DMF-water
C17H18N6S
338.42
285–286
DMF
C17H18N6OS
354.42

2
660
K. Gobis et al.
TABLE II Physical Constants of
◦
Compound
no.
Yield
[%]
M.p.[ C] solvent
Formula
MW
for crystallization
11
63
168–169
Ethanol
C5H11N3S
145.22
1
1
2
3
24
28
86–87
Ethanol-water
C6H13N3S
159.24
115–116
Ethanol-water
C7H15N3S
173.27
1
1
1
1
4
5
6
7
49
55
55
57
170–171
Ethanol
C5H11N3OS
161.22
178–179
Ethanol
C11H16N4S
236.33
167–168
Ethanol
C12H18N4S
250.35
179–180
Ethanol
C10H15N5S
237.32
solution. The precipitate was filtered, washed with cold water, and re-
crystallized. For compound 6, a mass spectrum was taken. MS: (m/z) =
+
2
26 (30), 242 (100 MH ), 243 (10), 466 (25), 482 (66), 483 (13), and 484
(
12).
4-Substituted Thiosemicarbazides (11–17)
Methyl dithiocarbazinate (2.44 g, 20 mmol), made according to Kleyman
9
and colleagues, was dissolved in 20 mL of water. The solution was
treated with appropriate amine (60 mmol). The mixture was heated
under reflux for about 6 h until the evolution of methyl mercaptan
almost completely ceased. Methyl mercaptan was detected by the yellow
color it imparted to moisten the Pb(OAc)2 paper, which was placed at
the mouth of the reflux condenser. In the case of 1-phenylpiperazine
and its derivatives, the reactions were carried out in ethanol. Then the
solution was cooled and neutralized with AcOH. Further cooling yielded
the desired thiosemicarbazides, which were filtered and recrystallized.

2661

2
662

2663

2
664

2
-Aminoaryl-5-Substituted-1,3,4-Thiadiazoles
2665
2-Amino-5-Aminopyrazinyl-1,3,4-Thiadiazoles (18–24)
N-hydroxy-pyrazinecarboximidoyl chloride (0.39 g, 5 mmol) was dis-
solved in 20 mL of DMF and treated with 10 mol of appropriate
thiosemicarbazide 11–17. The reaction mixture was refluxed for 10 h,
cooled and the precipitate was filtered and recrystallized. For compound
+
2
2, a mass spectrum was taken. MS: (m/z) = 340 (100 MH ), 341 (19),
and 342 (7).
2-Amino-5-(Aminopyridin-2-yl)-1,3,4-Thiadiazoles (25–31)
N-hydroxy-pyrazincarboxyimidoyl chloride (0.39 g, 5 mmol) was dis-
solved in 20 mL of DMF and treated with 10 mmol of appropriate
thiosemicarbazide 11–17. The reaction mixture was refluxed for 10 h
and was concentrated to about 5 mL and cooled. The precipitate was
filtered and recrystallized.
2
1
-(Aminopyridin-3-Yl)-5-(4-Phenylpiperazin-1-yl)-
,3,4-Thiadiazole (32)
The synthesis was carried out as described for 25–31. The concentrated
mixture was treated with a small amount of ethyl acetate. After cooling,
the precipitate was filtered and recrystallized.
2
-(Aminopyridin-4-yl)-5-(4-Phenylpiperazin-1-yl)-1,3,4-
Thiadiazole (33) and 2-(Amino-1-Oxy-Isonicotin)-5-
4-Phenylpiperazin-1-yl)-1,3,4-Thiadiazole (34)
(
The synthesis was carried out as described for 25–31 but the solvent
was evaporated to dryness and the residue was treated with 15 mL of
ethanol. After cooling, the precipitate was filtered and recrystallized.
Antituberculotic Activity
In vitro investigations were performed by a classical test-tube method
of successive dilution with Youman’s liquid medium containing 10% of
a bovine serum.11
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