The synthesis of 3-amino-pyrazine-2-carbohydrazide and 3-Amino-N'- methylpyrazine-2-carbohydrazide derivatives

Article abstract of DOI:10.1002/jhet.877

In research of new biologically active compounds, the reactions of amino-pyrazin-2-hydrazide and methylhydrazide with isothiocyanates, aromatic aldehydes, ketones, CS₂, and formic acid were made. New thiosemicarbazides, 1,3,4-thiadiazoles, 1,3,4-oxadiazoles, and 1,2,4-triazoles were obtained. New 4-oxopteridine derivative 26 was also synthesized.

Full text of DOI:10.1002/jhet.877

July 2012
The Synthesis of 3-Amino-pyrazine-2-carbohydrazide and 3-Amino-N0-
845
methylpyrazine-2-carbohydrazide Derivatives
a
a
a
a
b
*
Barbara Milczarska, Katarzyna Gobis, Henryk Foks, Lukasz Golunski, and Pawel Sowinski
aDepartment of Organic Chemistry, Medical University of Gdansk, Gdansk 80-438, Poland
bLaboratory of NMR Spectroscopy, Department of Chemistry, Gdansk University of Technology, Gdansk, Poland
*
E-mail: kgobis@gumed.edu.pl
Received November 19, 2010
DOI 10.1002/jhet.877
View this article online at wileyonlinelibrary.com.
In research of new biologically active compounds, the reactions of amino-pyrazin-2-hydrazide and
methylhydrazide with isothiocyanates, aromatic aldehydes, ketones, CS2, and formic acid were made.
New thiosemicarbazides, 1,3,4-thiadiazoles, 1,3,4-oxadiazoles, and 1,2,4-triazoles were obtained. New
4-oxopteridine derivative 26 was also synthesized.
J. Heterocyclic Chem., 49, 845 (2012).
INTRODUCTION
7 heated in NaOH aqueous solution transformed to 1,2,4-
triazole-3-thione 9. In turn, its methyl analog derivative
10 was obtained directly from methylhydrazide 2
in K2CO3 aqueous solution and in the presence of
allyl isothiocyanate. Analogical reaction with ethyl
isothiocyanate in the presence of K2CO3 was performed
by Shutske [10].
The condensation reaction of hydrazide 1 with aro-
matic aldehydes in EtOH in the presence of piperidine
resulted formation of hydrazones 11–14. Condensations
with ketones were performed in dioxane with double
excess of ketone or by refluxing reactants without sol-
vent giving products 15–17.
Reactions of carbohydrazide 1 with CS2 led to 1,3,4-
thiadiazole-2-thione 18 or 1,3,4-oxadiazole-2-thione 21
according to reaction conditions (Scheme 2). Compound
18 was synthesized from hydrazide 1 through the stage of
potassium salt of 2-(3-amino-pyrazine-2-carbonyl)hydra-
zinecarbodithioic acid, which in concentrated H2SO4
underwent cyclization to 1,3,4-triazole-2-thione. Derivative
21 was obtained in a result of the reaction between hydra-
zide 1 and CS2 in a presence of 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) as cyclization agent. However, in
earlier reports, in reaction of CS2 with antranile hydrazide
or 2-aminonicotinic hydrazide, 3-amino-2- thioxo-quinazolin-
4(3H)-one and 2-thioxo-1,3,4-benzotriazepin-5-one were got
mainly [7,8,22]. In analogical reaction of 2-picolinhydrazide
with CS2 in alcohol, Liszkiewicz et al. [6] obtained 1,3,4-
oxadiazole-2-thione.
Nitrogen heterocyclic compounds exhibit multidirec-
tional pharmacological activity like diuretic [1,2], antitu-
mor [3–6], and hypotensic [7–9]. 1,2,4-Triazole [10–12],
1,3,4-oxadiazole and 1,3,4-oxadiazole-2-thiones [6], qui-
nazolones [13], pyrido[2,3-d]pyrimidines [1,2,14,15], and
pteridine [5,16–19] belong to the most active group.
Searching of the prospective biologically active compound
we had interested in 3-amino-pyrazin-2-hydrazide analogs.
The pyrazine derivatives are also used in many pharmaceu-
ticals and plant protection products [20,21]. Our research
concerns especially on compounds with potential tubercu-
lostatic activity. Pyrazine derivatives like pyrazinamide
are well known as therapeutics effective in infections cased
by M. tuberculosis. Therefore, we have taken the synthesis
of series of 3-amino-pyrazine derivatives bearing another
heterocyclic system in C-2 position. Now, we report on
the reactions of 3-amino-pyrazin-2-carbohydrazide 1 and
its N0-methyl derivative 2.
RESULTS AND DISCUSSION
The starting 3-amino-pyrazine-2-carbohydrazide 1 and 3-
amino-N0-methylpyrazine-2-carbohydrazide 2 were obtained
from methyl 3-amino-pyrazine-2-carboxylate in reaction
with hydrazine hydrate or methylhydrazine (Scheme 1).
Carbohydrazides 1 and 2 under treatment of appropriate
isothiocyanates gave thiosemicarbazides 3–8. Compound
© 2012 HeteroCorporation

846
B. Milczarska, K. Gobis, H. Foks, L. Golunski, and P. Sowinski
Vol 49
Scheme 1
Scheme 2
1,3,4-Thiadiazole-2-thione 18 and 1,3,4-oxadiazole-2-
to reaction performed for 2-aminobenzamide by Reddy
and coworkers [23]. However, we received formamide
derivative 26. Reaction details and physical constants of
newly synthesized compounds are given in Table 1.
thione 21 were undergone an alkylation to appropriate sulfides
with methyl iodide (19 and 22) and ethyl bromoacetate (20 and
23) in ethanol–water solution of KOH. For 1,3,4-oxadiazole-2-
thione 21, reactions with N,N-diethylchloroethyleneamine hy-
drochloride and 2-chloro-1-(4-phenylpiperazin-1-yl)ethanone
were also performed, and sulfides 24 and 25 were obtained.
In reaction of carbohydrazide 1 with formic acid, we
expected to obtain 3-aminopteridin-4-(3H)-one according
EXPERIMENTAL
All materials and solvents were of analytical reagent grade.
Thin-layer chromatography was performed on Merck silica gel
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
The Synthesis of 3-Amino-pyrazine-2-carbohydrazide and
847
3-Amino-N0-methylpyrazine-2-carbohydrazide Derivatives
Table 1
Characteristics of newly synthesized compounds 1–29.
m.p. (ꢁC)
Solvent
Formula
MW
Calcd/found
H
No
1
Yield (%)
92
C
N
210–214
C5H7N5O
39.21
43.11
37.16
51.64
39.25
44.65
42.85
45.10
46.14
48.37
51.95
52.28
46.47
54.38
61.17
53.89
56.64
34.11
37.32
40.39
36.92
40.18
42.70
48.96
54.39
43.98
39.18
43.09
37.21
51.61
39.19
44.71
42.83
45.08
46.17
48.39
51.91
52.24
46.51
54.40
61.22
53.87
56.66
34.13
37.28
40.35
36.88
40.22
42.75
48.89
54.41
43.92
4.61
4.60
5.41
4.41
4.66
3.02
3.44
4.80
5.28
4.29
4.87
3.92
3.66
2.92
5.15
5.11
4.16
6.46
2.39
3.13
3.73
2.58
3.37
3.94
6.14
4.83
2.64
45.73
41.89
37.14
27.80
22.89
26.04
33.31
31.56
35.87
33.85
30.29
25.40
22.58
21.14
27.43
24.17
30.02
33.15
31.09
23.55
35.88
33.47
24.90
28.55
24.67
36.64
45.81
MeOH
107–108
MeOH
252–256
DMF + H2O
204–207
Dioxane + H2O
193–196
Dioxane
237–243
DMF + H2O
187–189
MeOH
140–141
Metanol
299–301
DMF + MeOH
139–140
MeOH
186–189
MeOH + H
259–262
Dioxane + H2O
246–249
Dioxane + H2O
229–232
Dioxane
230–232
Dioxane + MeOH
247–249
Dioxane
133–134
Dioxane + cyclohexane
198–199
DMF + MeOH
180–181
MeOH
258–260
DMF + MeOH
268–272
DMF + MeOH
192–193
MeOH
127–129
153.14
C6H9N5O
167.17
C7H10N6OS
226.26
2
82
5.43
4.45
4.67
3.02
3.44
4.79
5.30
4.30
4.87
3.92
3.66
2.92
5.17
5.13
4.17
6.48
2.39
3.13
3.73
2.58
3.37
3.94
6.16
4.82
2.64
41.90
37.15
27.79
22.90
26.03
33.32
31.56
35.85
33.87
30.30
25.40
22.59
21.15
27.43
24.16
30.03
33.15
31.10
23.54
35.89
33.47
24.91
28.54
26.67
36.61
3
89
4
60
C
13H14N6OS
302.35
12H11BrN6OS
367.22
C12H11ClN6OS
5
44
C
6
78
322.77
C9H12N6OS
252.30
C10H14N6OS
266.32
7
87
8
30
9
72
C9H10N6S
234.28
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
40
C
10H12N6S
248.31
10H9N5O2
231.21
12H10ClN5O
275.69
12H9Cl2N5O
310.14
15H17N5O4
331.33
13H13N5O
255.28
13H12ClN5O
289.72
11H15N5O
70
C
88
C
77
C
59
C
88
C
56
C
53
C
233.27
C6H5N5S2
211.27
57
34
C7H7N5S2 225.29
30
C10H11N5O2S2
297.36
C6H5N5OS
195.20
C7H7N5OS
209.23
83
73
77
C
10H11N5O3S
294.38
12H18N6OS
294.38
18H19N7O2S
EtOH
164–165
MeOH
227–229
DMF + MeOH
213–214
EtOH + H2O
58
C
39
C
397.45
C7H5N5O2
191.15
62
60F254 plates and visualized with UV. The results of elemen-
tal analyses (%C, H, N) for all of obtained compounds were
in agreement with calculated values within ꢀ0.3% range.
1H-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 spectro-
photometer. Mass spectra for compounds 11, 18, 19, 21,
22, and 26 were taken on Biosystem Qstar XL MS/MS
spectrometer with electro spray ionization system (70 eV).
Melting points were determined on BOETIUS apparatus and
were uncorrected.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

848
B. Milczarska, K. Gobis, H. Foks, L. Golunski, and P. Sowinski
Vol 49
3-Amino-pyrazine-2-carbohydrazide (1). The suspension of
N-Allyl-2-(amino-pyrazine-2-carbonyl)hydrazinecarbothioamide
(7). This compound was obtained as colorless crystals. IR:
3310 (n N―H), 3100 (n N―H), 2979 (n C―H), 2900
(n C―H), 1680 (n C═O), 1614 (n C═N), 1546 (d N―H),
4.6 g (30 mmol) of methyl 3-amino- pyrazine-2-carboxylate and
3 mL (60 mmol) of 98% hydrazine hydrate in 30 mL of EtOH
was refluxed for 4 h. Then, the mixture was cooled, and the
product was filtered and recrystallized from MeOH. Yield 92%;
m.p. 211–213ꢁC. (lit. ref. [19], m.p. 210–211ꢁC).
1062 (n C═S), 927 (g C―H), 860 (g C―H) cmꢂ1
;
1H-NMR (200 MHz, DMSO-d6): d 4.05–4.09 (m; 2H, CH2),
5.08 (dd; 2H, CH2, J 1.8 Hz), 5.80–5.83 (m; 1H, CH), 7.45
(brs; 2H, NH2), 7.84 (d, 1H, pyrazine, J 2.3 Hz), 8.15–8.19
(m; 1H, NHCH2), 8.22 (d; 1H, pyrazine, J 2.3 Hz), 9.31 (s;
1H, NH), 10.45 (s; 1H, NH) ppm.
3-Amino-N0-methylpyrazine-2-carbohydrazide (2). To the
solution of 4.6 g (30 mmol) of methyl 3-amino-pyrazine-2-
carboxylate in 10 mL of EtOH and 20 mL of dioxane, 3.2 mL
(80 mmol) of methylhydrazine was added. The mixture was
refluxed for 4 h. Then, the solvent was evaporated, and
the residue was treated with 2 mL of MeOH and 5 mL of
diethyl ether. The precipitate was filtered and recrystallized
from MeOH. Yield 82%; m.p. 107–108ꢁC. (lit. ref. [10], m.p.
105–107ꢁC).
N-Allyl-2-(amino-pyrazine-2-carbonyl)-1-methylhydrazine-
carbothioamide (8). To 0.25 g (1.5 mmol) of methylhydrazide 2
dissolved in 15 mL of dioxane 0.15 mL (1.5 mmol) of allyl
isothiocyanate was added. The mixture was refluxed for 1.5 h
and cooled down. Then, solvent was evaporated, and 15 mL of
diethyl ether was added to the residue. Crude product was
filtered and recrystallized. IR: 3410 (n N―H), 3270 (n N―H),
1679 (n C═O), 1604 (n C═N), 1528 (d N―H), 1480 (d N―H),
General procedure for the synthesis of 2-(3-amino-pyrazine-2-
carbonyl)hydrazinecarbothioamides (3–7). Carbohydrazide 1 (0.38 g,
2.5 mmol) was dissolved in 15 mL of anhydrous dioxane, and
2.5 mmol of suitable isothiocyanate was added. The mixture
was refluxed for 4–8 h. Reaction progress was controlled with
TLC method. Then, the solvent was evaporated, and the residue
was treated with toluene. The crude solid was filtered and
recrystallized.
1050 (n C═S), 923 (g C―H), 812 (g C―H) cmꢂ1 1H-NMR
;
(500 MHz, CDCl3): d 3.69 (s; 3H, CH3), 4.27–4.31 (m; 2H,
CH2), 5.13–5.16 (m; 2H, CH2), 5.84–5.88 (m; 1H, CH), 6.58
(brs; 2H, NH2), 7.84 (d; 1H, pyrazine, J 2.0 Hz), 8.22 (d; 1H,
pyrazine, J 2.0 Hz), 9.40 (s; 1H, NH) ppm.
2-(3-Amino-pyrazine-2-carbonyl)-N-methylhydrazine-
carbothioamide (3). This compound was obtained as colorless small
needles. IR: 3359 (n N―H), 3307 (n N―H), 3210 (n N―H), 2933
(n C―H), 1655 (n C═O), 1625 (n C═N), 1556 (d N―H), 1491
4-Allyl-3-(3-amino-pyrazin-2-yl)-1H-1,2,4-triazole-5 (4H)-
thione (9). Compound 7 (1.26 g, 5 mmol) was refluxed for 2 h
in 20 mL of 10% NaOH aqueous solution. The mixture was
cooled and acidified with acetic acid. The precipitate was
filtered and recrystallized. IR: 3386 (n N―H), 3162 (n N―H),
1621 (n C═N), 1555 (d N―H), 1469 (d N―H), 984 (g C―H),
(d N―H), 1070 (n C═S), 926 (g C―H), 760 (g N―H) cmꢂ1
;
1H-NMR (200 MHz, DMSO-d6): d 2.82 (d; 3H, CH3, J 4.4 Hz),
7.40 (brs; 2H, NH2 + D2O [-]), 7.80 (d; 1H, pyrazine, J 2.3 Hz),
7.93–7.96 (m; 1H, NH + D2O exchangeable), 8.24 (d; 1H,
pyrazine, J 2.3 Hz), 9.20 (brs; 1H, NH + D2O exchangeable),
10.40 (brs; 1H, NH + D2O exchangeable) ppm.
835 (g C―H) cmꢂ1 1H-NMR (500 MHz, DMSO-d6): d 4.95
;
(d; 1H, CH, J 17,1 Hz), 5.06 (d; 1H, CH, J 10.3 Hz), 5.15 (d;
2H, J 4.9 Hz), 5.84–5.22 (m; 1H, CH), 7.20 (s; 2H, NH2), 7.94
(d; 1H, pyrazine, J 2.0 Hz), 14.28 (s; 1H, NHCS) ppm.
2-(3-Amino-pyrazine-2-carbonyl)-N-benzylhydrazinecarbothiamide
(4). This compound was obtained as light beige prisms. IR:
3270 (n N―H), 3180 (n N―H), 2957 (n C―H), 2851
(n C―H), 1680 (n C═O), 1602 (n C═N), 1552 (d N―H),
1046 (n C═S), 871 (g C―H), 815 (g C―H), 742 (g N―H)
4-Allyl-3-(3-amino-pyrazin-2-yl)-1-methyl-1,2,4-triazole-5
(4H)-thione (10). Methylhydrazide 2 (0.25 g, 1.5 mmol) was
dissolved in 5 mL of 10 % K2CO3. Then, 1.5 mL (15 mmol)
of allyl isothiocyanate and 2 mL of dioxane were added. The
mixture was refluxed for 1.5 h, cooled and 10 mL of water
was added. The crude product was filtered and recrystallized
yielding bright needles. IR: 3389 (n N―H), 3128 (n N―H),
cmꢂ1 1H-NMR (200 MHz, DMSO-d6): d 4.70 (d; 2H,CH2,
;
J 6.14), 7.26–7.29 (m; 5H, Ph), 7.44 (brs; 2H, NH2), 7.80
1
(d; 1H, pyrazine, 2.3 Hz), 8.20 (d; 1H, pyrazine,
J
1625 (n C═N), 1469 (d N―H), 925 (g C―H) cmꢂ1; H-NMR
J 2.4 Hz), 8.54 (brs; 1H, NHCH2), 9.40 (s; 1H, NH), 10.53
(s; 1H, NH) ppm.
(500 MHz, CDCl3): d 3.95 (s; 3H, CH3), 5.20 (m; 2H, CH2),
5.44 (d; 2H, CH2, J 5.9 Hz), 5.96 (m; 1H, CH), 6.60 (brs; 2H,
NH2), 8.02 (d; 1H, pyrazine, J 2.4 Hz), 8.09 (d, 1H, pyrazine,
J 2.4 Hz) ppm.
2-(3-Amino-pyrazine-2-carbonyl)-N-(4-bromophenyl)
hydrazinecarbothioamide (5). This compound was obtained as
white prisms. IR: 3373 (n N―H), 3273 (n N―H), 3198
(n N―H), 2957 (n C―H), 2913 (n C―H), 1675 (n C═O), 1624
(n C═N), 1530 (d N―H), 1045 (n C═S), 870 (g C―H), 727
General procedure for the synthesis of 3-amino-N0-
methylenepyrazine-2-carbohydrazide derivatives (11–14).
Hydrazide 1 (0.25 g, 1.6 mmol) was dissolved in 10 mL of
anhydrous ethanol and equimolar amount of suitable aldehyde
and four drops of piper dine were added. The mixture was
refluxed for 4–8 h. The reaction progress was observed with
TLC method. Then the solvent was evaporated to 1/3 of the
volume. The solution was cooled, and the given precipitate was
filtered and recrystallized.
(g N―H) cmꢂ1 1H-NMR (200 MHz, DMSO-d6): d 7.46–7.48
;
(m; 6H, 4H Ph and 2H NH2), 7.85 (d; 1H, pyrazine, J 2.4 Hz),
8.25 (d; 1H, pyrazine, J 2.4 Hz), 8.58 (s; 1H, NH), 9.75 (brs; 1H,
NH), 10.62 (s; 1H, NH) ppm.
2-(3-Amino-pyrazine-2-carbonyl)-N-(4-chlorophenyl)
hydrazinecarbothioamide (6). This compound was obtained as small
prisms. IR: 3374 (n N―H), 3289 (n N―H), 3171 (n N―H),
3100 (n N―H), 2912 (n C―H), 1678 (n C═O), 1627
(n C═N), 1561 (d N―H), 1525 (d N―H), 1060 (n C═S), 889
3-Amino-N0-(furan-2-ylmethylene)pyrazine-2-carbohydrazide
(11). This compound was obtained as white powder. IR: 3289
(n N―H), 3230 (n N―H), 3142 (n N―H), 1680 (n C═O),
1644 (n C═N), 1598 (d N―H), 1519 (d N―H), 1160
(g C―H), 848 (g C―H), 789 (g N―H) cmꢂ1 1H-NMR
;
(200 MHz, DMSO-d6): d 7.30–7.50 (m; 6H, 4H Ph, and 2H
NH2), 7.86 (d; 1H, pyrazine, J 2.3 Hz), 8.24 (d; 1H, pyrazine,
J 2.3 Hz), 8.62 (s; 1H, NH), 9.75 (s; 1H, NH), 10.62 (s; 1H,
NH) ppm.
(n C―O), 946 (g C―H), 858 (g C―H), 749 (g N―H) cmꢂ1
;
1H-NMR (500 MHz, DMSO-d6): d 6.63 (t, 1H, furan, J 3.4 Hz)
6.88 (d; 1H, furan, J 3.3 Hz), 7.60 (brs; 2H, NH2), 7.84 (d; 1H
furan, J 1.8 Hz), 7.88 (d; 1H, pyrazine, J 2.3 Hz), 8.27 (d; 1H,
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DOI 10.1002/jhet

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The Synthesis of 3-Amino-pyrazine-2-carbohydrazide and
849
3-Amino-N0-methylpyrazine-2-carbohydrazide Derivatives
pyrazine, J 2.4 Hz), 8.48 (s; 1H, CH), 12.08 (s; 1H, NHCO + D2O
exchangeable) ppm; MS: m/z 231 (M+).
5-(3-Amino-pyrazin-2-yl)-1,3,4-thiadiazole-2(3H)-thione
(18). To 1.53 g (10 mmol) of hydrazide 1, the solution of 0.68 g
(12 mmol) of KOH in 3 mL of water and 20 mL of ethanol was
added. The mixture was refluxed for 2 h. Then, 30 mL of
diethyl ether was added the precipitated salt, and solid was
filtered. Yield 88%; m.p. 316–319ꢁC.
3-Amino-N0-(4-chlorobenzylidene)pyrazine-2-carbohydrazide
(12). This compound was obtained as white powder. IR: 3317
(n N―H), 3256 (n N―H), 3148 (n N―H), 1674 (n C═O), 1612
(n C═N), 1593 (d N―H), 1513 (d N―H), 866 (g C―H), 733
1
(g N―H), 700 (n C―Cl) cmꢂ1; H-NMR (200 MHz, DMSO-d6):
The obtained potassium salt (2.65 g, 10 mmol) was heated in
20 mL of concentrated H2SO4 at 90ꢁC for 1 h. Then, the mixture
was poured onto 50 g of ice. The solid was filtered, dissolved in
30% NaOH aqueous solution, precipitated with acetic acid, and
recrystallized. IR: 3421 (n N―H), 3160 (n N―H), 2853
(n C―H), 1620 (n C═N), 1560 (d N―H), 1071 (n C═S), 995
d 7.52 (d; 2H, Ph, J 8.5 Hz), 7.60 (brs; 2H, NH2), 7.70 (d; 2H, Ph,
J 8.6 Hz), 7.89 (d; 1H, pyrazine, J 2.4 Hz), 8.27 (d; 1H, pyrazine,
J 2.3 Hz), 8.58 (s; 1H, CH), 12.10 (s; 1H, NHCO) ppm.
3-Amino-N0-(3,4-chlorobenzylidene)pyrazine-2-carbohydrazide
(13). This compound was obtained as white powder. IR: 3385
(n N―H), 3250 (n N―H), 3148 (n N―H), 2962 (n C―H), 1672
(n C═O), 1612 (n C═N), 1530 (d N―H), 881 (g C―H), 836
(g C―H) cmꢂ1; 1H-NMR (200 MHz, DMSO-d6): d 7.60 (brs; 2H,
NH2), 7.66–7.70 (m; 2H, Ph), 7.85 (s; 1H, Ph), 7.88 (d; 1H,
pyrazine, J 2.3 Hz), 8.27 (d; 1H, pyrazine, J 2.3 Hz), 8.55 (s; 1H,
CH), 12.20 (s; 1H, NHCO) ppm.
(g C―H), 734 (g N―H) cmꢂ1 1H-NMR (200 MHz, DMSO-
;
d6): d 7.10 (brs; 2H, NH2), 8.00 (d; 1H, pyrazine, J 2.3 Hz),
8.24 (d; 1H, pyrazine, J 2.3 Hz), 14.00 (s; 1H, NHCO) ppm;
MS: m/z 211 (M+).
General procedure for the synthesis of sulfide derivatives
(19, 20). Compound 18 (2.5 mmol) was added to the solution of
0.2 g of KOH in 10 mL of water and 10 mL of ethanol. The
mixture was stirred until dissolved. Then, 0.21 mL (3.3 mmol)
of iodomethane or 0.28 mL (2.5 mmol) of ethyl bromoacetate
was added and refluxed for 1 h. Then, mixture was cooled, and
solid was filtered and recrystallized.
3-Amino-N0-(3,4,5-trimethoxybenzylidene)pyrazine-2-
carbohydrazide (14). This compound was obtained as white
powder. IR: 3438 (n N―H), 3260 (n N―H), 3103 (n N―H), 2936
(n C―H), 2842 (n C―H), 1672 (n C═O), 1612 (n C═N), 1577
(d N―H), 1527 (d N―H), 1166 (n C―O), 925 (g C―H), 853
1
(g C―H) cmꢂ1; H-NMR (200 MHz, DMSO-d6): d 3.69 (s; 3H,
2-(3-Amino-pyrazin-2-yl)-5-methylthio-1,3,4-thiadiazole (19).
This compound was obtained as white powder. IR: 3372
(n N―H), 3153 (n N―H), 1637 (n C═N), 992 (g C―H), 751
CH3), 3.83 (s, 6H, 2CH3), 6.97 (s; 2H, Ph), 7.60 (s; 2H, NH2), 7.88
(d; 1H, pyrazine, J 2.4 Hz), 8.27 (d; 1H, J 2.4 Hz) 8.49 (s; 1H, CH),
12.00 (s; 1H, NHCO + D2O exchangeable) ppm.
(g N―H) cmꢂ1 1H-NMR (200 MHz, CDCl3): d 2.86 (s; 3H,
;
General procedure for the synthesis of 3-amino-N0-
methylenepyrazine-2-carbohydrazide derivatives (15–17).
To 0.25 g (1.6 mmol) of hydrazide 1 in 15 mL of dioxane
double excess (3.2 mmol) of suitable ketone was added. The
mixture was refluxed for 12–24 h. Then mixture was
concentrated to 1/3 of its volume and cooled. The precipitate
was filtered and recrystallized. Compound 16 was obtained
from hydrazide 1 (1.6 mmol) by refluxing in 6 mL of
cyclohexanone. After concentration 10 mL of toluene was
added. The solid was filtered and recrystallized.
CH3), 7.15 (brs; 2H, NH2), 7.99–8.04 (m; 2H, pyrazine) ppm;
MS: m/z 225 (M+).
Ethyl 2-(5-(3-amino-pyrazin-2-yl)-1,3,4-thiadiazol-2-ylthio)
acetate (20). This compound was obtained as white powder. IR:
3384 (n N―H), 3155 (n N―H), 1733 (n C═O), 1632 (n C═N),
1
1558 (d N―H), 1025 (n C―O), 762 (g N―H) cmꢂ1; H-NMR
(200 MHz, CDCl3): d 1.31 (t, 3H, CH3, J 7 Hz), 4.20 (s; 2H,
CH2), 4.29 (q; 2H, CH2, J 7.1 Hz), 7.17 (brs; 2H, NH2), 7.95–
8.05 (m; 2H, pyrazine) ppm.
3-Amino-N0-(1-phenylethylidene)pyrazine-2-carbohydrazide
(15). This compound was obtained as white powder. IR: 3336
(n N―H), 3247 (n N―H), 3142 (n N―H), 1677 (n C═O), 1606
(n C═N), 1560 (d N―H), 1511 (d N―H), 857 (g C―H), 810
5-(3-Amino-pyrazin-2-yl)-1,3,4-oxadiazole-2(3H)-thione (21).
Hydrazide 1 (1.53 g, 10 mmol) was added to the solution of 1.5 mL
(10 mmol) of DBU and 1 mL (10 mmol) of CS2 in 50 mL of
ethanol. The mixture was refluxed for 10 h. Then, the solvent
was evaporated, and 20 g of ice was added to the residue. The
mixture was acidified with acetic acid, solid was filtered and
recrystallized. IR: 3373 (n N―H), 3289 (n N―H), 3171
(n N―H), 2912 (n C―H), 1627 (n C═N), 1493 (d N―H), 1088
(g C―H) cmꢂ1 1H-NMR (200 MHz, CDCl3): d 2.40 (s; 3H,
;
CH3), 7.28 (brs; 2H, NH2), 7.38–7.41 (m; 3H, Ph), 7.84 (d; 1H,
pyrazine, J 2.4 Hz), 7.84–7.89 (m; 2H, Ph), 8.20 (d; 1H, pyrazine,
J 2.4 Hz), 10.78 (s; 1H, NHCO) ppm.
(n C═S), 949 (g C―H) 788 (g N―H) cmꢂ1 1H-NMR
;
3-Amino-N0-(1-(4-chlorophenyl)ethylidene)pyrazine-2-
carbohydrazide (16). This compound was obtained as light beige
powder. IR: 3396 (n N―H), 3258 (n N―H), 3147 (n N―H),
1680 (n C═O), 1613 (n C═N), 1562 (d N―H), 860 (g C―H),
(200 MHz, DMSO-d6): d 7.17 (brs; 2H, NH2), 7.99 (d; 1H,
pyrazine, J 2.4 Hz), 8.24 (d; 1H, pyrazine, J 2.4 Hz) ppm; MS:
m/z 195 (M+).
842 (g C―H), 764 (g N―H), 698 (n C―Cl) cmꢂ1
;
1H-NMR
General procedure for the synthesis of sulfides (22–25).
Compound 21 (0.49 g, 2.5 mmol) was added to the solution of 0.2 g
(3.5 mmol) of KOH in 10 mL of ethanol and 10 mL of water.
The mixture was stirred until dissolved. Then, 3.3 mmol
(0.21 mL) of iodomethane or 2.5 mmol of ethyl bromoacetate,
N,N-diethylchloroethylenediamine hydrochloride or 2-chloro-1-(4-
phenylpiperazin-1-yl)ethanone was added. The mixture was
stirred at room temperature for 2 h. Then, solid was filtered and
recrystallized.
2-(3-Amino-pyrazin-2-yl)-5-methylthio-1,3,4-oxadiazole (22).
This compound was obtained as light beige needles. IR: 3293
(n N―H), 3158 (n N―H), 1637 (n C═N), 1570 (d N―H),
1477 (d N―H), 1081 (n C―O), 992 (g C―H), 843 (g C―H)
(200 MHz, CDCl3): d 2.38 (s; 3H, CH3), 7.18 (brs; 2H, NH2),
7.34–7.38 (m; 2H, Ph), 7.80–7.86 (m; 3H, 2H Ph and 1H
pyrazine), 8.22 (d; 1H, pyrazine, J 2.4 Hz), 10.80 (s; 1H,
NHCO) ppm.
3-Amino-N0-cyclohexylidenepyrazine-2-carbohydrazide
(17). This compound was obtained as small white crystals. IR: 3395
(n N―H), 3264 (n N―H), 3150 (n N―H), 2937 (n C―H), 2851
(n C―H), 1680 (n C═O), 1616 (n C═N), 1502 (d N―H), 935
(g C―H), 856 (g C―H) cmꢂ1
;
1H-NMR (500 MHz, CDCl3):
d 1.70–1.80 (m; 6H, 2CH3), 2.40–2.43 (m; 4H, 2CH2), 7.05 (brs;
2H, NH2), 7.78 (d; 1H, pyrazine, J 2.2 Hz), 8.17 (d; 1H, pyrazine,
J 2.3 Hz), 10.56 (s; 1H, NHCO) ppm.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

850
B. Milczarska, K. Gobis, H. Foks, L. Golunski, and P. Sowinski
Vol 49
cmꢂ1; 1H-NMR (200 MHz, CDCl3): d 2.82 (s; 3H, CH3), 6.67 (brs;
2H, NH2), 8.07 (d; 1H, pyrazine, J 2.4 Hz), 8.17 (d; 1H, pyrazine,
J 2.4) ppm; MS: m/z 209 (M+).
pyrazine, J 2.1 Hz), 8.08 (s; 1H, CH), 8.26 (d; 1H, pyrazine,
J 2.2 Hz), 8.39 (s; 1H, CHO) ppm; MS: m/z 191 (M+).
Ethyl 2-(5-(3-amino-pyrazin-2-yl)-1,3,4-oxadiazol-2-ylthio)
acetate (23). This compound was obtained as light beige
needles. IR: 3295 (n N―H), 3143 (n N―H), 2935 (n C―H),
1742 (n C═O), 1636 (n C═N), 1475 (d N―H), 1087 (n C―O),
REFERENCES AND NOTES
893 (g C―H) cmꢂ1 1H-NMR (200 MHz, DMSO-d6): d 1.19
;
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(t; 3H, CH3, J 7.0 Hz), 4.17 (q; 2H, CH2, J 7.1 Hz), 4.29 (s; 2H,
CH2), 7.46 (brs; 2H, NH2), 8.00 (d; 1H, pyrazine, J 2.4 Hz),
8.25 (d; 1H, pyrazine, J 2.4 Hz) ppm.
2-(3-Amino-pyrazin-2-yl)-5-(2-(diethylamino)ethylthio)-1,3,
4-oxadiazole (24). This compound was obtained as small beige
needles. IR: 3281 (n N―H), 3148 (n N―H), 2967 (n C―H),
1625 (n C═N), 1466 (d N―H), 1085 (n C―O), 849
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1
(g C―H), 757 (g N―H) cmꢂ1; H-NMR (200 MHz, CDCl3):
d 1.12–1.18 (m; 6H, 2CH3), 2.73–2.82 (m; 4H, 2CH2), 3.01
(m; 2H, CH2), 3.54–3.60 (m; 2H, SCH2), 6.56 (brs; 2H, NH2),
8.05 (d; 1H, pyrazine, J 2.4 Hz), 8.16 (d; 1H, pyrazine,
J 2.4 Hz) ppm.
2-(5-(3-Amino-pyrazin-2-yl)-1,3,4-oxadiazol-2-ylthio)-1-(4-
phenylpiperazin-1-yl)ethanone (25). This compound was
obtained as small white needles. IR: 3287 (n N―H), 3163
(n N―H), 3053 (n N―H), 2923 (n C―H), 1669 (n C═O),
1470 (d N―H), 1085 (n C―O), 930 (g C―H), 763 (g N―H)
cmꢂ1 1H-NMR (200 MHz, DMSO-d6): d 3.18–3.22 (m; 4H,
;
CH2NCH2), 3.62–3.67 (m; 4H, CH2NCH2), 4.63 (s; 2H,
CH2), 6.80 (t; 1H, Ph, J 7.3 Hz), 6.97 (d; 2H, Ph, J 7.6 Hz),
7.24 (t; 2H, Ph, J 7.4 Hz), 7.47 (brs; 2H, NH2), 9.97 (d; 1H,
pyrazine, J 2.3 Hz), 8.24 (d; 1H, pyrazine, J 2.2 Hz) ppm.
N-(4-Oxopteridin-3-(4H)-yl)formamide (26). Hydrazide 1
(0.76 g (5 mmol) and 5 mL of formic acid were refluxed for 4 h.
Then, mixture was cooled, and ammonium hydroxide was added.
The solid precipitate was filtered and recrystallized. IR: 3298
(n N―H), 2999 (n C―H), 1687 (n C═O), 1621 (n C═N), 1461
[16] Fernandez, A. M.; Duhamel, L. J Org Chem 1996, 61, 8698.
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Acta Polon Pharm 1994, 51, 243.
(d N―H), 933 (g C―H), 737 (g N―H), cmꢂ1
;
1H-NMR
(200 MHz, DMSO-d6): d 7.47 (s; 1H, NH), 7.85 (d; 1H,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet