Synthesis and tuberculostatic activity of novel 1,2,4-triazoles obtained from heterocyclic carbohydrazides

Article abstract of DOI:10.3987/COM-09-11888

The novel 1,2,4-triazole derivatives have been synthesized by a few different pathways. Heterocyclic carbohydrazides were used to obtain monoesters of hydrazine acids (16), thiosemicarbazide derivatives (717), and finaly 1,2,4-triazole-5-thiones (1838). Carbohydrazides were also cyclized with methyl carbamodithioates in the presence of DBU giving 1,2,4-triazole-5-thiones (18, 19, 3947). Two of final products (39, 40) were undergone alkylation in alkaline solution to appropriate sulfides (4853). Then methylsulfides (48, 49) were oxidized with peroxyacetic acid to sulfoxides (54, 55). The obtained compounds were tested in vitro towards Mycobacterium tuberculosis.

Full text of DOI:10.3987/COM-09-11888

HETEROCYCLES, Vol. 81, No. 4, 2010
917
HETEROCYCLES, Vol. 81, No. 4, 2010, pp. 917 - 934. © The Japan Institute of Heterocyclic Chemistry
Received, 16th December, 2009, Accepted, 18th February, 2010, Published online, 19th February, 2010
DOI: 10.3987/COM-09-11888
SYNTHESIS AND TUBERCULOSTATIC ACTIVITY OF NOVEL
1,2,4-TRIAZOLES
OBTAINED
FROM
HETEROCYCLIC
CARBOHYDRAZIDES
Katarzyna Gobis,1* Henryk Foks,1 Zofia Zwolska2, and Ewa
Augustynowicz-Kopeć2
Department of Organic Chemistry, Medical University of Gdansk, 107 Gen.
Hallera Str., 80-416 Gdansk, Poland. E-mail: kgobis@gumed.edu.pl
Department of Microbiology, Institute of Tuberculosis and Pulmonary Diseases,
26 Płocka Str., 01-138 Warsaw, Poland
Abstract – The novel 1,2,4-triazole derivatives have been synthesized by a few
different pathways. Heterocyclic carbohydrazides were used to obtain monoesters
of hydrazine acids (1-6), thiosemicarbazide derivatives (7-17), and finaly
1,2,4-triazole-5-thiones (18-38). Carbohydrazides were also cyclized with methyl
carbamodithioates in the presence of DBU giving 1,2,4-triazole-5-thiones (18, 19,
39-47). Two of final products (39, 40) were undergone alkylation in alkaline
solution to appropriate sulfides (48-53). Then methylsulfides (48, 49) were
oxidized with peroxyacetic acid to sulfoxides (54, 55). The obtained compounds
were tested in vitro towards Mycobacterium tuberculosis.
INTRODUCTION
Tuberculosis (TB) caused by Mycobacterium tuberculosis is one of the major global health issues.1 The
increasing emergence of drug-resistant TB, especially multidrug-resistant TB (MDR-TB and XDR-TB)
are particularly alarming. MDR-TB and XDR-TB are highly lethal in people living with HIV, with case
of fatality rates of over 90%. At the same time, there are not many drugs effective in TB chemotherapy.
Among others isoniazide (INH), pyrazinamide (PZA), and morinamide (MZA) are the most popular
frontline agents recommended in TB treatment.2 Unfortunately, the most active therapeutics rapidly
induce MDR and caused serious side effects such as hepatotoxicity, neurotoxicity, acute pancreatitis and
hypersensitivity reactions.3,4 Therefore, there is an urgent need for novel MDR-TB active and less toxic
TB chemotherapeutic drugs. Our previous research works5,6 as well as chemical literature7,8 have

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HETEROCYCLES, Vol. 81, No. 4, 2010
indicated that 1,2,4-triazole derivatives exhibit wide range of biological activity, inclusive tuberculostatic
action. These observations prompted us to synthesize some new 1,2,4-triazole-5-thiones substituted in
C-3 position with heterocyclic rings of 2-, 3-, 4-pyridine, 3-, 4-pyridine-N-oxide, 3-pyrazine-N-oxide,
2-pyrimidine, and 2-quinoline. Additionally, performed syntheses led to gain derivatives bearing among
others cycloalkylamine substituents in N-4 position. Only two reports on that class of compounds have
appeared up till now.9,10
RESULTS AND DISCUSSION
In this work, we investigate and compare few pathways of 1,2,4-triazole-5-thiones synthesis. The starting
heterocyclic carbohydrazides and carbomethylhydrazides were obtained from methyl esters of carboxylic
acids in a result of typical reactions described in the literature.11,12 Carbohydrazides under treatment of
CS2 and dimethyl sulfate in ethanol – aqueous solution and of lye excess gave hydrazinecarbodithioic
acid methyl esters (1-3) (Scheme 1).
O
No
3
4
5
1
2
6
R1
N
S
N
N
N
Het
NH
Het
N
N
N
N
O
N
O
H
KOH or Et3N
CS2
N
SMe
1-6
R1
H
H
Me
Me
Me
MeI or Me2SO4
R2NH2
O
1, 2
for
Het
NH NHR1
R1
O
R1
N N
S
R2NCS
NaOH or K2CO3
Het
NH N
Het
S
N
NH R2
R2
7-17
18-28
9, 20
7, 18
8, 19
10, 21
11, 22
12, 23
No
N
N
N
Het
N
N
O
H
N
N
H
N
R1
R2
H
H
N
H
N
H
CH2CH CH2
CH2CH CH2
Me
No
13, 24
14, 25
15, 26
16, 27
17, 28
N
Het
N
N
N
N
N
H
R1
R2
Me
Me
Me
Me
Me
p-Cl-Ph
CH2CH CH2 p-Cl-Ph
CH2CH CH2
Scheme 1

HETEROCYCLES, Vol. 81, No. 4, 2010
919
Those reactions occurred with good yields at room temperature. Because of acidic properties of
unsubstituted sulfur atom products were isolated from alkaline solution by acidification with acetic acid.
Usage of dimethyl sulfate protected that sulfur atom from methylation which occurred faster under
influence of methyl iodide. That efficient reactant was used in the case of methylhydrazinecarbodithioates
(4-6). Those reactions were performed in ethanol solution of triethylamine. In a reaction of methyl
carbodithioates (1, 2) with N-aminopiperidine in dry pyridine methyl mercaptane was eliminated and
hydrazinecarbothioamides (7, 8) of thiosemicarbazide structure were formed. That class of compounds
was also obtained in direct reaction of started hydrazides with appropriate isothiocyanates: methyl, allyl,
cyclohexyl, and 4-chlorophenyl. Those reactions occurred in 15 minutes with better yields than
hydrazinecarbothioamides (7, 8) synthesis. Condensations to thiosemicarbazides (9-17) were carried in
neutral solvent like dioxane or DMF. The heating of thiosemicarbazide derivatives (7-17) in weak basic
solution of 10% K2CO3 or 10% NaOH resulted cyclization and 1,2,4-triazole-5-thiones (18-28) were
obtained. Because of weak acidic properties of the products isolation of derivatives (20-24) required
acidification of reaction mixture with concentrated hydrochloric acid. Those syntheses enable to gain new
class of 1,2,4-triazole-5-thiones bearing cycloalkylamine substituent in N-4 position.
1,2,4-Triazole-5-thione structures (29-33) substituted with amine or methylamine group in N-4 position
were synthesized by refluxing methyl carbodithioates (3-5) with hydrazine hydrate or methylhydrazine
(Scheme 2).
4
5
No
3
No
31
32
33
29
30
34
N
N
N
N
N
N
Het
Het
N
N
O
N
N
N
N
O
H
N
O
N
O
N
O
R1
Me
R1
R2
Me
Me
H
H
Me
Me
H
Me
H
Me
H
H
Me
O
R1
S
Het
NH
N
SMe
R2NHNH2
3-5
R1
R1
R'CHO
or R'NCS
N
N
N N
Het
S
Het
S
N
N
R2
NHR2
29-34
O
Et3N, CS2
NH2NH2
Het
NH NHR1
35-38
35
37
38
No
36
N
N
N
Het
N
N
O
N
R1
R2
Me
N CH
Me
H
S
Me
N CH
NH
C
S
NHCH2CH CH2
p-Cl-Ph
NO2
NO2
S
Scheme 2

920
HETEROCYCLES, Vol. 81, No. 4, 2010
Reactions required triple excess of appropriate hydrazine and were performed in various solvents:
dioxane, ethanol, and water. The kind of the solvent had no distinct influence for reactions yield which
was moderate and depended rather on the substrate structure. The best yield was gained for derivative
(31) with pyrazine 1-oxide ring in C-3 position. Pyrimidine derivative (34) formed while refluxing of
carbohydrazide with CS2 and hydrazine hydrate in ethanol-aqueous solution of triethylamine. The yield of
that direct reaction seemed to be a little better than acquired for compounds (29-33). Obtained
1,2,4-triazole-5-thione (29) was condensed with 5-nitro-2-thiophenecarboxaldehyde giving product (36).
Analogical reaction for 1,2,4-triazole-5-thione (34) led to derivative (35). For 1,2,4-triazole-5-thione (32)
condensation with 4-chlorobenzaldehyde result hydrazone derivative (37). All condensation reactions
were ran fast with good yields in alcohol solution while few drops of acetic acid were added as a catalyst.
1,2,4-Triazole-5-thione (29) was also condensed with allyl isothiocyanate and hydrazinecarbothioamide
(38) was obtained.
An alternative method of 1,2,4-triazole-5-thiones (18, 19 and also 39-44, 46) synthesis was cyclization of
starting carbohydrazides with N-amino substituted carbamodithioic acid methyl esters in the presence of
equimolar amount of DBU in dry pyridine (Scheme 3).
R1
R2NH C SMe DBU
/
O
N N
or K2CO3
R3X, NaOH
N N
S
NHR1
SR3
Het
NH
Het
S
Het
R2NCS / K2CO3
N
N
R2
R2
18, 19, 39-47
48-53
AcOH
30% H2O2
No
39
40
42
43
44
45
41
46
47
N
N
N
N N
Het
N
N
N
O
N
O
N
O
H
N
H
N
H
N
Het
SR3
N
N
H
O
H
O
R1
R2
Me
R2
Me
N
Me
H
N
N
O
O
54, 55
N
N
O
N
O
CH2-Ph
O
N
O
N
48, 54 49, 55
50
53
No
51
52
Het
N
N
N
N
N
N
R2
R3
N
O
N
N
O
N
N
N
O
N
N
O
CH2CH2
Me
Me
CH2CH2
N
O
N
CH2CH2
CH2CH2
Scheme 3

HETEROCYCLES, Vol. 81, No. 4, 2010
921
In spite of our expectation the yields of that reaction for compounds (18, 19) were lower than for
cyclization of appropriate thiosemicarbazides (7, 8). Additionally they seem to be less comfortable
because of pyridine usage.
It was also possible to carry cyclization of hydrazides with carbamodithioates using other basic
environment. In the case of derivative (45) aqueous solution of K2CO3 and dioxane mixture was used. It
had no influence on reaction yield which was also moderate. At the similar conditions
1,2,4-triazole-5-thione (47) was obtained with better yield in a result of condensation reaction between
3-(hydrazinecarbonyl)pyrazine 1-oxide and benzyl isothiocyanate. While lack of basic environment led to
thiosemicarbazide structures of earlier described compounds (9-17).
Next, 1,2,4-triazole-5-thiones (39, 40) were undergone an alkylation to appropriate sulfides with methyl
iodide (48, 49), 4-(2-chloroethyl)morpholine hydrochloride (50, 51), and 1-(2-chloroethyl)pyrrolidine (52,
53) in NaOH aqueous solution. Subsequent oxidation of methylsulfides (48, 49) using an excess of 30%
hydrogen peroxide and glacial acetic acid gave methylsulfoxides (54, 55).
Some reactions described above such as formation of products (8, 27, 30, 33 and 42) had rather low yields.
Thin-layer chromatography analysis of those crude compounds indicated presence of some impurities
perhaps products of side reactions. Those impurities have not been isolated and analyzed. Purification of
main products by crystallization resulted in considerable loss of those compounds and low reaction
yields.
The characteristics of newly synthesized compounds are given in Table1.
Table 1 Characteristics of the newly synthesized compounds
Elemental Analysis [%]
mp [ºC]
Solvent
Yield
[%]
Molecular formula
MW
No
Calcd/Found
C
H
N
159-160
MeOH/H2O
C8H9N3OS2
227.31
42.27
42.16
3.99
3.98
18.49
18.45
1
2
3
4
5
6
7
8
69
85
73
60
80
25
45
9
192-193
EtOH
C8H9N3OS2
227.31
42.27
42.31
3.99
4.00
18.49
18.47
252-254 decomp.
C7H8N4O2S2
244.29
34.42
34.53
3.30
3.30
22.93
22.97
H2O
155-157
EtOH
C9H11N3OS2
241.33
44.79
44.82
4.59
4.57
17.41
17.42
200-203
EtOH
C8H10N4O2S2
258.32
37.20
37.12
3.90
3.89
21.69
21.65
254-255
MeOH
C8H10N4OS2
242.32
39.65
39.51
4.16
4.17
23.12
23.13
105-107
MeOH
C12H17N5OS
279.36
51.59
51.71
6.13
6.11
25.07
25.06
176-177
H2O
C12H17N5OS
279.36
51.59
51.48
6.13
6.15
25.07
25.09

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HETEROCYCLES, Vol. 81, No. 4, 2010
214-216
DMF/H2O
C12H17N5O2S
88
48.80
48.89
5.80
5.81
23.71
23.75
9
295.36
177-199
MeOH
C9H11N5OS
88
45.56
45.45
4.67
4.68
29.51
29.57
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
237.28
218-219
dioxane/MeOH
C12H12N4OS
58
55.37
55.48
4.65
4.66
21.52
21.57
260.31
187-188
EtOH
C14H14N4OS
70
58.72
58.51
4.93
4.94
19.57
19.56
286.35
177-179
dioxane/H2O
C17H13ClN4OS
66
57.22
57.03
3.67
3.66
15.70
15.79
356.83
157-159
H2O
C10H13N5OS
75
47.79
47.90
5.21
5.19
27.87
27.84
251.31
212-214
dioxane/MeOH
C13H14N4OS
88
56.91
57.05
5.14
5.13
20.42
20.45
274.34
187-188
MeOH
C15H16N4OS
89
59.98
60.10
5.37
5.39
18.65
18.69
300.38
179-180
dioxane/MeOH
C18H15ClN4OS
93
58.30
58.45
4.08
4.08
15.11
15.09
370.86
265-267
DMF/EtOH
A: 75
B: 45
C12H15N5S
261.35
55.15
54.99
5.79
5.77
26.80
26.87
263-264
EtOH
A: 69
B: 42
C12H15N5S
261.35
55.15
55.08
5.79
5.78
26.80
26.78
224-226
DMF/H2O
C12H15N5OS
277.35
51.97
52.03
5.45
5.43
25.25
25.17
43
83-84
MeOH/H2O
C9H9N5S
219.27
49.30
49.37
4.14
4.15
31.94
31.99
84
88
289-290
DMF/H2O
C12H10N4S
242.30
59.48
59.43
4.16
4.16
23.12
23.08
237-239
dioxane/H2O
C14H12N4S
268.34
62.66
62.48
4.51
4.52
20.88
20.92
90
86
105-106
H2O
C10H11N5S
233.29
51.48
51.47
4.75
4.76
30.02
30.05
241-243
dioxane/H2O
C17H11ClN4S
338.81
60.26
60.13
3.27
3.28
16.54
16.52
82
93
25
93
34
19
44
43
16
53
237-239
dioxane/MeOH
C13H12N4S
256.33
60.91
60.87
4.72
4.71
21.86
21.91
125-127
dioxane/H2O
C15H14N4S
282.36
63.80
63.85
5.00
5.01
19.84
19.87
208-210
dioxane/MeOH
C18H13ClN4S
352.84
61.27
61.11
3.71
3.70
15.88
15.84
162-164
EtOH
C8H9N5S
207.26
46.36
46.51
4.38
4.37
33.79
33.78
85-87
H2O
C9H11N5S
221.28
48.85
48.95
5.01
5.02
31.65
31.68
191-193
H2O
C6H6N6OS
210.22
34.28
34.19
2.88
2.87
39.98
39.91
166-167
H2O
C7H8N6OS
224.24
37.49
37.51
3.60
3.61
37.48
37.52
100-102
cyclohexane
C8H10N6OS
238.27
40.33
40.21
4.23
4.24
35.27
35.25
167-169
H2O
C6H6N6S
194.22
37.10
37.18
3.11
3.10
43.27
43.21

HETEROCYCLES, Vol. 81, No. 4, 2010
923
196-199
EtOH
C13H9ClN6S
64
49.29
49.34
2.86
2.86
26.53
26.51
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
316.77
188-190
EtOH
C13H10N6O2S2
65
45.08
45.12
2.91
2.90
24.26
24.28
346.39
195-198
DMF/H2O
C12H9N7O3S2
71
39.66
39.72
2.50
2.49
26.98
26.91
363.37
182-185
MeOH
C12H14N6S2
87
47.04
47.08
4.61
4.60
27.43
27.48
306.41
243-245
H2O
C11H13N5OS
67
50.14
50.09
4.98
4.99
26.60
26.63
263.32
105-108
MeOH/H2O
C12H15N5S
33
55.15
55.08
5.79
5.43
26.80
26.77
261.35
179-180
MeOH
C12H15N5OS
52
51.97
52.02
5.45
5.43
25.25
25.28
277.35
123-125
MeOH
C13H17N5S
25
56.70
56.77
6.22
6.21
25.43
25.41
275.37
273-275
EtOH
C11H13N5OS
80
50.17
50.07
4.98
4.99
26.60
26.58
263.32
290-292
EtOH
C11H13N5O2S
65
47.30
47.34
4.69
4.68
25.07
25.09
279.32
218-220
H2O
C10H12N6O2S
46
42.85
42.89
4.32
4.34
29.98
29.96
280.31
219-221
EtOH
C11H14N6O2S
39
44.89
44.85
4.79
4.77
28.55
28.53
294.33
157-159
EtOH
C13H11N5OS
71
54.72
54.68
3.89
3.90
24.55
24.57
285.32
172-175
MeOH/H2O
C12H15N5OS
37
51.97
51.89
5.45
5.47
25.25
25.27
277.35
95-98
H2O
C13H17N5S
55
56.70
56.74
6.22
6.20
25.43
25.41
275.37
118-120
H2O
C17H24N6O2S
60
54.23
54.28
6.43
6.44
22.32
22.29
376.48
108-110
H2O
C18H26N6OS
62
57.73
57.70
7.00
7.02
22.44
22.46
374.50
95-98
H2O
C14H24N6OS
40
56.64
56.67
6.71
6.70
23.31
23.35
360.48
88-90
H2O
C18H26N6S
62
60.30
60.32
7.31
7.33
23.44
23.41
358.50
188-190
H2O
C12H15N5O2S
32
49.13
49.07
5.15
5.16
23.87
23.80
293.34
120-122
H2O
C13H17N5OS
31
53.59
53.49
5.88
5.88
24.04
24.10
291.37
Tuberculostatic activity
The new synthesized derivatives were examined for their tuberculostatic activity towards the
Mycobacterium tuberculosis H37Rv strain and two “wild” strains from tubeculotic patients: one (Spec.
210) resistant to p-aminosalicilic acid (PAS), isonicotinic acid hydrazide (INH), etambutol (ETB), and
rifampicine (RFP); another (Spec. 192) fully sensitive to the administrated drugs. In vitro investigations

924
HETEROCYCLES, Vol. 81, No. 4, 2010
were performed by a classical test-tube method of successive dilution with Youman’s liquid medium
containing 10% of bovine serum.13
The determined minimum concentrations (MIC) inhibiting the growth of tuberculous strains for all the
tested 1,2,4-triazole derivatives were within the limits 50-100 µg/mL, which indicates low
antituberculosis activity. Although obtained 1,2,4-triazoles exhibited low tuberculostatic activity might be
useful for further syntheses of tuberculostatic drugs. They are also planed to be tested with regard to other
biological action.
Unexpectedly the most active compound appeared intermediate methyl hydrazinecarbodithioate (3). The
MICs for that compound were 15.6 µg/mL (H37Rv) and 31.2 µg/mL (Spec. 192). Compound (3) exhibited
low activity against resistant strain (Spec. 210), MIC 100 µg/mL. Those interesting results demands
farther syntheses and structure – activity relationship analysis for that class of chemical compounds.
EXPERIMENTAL
All materials and solvents were of analytical reagent grade. Thin-layer chromatography was performed on
Merck silica gel 60F254 plates and visualized with UV. The results of elemental analyses (% C, H, N) for
1
all of obtained compounds were in agreement with calculated values within ± 0.3% range. H NMR
spectra in CDCl3 or DMSO-d6 were recorded on Varian Unity Plus (500 MHz) and Varian Gemini (200
MHz) instruments. IR Spectra (KBr) were determined as KBr pellets of the solids on a Satellite FT-IR
spectrophotometer. Mass spectra for compound 31 was taken on Finingan MAT 95 (15 eV). Melting
points were determined on BOETIUS apparatus and were uncorrected.
Methyl carbamodithiates required for further syntheses were obtained by the method described earlier10
and followed after Podgornaya and co-workers.12
Methyl 2-carbonylhydrazinecarbodithioates (1-3). In the solution of 12.3 g (0.22 mole) of KOH in
water (40 mL) and EtOH (40 mL) 0.1 mole of appropriate carbohydrazide was dissolved. Then 7.2 mL
(0.12 mole) of CS2 was added. The mixture was stirred at room temperature for 15 min and 4.7 mL (0.05
mole) of dimethyl sulfate was added. The solution was stirred for 30 min and 150 g of ice was added.
Then mixture was acidified with AcOH. Precipitate was filtered, washed with water and dried.
Methyl 2-nicotinoylhydrazinecarbodithioate (1). IR: 3156, 2961, 1644, 1595, 1521, 1303, 1047, 1025,
1
694, 559 cm-1. H NMR (200 MHz, CDCl3) : 2.55 (s, 3H, SCH3), 7.59 (m, 1H, pyridine), 8.30 (m, 1H,
pyridine), 8.76 (m, 1H, pyridine), 8.87 (m, 1H, pyridine), 10.08 (s, 1H, NH), 10.85 (s, 1H, NH) ppm.
Methyl 2-isonicotinoylhydrazinecarbodithioate (2). IR: 3225, 2954, 1693, 1463, 1361, 1271, 1063,
1032, 755, 694, 591, 499 cm-1. 1H NMR (200 MHz, CDCl3) : 2.58 (s, 3H, SCH3), 7.86 (d, 2H, pyridine,
J = 6.5 Hz), 8.82( d, 2H, pyridine, J = 6.5 Hz), 9.52 (s, 1H, NH), 10.26 (s, 1H, NH) ppm.
3-[2-(Methylthiocarbonothioyl)hydrazinecarbonyl]pyrazine 1-oxide (3). IR: 3302, 3078, 1676, 1590,

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925
1450, 1008, 855, 576 cm-1. 1H NMR (200 MHz, DMSO-d6 + TFA) : 3.25 (s, 3H, SCH3), 8.20 - 8.80 (m,
3H, pyrazine 1-oxide), 10.15 (s, 1H, NH), 11.25 (s, 1H, NH) ppm.
Methyl 1-methyl-2-carbonylhydrazinecarbodithioates (4-6). Appropriate N΄-methylcarbohydrazide
(0.1 mole) was dissolved in 80 mL of EtOH. Then 17 mL (0.12 mole) of Et3N and 7.2 mL (0.12 mole) of
CS2 were added. The solution was stirred at room temperature for 15 min and 7.5 mL (0.12 mole) of
methyl iodide was added. Then mixture was stirred for 1 h and 150 g of ice was added. Precipitate was
filtered, washed with cold water and dried.
Methyl 1-methyl-2-picolinoylhydrazinecarbodithioate (4). IR: 3302, 2925, 1686, 1462, 1420, 1357,
1101, 746, 605 cm-1. 1H NMR (200 MHz, CDCl3) : 2.56 (s, 3H, SCH3), 3.82 (s, 3H, NCH3), 7.52 - 7.58
(m, 1H, pyridine), 7.89-7.97 (m, 1H, pyridine), 8.22 (d, 1H, pyridine, J = 7.9 Hz), 8.62 (m, 1H, pyridine),
10.11 (s, 1H, NH) ppm.
3-(2-Methyl-2-(methylthiocarbonothioyl)hydrazinecarbonyl)pyrazine 1-oxide (5). IR: 3264, 3073,
1
1698, 1497, 1336, 1123, 1011, 850, 569 cm-1. H NMR (200 MHz, DMSO-d6 + TFA) : 3.11 (s,
3H,SCH3), 3.95 (s, 3H, NCH3), 8.60 - 8.90 (m, 3H, pyrazine 1-oxide), 10.08 (s, 1H, NH) ppm.
Methyl 1-methyl-2-(pyrimidine-2-carbonyl)hydrazinecarbodithioate (6). IR: 3172, 2913, 1704, 1568,
1
1505, 1410, 1361, 1096, 958, 634 cm-1. H NMR (500 MHz, CDCl3) : 2.58 (s, 3H, SCH3), 3.85 (s, 3H,
NCH3), 7.56 (t, 1H, pyrimidine, J = 5 Hz), 8.97 (d, 2H, pyrimidine, J = 5 Hz), 10.03 (s, 1H, NH) ppm.
Hydrazinecarbothioamides (7, 8). In 5 mL of pyridine 2.3 g (0.01 mole) of methyl
hydrazinecarbodithioate (1, 2) was dissolved and 1.6 mL (0.01 mole) of 1-aminopiperidine was added.
The mixture was refluxed for 1 h. Then solvent was evaporated and 5 g of ice was added. The mixture
was acidified with AcOH and precipitate was filtered, washed with water and dried.
2-Nicotinoyl-N-(piperidin-1-yl)hydrazinecarbothioamide (7). IR: 2938, 2827, 1680, 1530, 1320, 1249,
1
1034, 908, 781, 704 cm-1. H NMR (200 MHz, CDCl3) : 1.18 (m, 2H, CH2), 1.58 (m, 4H, 2CH2), 3.15
(m, 4H, 2NCH2), 7.62 (m, 1H, pyridine), 8.25 (s, 1H, NH), 8.75 (m, 1H, pyridine), 8.99 (m, 1H, pyridine),
9.90 (s, 1H, NH), 11.20 (s, 1H, NH) ppm.
2-Isonicotinoyl-N-(piperidin-1-yl)hydrazinecarbothiamide (8). IR: 1698, 1677, 1520, 1485, 1311,
1244, 994, 754 cm-1. 1H NMR (200 MHz, CDCl3) : 1.15 (m, 2H, CH2), 1.59 (m, 4H, 2CH2), 2.93 (m, 4H,
2NCH2), 7.85 (d, 2H, pyridine, J = 6.5 Hz), 8.40 (s, 1H, NH), 8.84 (d, 2H, pyridine, J = 6.5 Hz), 9.20 (s,
1H, NH), 10.00 (s, 1H, NH) ppm.
3-(2-(Cyclohexylcarbamothioyl)hydrazinecarbonyl)pyrazine 1-oxide (9).
3-(Hydrazinecarbonyl)pyrazine 1-oxide (0.39 g, 2.5 mmole) and cyclohexyl isothiocyanate (0.35 mL, 2.5
mmole) were refluxed in 5 mL of DMF for 15 min. The mixture was cooled and 40 mL of water was
added. Precipitate was filtered, washed with water and dried. IR: 3280, 2923, 1703, 1600, 1524, 1323,

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1003, 864, 550 cm-1. 1H NMR (200 MHz, DMSO-d6 + TFA) : 0.85-2.50 (m, 11 H, cyclohexyl), 8.48 (s,
1H, NH), 8.53 - 8.82 (m, 1H, pyrazine 1-oxide), 9.55 (m, 2H, pyrazine 1-oxide), 9.81 (s, 1H, NH), 11.10
(s, 1H, NH) ppm.
Thiosemicarbazides (10, 14). Appropriate carbohydrazide or N’-methylcarbohydrazide (5 mmole) was
added to 5 mL of dioxane. Suspension was heated until substrate was dissolved and 0.44 mL (5 mmole)
of allyl isothiocyanate was added. The mixture was refluxed for 15 min, then cooled. Precipitate was
filtered and dried. In the case of compound 10 the mixture of 5 mL of dioxane and 5 mL of MeOH was
used as a solvent. Precipitation of product 14 was induced by 30 mL of petroleum ether addition.
N-Allyl-2-(pyrimidine-2-carbonyl)hydrazinecarbothioamide (10). IR: 3333, 3272, 1704, 1541, 1409,
1295, 1177, 634 cm-1. 1H NMR (200 MHz, DMSO-d6) : 4.10 (s, 2H, CH2), 5.10 (2H, m, CH2), 5.80 (m,
1H, CH), 7.71 (t, 1H, pyrimidine, J = 5 Hz), 8.20 (s, 1H, NH), 8.99 (d, 2H, pyrimidine, 9.49 (s, 1H, NH),
10.72 (s, 1H, NH) ppm.
N-Allyl-1-methyl-2-(pyrimidine-2-carbonyl)hydrazinecarbothioamide (14). IR: 3297, 3056, 2918,
1
1704, 1534, 1487, 1411, 1341, 1171, 1096, 944 cm-1. H NMR (500 MHz, DMSO-d6) : 3.48 (s, 3H,
NCH3), 4.07 (s, 2H, CH2), 5.06 (m, 2H, CH2), 5.80 (m, 1H, CH), 7.75 (t, 1H, pyrimidine, J = 5 Hz), 8.30
(s, 1H, NH), 9.01 (d, 2H, pyrimidine, J = 5 Hz), 11.15 (s, 1H, NH) ppm.
Thiosemicarbazides (11-13, 15-17). Quinoline-2-carbohydrazide (0.47 g, 2.5 mmole) and appropriate
isothiocyanate were dissolved in 5 mL of dioxane. Mixture was heated to boiling and left at room
temperature for 1 h. Then 30 mL of Et2O was added, precipitate was filtered, washed with Et2O and dried.
N-Methyl-2-(quinoline-2-carbonyl)hydrazinecarbothioamide (11). IR: 3336, 3204, 1676, 1548, 1494,
1
1423, 1264, 1078, 841, 774 cm-1. H NMR (200 MHz, DMSO-d6) : 2.86 (s, 3H, CH3), 7.65 – 8.63 (m,
7H, 6H quinoline and 1H NH), 9.44 (s, 1H, NH), 10.33 (s, 1H, NH) ppm.
N-Allyl-2-(quinoline-2-carbonyl)hydrazinecarbothioamide (12). IR: 3335, 3269, 3165, 1693, 1555,
1476, 1306, 1142, 780 cm-1. 1H NMR (200 MHz, CDCl3) : 4.30 (m, 2H, CH2), 5.20 (m, 2H, CH2), 5.90
(m, 1H, CH), 6.85 (s, 1H, NH), 7.40 – 8.40 (m, 7H, 6H quinoline and 1H NH), 10.03 (s, 1H, NH) ppm.
N-(4-Chlorophenyl)-2-(quinoline-2-carbonyl)hydrazinecarbothioamide (13). IR: 3322, 3217, 3161,
1
1688, 1534, 1493, 1351, 1092, 925, 837, 772 cm-1. H NMR (500 MHz, DMSO-d6) : 7.30 - 8.60 (m,
10H, 6H quinoline and 4H Ph), 9.86 (s, 1H, NH), 9.95 (s, 1H, NH), 10.95 (s, 1H, NH) ppm.
N,1-Dimethyl-2-(quinoline-2-carbonyl)hydrazinecarbothioamide (15). IR 3322, 3162, 2936, 1687,
1540, 1491, 1427, 1343, 1292, 1075, 840, 777, 681, 623 cm-1. 1H NMR (500 MHz, CDCl3) : 3.14 (s, 3H,
CH3), 3.78 (s, 3H, CH3), 6.73 (s, 1H, NH), 7.54 – 8.50 (m, 6H, quinoline), 10.04 (s, 1H, NH) ppm.
N-Allyl-1-methyl-2-(quinoline-2-carbonyl)hydrazinecarbothioamide (16). IR: 3327, 3193, 3056, 2975,
1
2918, 1690, 1528, 1490, 1381, 1333, 1162, 1093, 926, 841, 777, 678 cm-1. H NMR (500 MHz, CDCl3)

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927
: 3.77 (s, 3H, CH3), 4.32 (m, 2H, CH2), 5.10 – 5.26 (m, 2H, CH2), 5.85 (m, 1H, CH), 6.69 (s, 1H, NH),
7.65 – 8.45 (m, 6H, quinoline), 9.93 (s, 1H, NH) ppm.
N-(4-Chlorophenyl)-1-methyl-2-(quinoline-2-carbonyl)hydrazinecarbothioamide (17). IR: 3292,
1
2925, 2854, 1686, 1507, 1427, 1339, 1086, 1024, 830, 775, 729 cm-1. H NMR (500 MHz, CDCl3) :
3.83 (s, 3H, CH3), 6.83 (s, 1H, NH), 7.30 – 8.46 (m, 10H, 6H quinoline and 4H Ph), 10.00 (s, 1H, NH)
ppm.
1,2,4-Triazole-5-thiones (18, 19). Method A. Appropriate thiosemicarbazide (7, 8) (0.2 g, 0.7 mmole)
was refluxed with K2CO3 (1 g, 7 mmole) in 5 mL of water for 3 h. Mixture was cooled and acidified with
AcOH. Precipitate was filtered, washed with water and dried.
Method B. Appropriate pyridinecarbohydrazide (1.4 g, 10 mmole) and methyl piperidin-1-
ylcarbamodithioate (1.9 g, 10 mmole) were dissolved in 6 mL of dry pyridine. Then 1.5 mL (10 mmole)
of DBU was added. Mixture was refluxed for 3h. Then solvent was evaporated and 5 g of ice was added
to residue. Water solution was acidified with AcOH, precipitate was filtered, washed with water and
dried.
4-(Piperidin-1-yl)-3-(pyridin-3-yl)-1H-1,2,4-triazole-5(4H)-thione (18). IR: 2938,2855, 1555, 1415,
1188, 1029, 947, 801, 742, 695 cm-1. 1H NMR (200 MHz, DMSO-d6) : 1.72 (m, 2H, CH2), 3.05 (m, 4H,
2CH2), 4.36 (m, 4H, 2NCH2), 7.50 (q, 1H, pyridine, J1 = 7.5 Hz, J2 = 4.5 Hz), 8.22 (d, 1H, pyridine, J =
7.5), 8.71 (d, 1H, pyridine, J = 4.5 Hz), 8.93 (s, 1H, pyridine), 13.90 (s, 1H, NH) ppm.
4-(Piperidin-1-yl)-3-(pyridin-4-yl)-1H-1,2,4-triazole-5(4H)-thione (19). IR: 2855, 1611, 1574, 1426,
1314, 1292, 1216, 1007, 954, 827, 625, 538 cm-1. 1H NMR (200 MHz, DMSO-d6) : 1.10 – 1.75 (m, 2H,
CH2), 3.05 (m, 4H, 2CH2), 4.37 (m, 4H, 2NCH2), 7.85 (d, 2H, pyridine, J = 6.6 Hz), 8.76 (d, 2H, J = 6.5
Hz), 13.60 (s, 1H, NH) ppm.
1,2,4-Triazole-5-thiones (20-24). Appropriate thiosemicarbazide (9, 10, 12-14) (1 mmole) was refluxed
in 10 mL of 10% aqueous NaOH for 2 h. Then solution was cooled and acidified with concentrated HCl.
Precipitate was filtered, washed with cold water and dried.
3-(4-Cyclohexyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrazine 1-oxide (20). IR: 2923, 1583,
1440, 1183, 912 cm-1. 1H NMR (200 MHz, DMSO-d6 + TFA) : 0.95-2.60 (m, 11H, cyclohexyl), 8.80 (m,
3H, pyrazine 1-oxide), 14.08 (s, 1H, NH) ppm.
4-Allyl-3-(pyrimidin-2-yl)-1H-1,2,4-triazole-5(4H)-thione (21). IR: 3407, 3160, 2925, 2735, 1569,
1447, 1388, 1273, 1197 cm-1. 1H NMR (500 MHz, CDCl3) : 5.16 (m, 2H, CH2), 5.41 (d, 2H, NCH2, J =
4.5 Hz), 5.98 (m, 1H, CH), 7.44 (t, 1H, pyrimidine, J = 5 Hz), 8.97 (d, 2H, pyrimidine, J = 5 Hz), 12.62 (s,
1H, NH) ppm.
4-Methyl-3-(quinolin-2-yl)-1H-1,2,4-triazole-5(4H)-thione (22). IR: 3448, 3015, 2927, 1600, 1493,

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1341, 1278, 965, 833,761 cm-1. 1H NMR (200 MHz, DMSO-d6) : 4.04 (s, 3H, CH3), 7.60 – 8.60 (m, 6H,
quinoline), 14.21 (s, 1H, NH) ppm.
4-Allyl-3-(quinolin-2-yl)-1H-1,2,4-triazole-5(4H)-thione (23). IR: 3095, 3010, 2925, 1597, 1459, 1360,
1
1271, 997, 832, 757 cm-1. H NMR (500 MHz, DMSO-d6) : 5.10 (m, 2H, CH2), 5.40 (d, 2H, CH2, J =
5.4 Hz), 6.00 (m, 1H, CH), 7.65 – 8.56 (m, 6H, quinoline), 14.31 (s, 1H, NH) ppm.
4-(4-Chlorophenyl)-3-(quinolin-2-yl)-1H-1,2,4-triazole-5(4H)-thione (24). IR: 3099, 2922, 1596, 1497,
1342, 1280, 1096, 833, 760 cm-1. 1H NMR (500 MHz, DMSO-d6) : 7.28 (d, 1H, quinoline, J = 8.3 Hz),
7.37 (d, 2H, Ph, J = 8.7 Hz), 7.53 (d, 2H, Ph, J = 8.7 Hz), 7.58 (t, 1H, quinoline, J = 6.8 Hz), 7.69 (t, 1H,
quinoline, J = 6.8 Hz), 7.95 (d, 1H, quinoline, J = 8.3 Hz), 8.08 (d, 1H, quinoline, J = 8.8 Hz), 8.43 (d,
1H, quinoline, J = 8.8 Hz), 14.24 (s, 1H, NH) ppm.
4-Allyl-1-methyl-3-(pyrimidin-2-yl)-1H-1,2,4-triazole-5(4H)-thione (25). Thiosemicarbazide (11)
(0.25 g, 1 mmole) was refluxed in the mixture of 5 mL of 10% aqueous K2CO3 and 3 mL of EtOH for 30
min. Then mixture was concentrated and 5 g of ice was added. Precipitate was filtered, washed with water
and dried. IR: 3446, 2941, 1562, 1465, 1349, 1296, 1209, 931, 814 cm-1. 1H NMR (500 MHz, CDCl3) :
3.98 (s, 3H, NCH3), 5.19 (m, 2H, CH2), 5.42 (d, 2H, NCH2, J = 5 Hz), 5.98 (m, 1H, CH), 7.43 (t, 1H,
pyrimidine, J = 5 Hz), 8.91 (d, 2H, pyrimidine, J = 5 Hz) ppm.
1,2,4-Triazole-5-thiones (26-28). Appropriate thiosemicarbazide (15-17) (1 mmole) was refluxed in 10
mL of 2M aqueous NaOH for 15 min. Ten mixture was cooled and precipitate was filtered, washed with
water and dried.
1,4-Dimethyl-3-(quinolin-2-yl)-1H-1,2,4-triazole-5(4H)-thione (26). IR: 3051, 2935, 1476, 1452, 1405,
1
1358, 1171, 1065, 876, 763 cm-1. H NMR (500 MHz, CDCl3) : 3.96 (s, 3H, CH3), 4.28 (s, 3H, CH3),
7.62 – 8.32 (m, 6H, quinoline) ppm.
4-Allyl-1-methyl-3-(quinolin-2-yl)-1H-1,2,4-triazole-5(4H)-thione (27). IR: 3103, 2929, 1600, 1470,
1423, 1341, 1063, 965, 833, 762 cm-1. 1H NMR (500 MHz, CDCl3) : 3.96 (s, 3H, NCH3), 5.18 – 5.30 (m,
2H, CH2), 5.60 (d, 2H, CH2, J = 5.8 Hz), 6.1 (m, 1H, CH), 7.60 – 8.30 (m, 6H, quinoline) ppm.
4-(4-Chlorophenyl)-1-methyl-3-(quinolin-2-yl)-1H-1,2,4-triazole-5(4H)-thione (28). IR: 3034, 2925,
1595, 1407, 1345, 1099, 1088, 834, 760 cm-1. 1H NMR (200 MHz, CDCl3) : 4.01 (s, 3H, NCH3), 7.30 –
8.26 (m, 10H, 6 H quinoline and 4H Ph) ppm.
4-Amino-1-methyl-3-(pyridine)-1H-1,2,4-triazole-5(4H)-thione (29). In the mixture of 6 mL of
dioxane and 4 mL of EtOH 2.1 g (9 mmole) of methyl hydrazinecarbodithioate (3) was dissolved. Then 1
mL (0.02 mole) of hydrazine hydrate was added. Reaction mixture was refluxed for 2 h, then cooled.
Precipitate was filtered, washed with cooled EtOH and dried. IR: 3212, 1682, 1611, 1466, 1317, 1122,
941, 790 cm-1. 1H NMR (200 MHz, CDCl3) : 3.89 (s, 3H, NCH3), 6.19 (s, 2H, NH2), 7.41 – 7.47 (m, 1H,

HETEROCYCLES, Vol. 81, No. 4, 2010
929
pyridine), 7.88 (q, 1H, pyridine, J1 = 7.8 Hz, J2 = 6.4 Hz), 8.08 (d, 1H, pyridine, J = 7.9 Hz), 8.71 (t, 1H,
pyridine, J = 4.9 Hz) ppm.
1-Methyl-4-(methylamino)3-(pyridine-2-yl)-1H-1,2,4-triazole-5(4H)-thione
(30).
Methyl
hydrazinecarbodithioate (3) (2.2 g, 9 mmole) was dissolved in 10 mL of dioxane and 2.1 g (0.04 mole) of
methylhydrazine was added. The mixture refluxed for 2 h, then cooled and 5 mL of water was added.
Precipitate was filtered after cooling, washed with water and dried. IR: 3224, 2963, 1462, 1446, 1397,
1
1337, 789 cm-1. H NMR (200 MHz, CDCl3) : 2.87 (s, 3H, NCH3), 3.88 (s, 3H, NHCH3), 6.03 (s, 1H,
NH), 7.44 (t, 1H, pyridine, J = 6.2 Hz), 7.87 (t, 1H, pyridine, J = 7.7 Hz), 8.16 (d, 1H, pyridine, J = 7.7
Hz), 8.74 (d, 1H, pyridine, J = 4.1 Hz) ppm.
3-(4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrazine
1-oxide
(31).
Methyl
hydrazinecarbodithioate (4) (1.2 g, 5 mmole) was suspended in 5 mL of water and 1 mL (0.032 mole) of
hydrazine hydrate was added. Mixture was refluxed for 6 h, then cooled and acidified with concentrated
HCl. Precipitate was filtered, washed with cold water and dried. IR: 3276, 1584, 1504, 1453, 1325, 1020,
960 cm-1. 1H NMR (200 MHz, DMSO-d6) : 6.25 (s, 2H, NH2), 8.80 (m, 2H, pyrazine 1-oxide), 9.45 (s,
1H, pyrazine 1-oxide), 14.05 (s, 1H, NH) ppm. MS (15 eV): 210 (100), 194 (75.72), 106 (14.82).
1,2,4-Triazole-5-thiones (32, 33): 1.3 g (5 mmole) of methyl hydrazinecarbodithioate (5) was suspended
in 5 mL of water and 0.31 mL (10 mmole) of hydrazine hydrate or 0.53 mL (10 mmole) of
methylhydrazine was added. Mixture was refluxed for 5 h, then cooled. Precipitate was filtered, washed
with water and dried.
3-(4-Amino-1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrazine 1-oxide (32). IR: 3143,
1
1601, 1463, 1325, 1015, 857 cm-1. H NMR (200 MHz, DMSO-d6) : 2.88 (s, 3H, NCH3), 6.28 (s, 2H,
NH2), 8.75 (m, 2H, pyrazine 1-oxide), 9.43 (d, 1H, pyrazine 1-oxide, J = 7.6 Hz) ppm.
3-(1-Methyl-4-(methylamino)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrazine 1-oxide (33). IR:
3234, 1510, 1457, 1342, 1015, 880 cm-1. 1H NMR (200 MHz, DMSO-d6) : 2.90 (s, 3H, NCH3), 3.91 (s,
3H, NHCH3), 6.05 (s, 1H, NH), 8.73 (d, 1H, pyrazine 1-oxide, J = 7.7 Hz), 9.41 (m, 1H, pyrazine
1-oxide) ppm.
4-Amino-1-methyl-3-(pyrimidin-2-yl)-1H-1,2,4-triazole-5(4H)-thione (34).
Pyrimidine-2-carbohydrazide (0.7 g, 5 mmole) was added to the mixture consisted of EtOH (15 mL),
water (2 mL), Et3N (1.8 mL, 12 mmole) and CS2 (0.5 mL, 8 mmole). Then 0.5 mL (15 mmole) of
hydrazine hydrate was added. Mixture was refluxed for 4 h, then concentrated. Residue was diluted with
1
water (20 mL) and acidified with AcOH. IR: 3273, 3181, 1567, 1484, 1286, 1143, 1014 cm-1. H NMR
(200 MHz, DMSO-d6) : 6.29 (s, 2H, NH2), 7.69 (t, 1H, pyrimidine, J = 5 Hz), 9.02 (d, 2H, pyrimidine, J
= 5 Hz), 12.03 (s, 1H, NH) ppm.

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Hydrazones (35-37). Appropriate 1,2,4-triazole-5-thione (29, 32, 34) (2 mmole) was dissolved in 20 mL
of MeOH, 2.5 mmole of aldehyde and 3 drops of acetic acid were added. Mixture was refluxed for 1 h,
then cooled. Precipitate was filtered, washed with cold MeOH and dried.
4-[(Nitrothiphen-2-yl)methyleneamino]-3-(pyrimidin-2-yl)-1H-1,2,4-triazole-5(4H)-thione (35). IR:
1
3184, 2963, 1488, 1240, 1084, 1010, 823, 787 cm-1. H NMR (500 MHz, DMSO-d6) : 7.50 - 8.90 (m,
7H, 3H pyrimidine and 4H Ph), 10.15 (s, 1H, CH), 12.65 (s, 1H, NH) ppm.
1-Methyl-4-((nitrothiophen-2-yl)methyleneamino)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5(4H)-thione
1
(36). IR: 1533, 1504, 1465, 1344, 1321, 1215 cm-1. H NMR (500 MHz, DMSO-d6) : 3.84 (s, 3H,
NCH3), 6.32 (s, 1H, thiophene), 7.59 (q, 1H, thiophene, J = 6.3 Hz, J = 4.9 Hz), 7.93 (t, 1H, pyridine, J =
4.4 Hz), 8.04 (m, 1H, pyridine), 8.21 (m, 1H, pyridine), 8.73 (q, 1H, pyridine, J = 4.9 Hz), 10.11 (s, 1H,
CH) ppm.
3-(4-(4-Chlorophenyl)-1-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrazine 1-oxide (37).
1
IR: 1507, 1344, 1208, 816, 731 cm-1. H NMR (200 MHz, DMSO-d6) : 3.84 (s, 3H, CH3), 7.95 (d, 1H,
thiophene, J = 4 Hz), 8.20 (d, 1H, thiophene, J = 4 Hz), 8.84 (s, 1H, pyrazine), 9.13 (s, 2H, pyrazine),
10.26 (s, 1H, CH) ppm.
1-Allyl-3-(1-methyl-3-(pyridine-2-yl)-5-thioxo-1H-1,2,4-triazol-4(5H)-yl)thiourea (38).
1,2,4-Triazole-5-thione (30) (0.5 g, 2.4 mmole) and allyl isothiocyanate (0.53 mL, 5 mmole) dissolved in
5 mL of EtOH were refluxed for 1.5 h, then cooled. Precipitate was filtered, washed with cooled EtOH
and dried. IR: 3114, 2985, 2895, 1571, 1525, 1450, 1342, 1286, 1182 cm-1. 1H NMR (200 MHz, CDCl3)
: 3.92 (s, 3H, NCH3), 5.15 - 5.22 (m, 2H, NCH2), 5.49 (d, 2H, CH2, J = 6 Hz), 5.76 – 5.92 (m, 1H, CH),
7.49-7.55 (m, 1H, pyridine), 7.90-8.15 (m, 3H, 2H pyridine and 1H NH), 8.73 (d, 1H, pyridine, J = 4.1
Hz) ppm.
1,2,4-Triazole-5-thiones (39, 40). Picolinohydrazide (1.4 g, 10 mmole) and appropriate methyl
carbamodithioate (10 mmole) were dissolved in 6 mL of dry pyridine and 1.5 mL (10mmole) of DBU
was added. The mixture was refluxed for 48 h and concentrated. Then 20 mL of water was added and
solution was acidified with AcOH. Precipitate was filtered, washed with cold water and dried.
4-Morpholino-3-(pyridine-2-yl)-1H-1,2,4-triazole-5(4H)-thione (39). IR: 3090, 3048, 2924, 2857,
1560, 1499, 1460, 1448, 1322, 1291, 1277, 1108, 915, 799 cm-1. 1H NMR (500 MHz, CDCl3) : 3.06 (s,
2H, NCH2), 3.63 (s, 2H, NCH2), 3.93 (d, 2H, OCH2, J = 12.7 Hz), 4.69 (s, 2H, OCH2), 7.45 (t, 1H,
pyridine, J = 4.4 Hz), 7.88 (m, 2H, pyridine), 8.81 (s, 1H, pyridine), 11.58 (s, 1H, NH) ppm.
4-(Piperidin-1-yl)-3-(pyridine-2-yl)-1H-1,2,4-triazole-5(4H)-thione (40). IR: 2934, 2855, 1546, 1501,
1451, 1412, 1300, 1283, 1252, 966, 786 cm-1. 1H NMR (500 MHz, CDCl3) : 1.40 - 1.79 (m, 6H, 3CH2),
3.10 (s, 2H, NCH2), 4.50 (s, 2H, NCH2), 7.27 – 7.44 (m, 2H, pyridine), 7.85- 8.02 (m, 1H, pyridine), 8.83

HETEROCYCLES, Vol. 81, No. 4, 2010
931
(s, 1H, pyridine), 11.89 (s, 1H, NH) ppm.
1,2,4-Triazole-5-thiones (41, 42). N’-Methylpicolinohydrazide (1.5 g, 10 mmole) and appropriate methyl
carbamodithioate (10 mmole) were dissolved in 6 mL of dry pyridine. Then 1.5 mL (10 mmole) of DBU
was added and mixture was refluxed for 2.5 h. Solvent was evaporated and 20 mL of water was added to
the residue. Precipitate was filtered, washed with water and dried.
1-Methyl-4-morpholino-3-(pyridine-2-yl)-1H-1,2,4-triazole-5(4H)-thione (41). IR: 3004, 2967, 2838,
1587, 1472, 1447, 1380, 1330, 1265, 1207, 1107, 845, 791 cm-1. 1H NMR (200 MHz, CDCl3) : 2.97 (d,
2H, NCH2, J = 10.4 Hz), 3.48 – 3.67 (m, 2H, NCH2), 3.83 (s, 3H, NCH3), 3.96 (d, 2H, OCH2, J = 11.2
Hz), 4.75 - 4.86 (m, 2H, OCH2), 7.44-7.51 (m, 1H, pyridine), 7.88 – 7.98 (m, 2H, pyridine), 880 (d, 1H,
pyridine, J = 4.5 Hz) ppm.
1-Methyl-4-(piperidin-1-yl)-3-(pyridine-2-yl)-1H-1,2,4-triazole-5(4H)-thione (42). IR: 3098, 3054,
1
2930, 2865, 1646, 1587, 1482, 1431, 1407, 1330, 1208, 1091, 788 cm-1. H NMR (500 MHz, CDCl3) :
1.33 - 1.80 (m, 6H, 3CH2), 3.05 (d, 2H, NCH2, J = 9.3), 3.84 (s, 3H, NCH3), 4.57 (t, 2H, NCH2, J = 11
Hz), 7.48 (m, 1H, pyridine), 7.90 (m, 1H, pyridine), 8.10 (d, 1H, pyridine, J = 7.8 Hz), 8.82 (d, 1H,
pyridine, J = 4.4 Hz) ppm.
1,2,4-Triazole-5-thiones (43, 44). These compounds were obtained according to method B described for
derivatives (18, 19) from 10 mmole of appropriate hydrazide and 1.9 g (10 mmole) of methyl
morpholinocarbamodithioate. In the case of compound (44) refluxing time was extended to 6 h.
4-Morpholino-3-(pyridine-4-yl)-1H-1,2,4-triazole-5(4H)-thione (43). IR: 2850, 2361, 1607, 1575,
1423, 1295, 1113, 832 cm-1. 1H NMR (500 MHz, DMSO-d6) : 3.03 (m, 2H, NCH2), 3.45 (m, 2H, NCH2),
3.85 (m, 2H, OCH2), 4.76 (m, 2H, OCH2), 7.85 (d, 2H, pyridine, J = 6.6 Hz), 8.76 (d, 2H, pyridine, J =
6.5 Hz), 14.12 (s, 1H, NH) ppm.
4-(4-Morpholino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridine 1-oxide (44). IR: 1517, 1452,
1
1404, 1322, 1236, 1182, 1107, 952, 842 cm-1. H NMR (200 MHz, DMSO-d6 + TFA) : 3.03 (m, 2H,
NCH2), 3.54 (m, 2H, CH2), 3.86 (m, 2H, OCH2), 4.60 (m, 2H, OCH2), 7.94 (d, 2H, pyridine 1-oxide, J =
6.1 Hz), 8.30 (d, 2H, pyridine 1-oxide, J = 6.1 Hz), 14.08 (s, 1H, NH) ppm.
4-(4-Morpholino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrazine 1-oxide (45). The mixture of
0.77 g (5 mmole) of 3-(hydrazinecarbonyl)pyrazine 1-oxide, 0.96 g (5 mmole) of methyl
morpholinocarbamodithiate, 10 mL of 10% aqueous K2CO3 and 10 mL of dioxane was refluxed for 12 h.
Then solvent was evaporated and the residue was diluted with 20 mL of water. Solution was acidified
with acetic acid and product precipitated. Solid was filtered, washed with cold water and dried. IR: 3134,
1
2977, 2855, 1687, 1592, 1450, 1105, 976 cm-1. H NMR (500 MHz, DMSO-d6 + TFA) : 3.02 (s, 2H,
NCH2), 3.65 (s, 2H, NCH2), 3.95 (d, 2H, OCH2, J = 11.5 Hz), 4.65 (s, 2H, OCH2), 8.30 - 8.70 (m, 3H,

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HETEROCYCLES, Vol. 81, No. 4, 2010
pyrazine 1-oxide), 14.02 (s, 1H, NH) ppm.
4-(1-Methyl-4-morpholino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrazine
1-oxide
(46).
Synthesis was performed according to method described for derivatives (41, 42) from 1.7 g (10 mmole)
of 3-(2-methylhydrazinecarbonyl)pyrazine 1-oxide and 1.9 (10 mmole) of methyl
g
morpholinocarbamodithioate. Refluxing time was extended to 6 h. IR: 2853, 1444, 1384, 1325, 1107, 846
1
cm-1. H NMR (500 MHz, DMSO-d6) : 3.09 (s, 2H, NCH2), 3.62 (s, 2H, NCH2), 3.82 (s, 3H, NCH3),
3.95 (d, 2H, OCH2, J = 12.7 Hz), 4.62 (s, 2H, OCH2), 8.20 - 8.80 (m, 3H, pyrazine 1-oxide) ppm.
3-(4-Benzyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrazine 1-oxide (47).
3-(Hydrazinecarbonyl)pyrazine 1-oxide (0.38 g, 2.5 mmole) was dissolved in 15 mL of 5% aqueous
K2CO3 and 0.31 mL (2.5 mmole) of benzyl isothiocyanate was added. Mixture was refluxed for 3 h, then
cooled and acidified with AcOH. Precipitate was filtered, washed with water and dried. IR: 3079, 1591,
1
1477, 1264, 916, 722 cm-1. H NMR (500 MHz, DMSO-d6 + TFA) : 5.12 (s, 2H, NCH2Ph), 7.21-7.40
(m, 5H, Ph), 8.32-8.75 (m, 3H, pyrazine 1-oxide), 14.03 (s, 1H, NH) ppm.
Methylsulfides (48, 49). In 10 mL of 1M NaOH appropriate 1,2,4-triazole-5-thione (41, 42) (1 g, 3.6
mmole) was dissolved. Then 0.31 mL (5 mmole) of methyl iodide in 2 mL of EtOH was added. Mixture
was stirred at room temperature for 2 h. Precipitate was filtered, washed with water and dried. IR: 3079,
1
1591, 1477, 1264, 916, 722 cm-1. H NMR (500 MHz, DMSO-d6) : 5.12 (s, 2H, NCH2Ph), 7.21 - 7.40
(m, 5H, Ph), 8.32-8.75 (m, 3H, pyrazine 1-oxide), 14.03 (s, 1H, NH) ppm.
4-(3-(Methylthio)-5-(pyridin-2-yl)-4H-1,2,4-triazol-4-yl)morpholine (48). IR: 2966, 2923, 1579, 1448,
1434, 1270, 1104, 919, 790 cm-1. 1H NMR (500 MHz, CDCl3) : 2.74 (s, 3H, SCH3), 2.89 (d, 2H, NCH2,
J = 10 Hz), 3.76 - 4.10 (m, 6H, 2H NCH2 and 4H OCH2), 7.37 (q, 1H, pyridine, J1 = 7.3 Hz, J2 = 5.4 Hz),
7.84 (t, 1H, pyridine, J = 7.8 Hz), 8.25 (d, 1H, pyridine, J = 7.8 Hz), 8.74 (d, 1H, pyridine, J = 3.9 Hz)
ppm.
2-(5-(Methylthio)-4-(piperidin-1-yl)-4H-1,2,4-triazol-3-yl)pyridine (49). IR: 2942, 2924, 2861, 1586,
1439, 1425, 1104, 1026, 795 cm-1. 1H NMR (500 MHz, DMSO-d6) : 1.62 (d, 6H, CH2, J = 8.6 Hz), 2.61
(s, 3H, NCH3), 2.95 (d, 2H, NCH2, J = 7.8 Hz), 3.54 (t, 2H, NCH2, J = 9.3 Hz), 7.53 (t, 1H, pyridine, J =
5.9 Hz), 8.00 (m, 2H, pyridine), 8.76 (d, 1H, pyridine, J = 3.9 Hz) ppm.
Sulfides (50-53). In 5 mL of 2M NaOH appropriate 1,2,4-triazole-5-thione (41, 42) (0.55 g, 2 mmole)
was dissolved. Then 2 mmole of 4-(2-chloroethyl)morpholine hydrochloride or 1-(2-chloroethyl)-
pyrrolidine hydrochloride was added. The mixture was stirred at room temperature for 12 h. Precipitate
was filtered, washed with water and dried.
4-(2-(4-Morpholino-5-(pyridine-2-yl)-4H-1,2,4-triazol-3-ylthio)ethyl)morpholine (50). IR: 2958, 2931,
2855, 1584, 1443, 1426, 1267, 1113, 1003, 791 cm-1. 1H NMR (200 MHz, CDCl3) : 2.64 (s, 4H, 2NCH2),

HETEROCYCLES, Vol. 81, No. 4, 2010
933
2.88 (s, 4H, 2OCH2), 3.48 (t, 2H, SCH2, J = 6.9 Hz), 3.78-4.11 (m, 10H, 4NCH2 and 2OCH2), 7.35 (q, 1H,
pyridine,J1 = 5.2 Hz, J2 = 6.9 Hz), 7.80 (m, 1H, pyridine), 8.20 (d, 1H, pyridine, J = 7.8 Hz), 8.72 (d, 1H,
pyridine, J = 4.4 Hz) ppm.
4-(2-(4-(Piperidin-1-yl)-5-(pyridine-2-yl)-4H-1,2,4-triazol-3-ylthio)ethyl)morpholine (51). IR: 2941,
2856, 1586, 1441, 1420, 1305, 1265, 1141, 1115 cm-1. 1H NMR (200 MHz, CDCl3) : 1.31-1.71 (m, 6H,
3CH2), 2.62 (s, 4H, 2OCH2), 2.84-3.01 (m, 4H, CH2 and NCH2), 3.45 (t, 2H, NCH2, J = 6.9 Hz), 3.71 (m,
6H, 3CH2), 7.30 (m, 1H, pyridine), 7.79 (m, 1H, pyridine), 8.15 (d, 1H, pyridine, J = 7.9 Hz), 8.68 (d, 1H,
J = 4.3 Hz) ppm.
4-(3-(Pyridine-2-yl)-5-(2-(pyrrolidin-1-yl)ethylthio)-4H-1,2,4-triazol-4-yl)morpholine (52). IR: 2953,
1
2921, 2855, 2790, 1585, 1442, 1426, 1111, 914, 979 cm-1. H NMR (500 MHz, CDCl3) : 1.87 (s, 4H,
2CH2), 2.90 (m, 8H, 3NCH2 and SCH2), 3.50 (t, 2H, NCH2, J = 6.3 Hz), 3.85 (m, 4H, OCH2), 4.07 (s, 2H,
NCH2), 7.36 (t, 1H, pyridine, J = 4.9 Hz), 7.81 (t, 1H, pyridine, J = 7.3 Hz), 8.22 (d, 1H, pyridine, J = 7.8
Hz), 8.73 (d, 1H, pyridine, J = 3.9 Hz) ppm.
2-(4-(Piperidin-1-yl)-5-(2-(pyrrolidin-1-yl)ethylthio)-4H-1,2,4-triazol-3-yl)pyridine (53). IR: 2935,
1
2855, 2793, 1585, 1439, 11420, 1289, 794 cm-1. H NMR (200 MHz, CDCl3) : 1.30-1.84 (m, 10H,
5CH2), 2.72 (s, 4H, NCH2), 3.00 (m, 4H, NCH2 and SCH2), 3.52 (m, 4H, 2NCH2), 7.30 (t, 1H, pyridine, J
= 5.7 Hz), 7.78 (t, 1H, pyridine, J = 7.1 Hz), 8.14 (d, 1H, pyridine, J = 7.7 Hz), 8.67 (d, 1H, pyridine, J =
2.8 Hz) ppm.
Methylsulfoxides (54, 55). Appropriate 1,2,4-triazole (48, 49) (1 mmole) was dissolved in 3 mL of
glacial acetic acid. Then 3 mL of 30% H2O2 was added. Mixture was heated at 50 °C for 3 h. Then
solution was cooled and alkalized with saturated aqueous solution of NaHCO3 and extracted with CHCl3.
Organic fractions were collected and dried with MgSO4. Then solvent was evaporated and residue was
washed with dry Et2O and dried.
4-(3-(Methylsulfinyl)-5-(pyridine-2-yl)-4H-1,2,4-triazol-4-yl)morpholine (54). 2962, 2927, 2869, 1586,
1439, 1103, 1046, 916, 792 cm-1. 1H NMR (200 MHz, CDCl3) : 2.45 (s, 2H, NCH2), 2.91 (d, 2H, NCH2,
J = 5.5 Hz), 3.28 (s, 3H, SCH3), 3.88 (t, 4H, OCH2, J = 5.9 Hz), 7.45 (m, 1H, pyridine), 7.89 (m, 1H,
pyridine), 8.32 (m, 1H, pyridine), 8.80 (m, 1H, pyridine) ppm.
2-(5-(Methylsulfinyl)-4-(piperidin-1-yl)-4H-1,2,4-triazol-3-yl)pyridine (55). IR: 2943, 2881, 2855,
1585, 1439, 1330, 1157, 1108, 952, 793, 555, 503 cm-1. 1H NMR (200 MHz, CDCl3) : 1.34-1.85 (m, 6H,
2NCH2), 3.17-3.50 (m, 2H, NCH2), 3.52 (s, 3H, SCH3), 3.73 (t, 2H, NCH2, J = 10 Hz), 7.48 (m, 1H,
pyridine), 7.87-7.95 (m, 1H, pyridine), 8.27 (d, 1H, pyridine, J = 8.0 Hz), 8.79 (d, 1H, pyridine, J = 4.8
Hz) ppm.

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