Convenient Synthesis of [1,2,4]Triazolo[4,3-a][1,3,5]triazin-5-amines, [1,2,4]Triazolo[4,3-c][1,3,5]thiadiazine-5-thiones, and [1,2,4]Triazolo[4,3-c][1,3,5]thiadiazin-5-imines from N-(4H-1,2,4-Triazol-3-yl) Carboximidates

Article abstract of DOI:10.1134/S107042801910018X

The condensation of 4H-1,2,4-triazol-3-amine with ortho esters derived from acetic, propionic, and benzoic acids gave the corresponding N-(4H-1,2,4-triazol-3-yl) carboximidates which were treated with cyan-amide, carbon disulfide, and sodium thiocyanate t

Full text of DOI:10.1134/S107042801910018X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 10, pp. 1580–1583. © Pleiades Publishing, Ltd., 2019.
Convenient Synthesis of [1,2,4]Triazolo[4,3-a][1,3,5]triazin-
5-amines, [1,2,4]Triazolo[4,3-c][1,3,5]thiadiazine-5-thiones,
and [1,2,4]Triazolo[4,3-c][1,3,5]thiadiazin-5-imines
from N-(4H-1,2,4-Triazol-3-yl) Carboximidates
A. Hajria* and L. Marzoukia
a Laboratory of Functional Physiology and Valuation of Bio-resources (UR17ES27),
Higher Institute of Biotechnology of Beja, University of Jendouba, Beja, Tunisia
*e-mail: lazharhajri.fsb@gmail.com
Received April 26, 2019; revised August 9, 2019; accepted August 15, 2019
Abstract—The condensation of 4H-1,2,4-triazol-3-amine with ortho esters derived from acetic, propionic, and
benzoic acids gave the corresponding N-(4H-1,2,4-triazol-3-yl) carboximidates which were treated with cyan-
amide, carbon disulfide, and sodium thiocyanate to afford 7-substituted [1,2,4]triazolo[4,3-a][1,3,5]triazin-5-
amines, [1,2,4]triazolo[4,3-c][1,3,5]thiadiazine-5-thiones, and [1,2,4]triazolo[4,3-c][1,3,5]thiadiazin-5-imines,
respectively. The structures of the synthesized compounds were confirmed by IR, 1H and 13C NMR, and mass
spectra and elemental analyses.
Keywords: 1,2,4-triazol-3-amine, carboximidates, [1,2,4]triazolo[4,3-a]triazin-5-amines, [1,2,4]triazolo[4,3-c]-
[1,3,5]thiadiazine-5-thiones, [1,2,4]triazolo[4,3-c][1,3,5]thiadiazin-5-imines, ortho esters.
DOI: 10.1134/S107042801910018X
The design, synthesis, and production of com-
pounds valuable as biological and therapeutic agents
remain one of the main objectives of organic and
medicinal chemistry. The importance of triazolotri-
azines is well recognized in the field of medicinal
chemistry because these heterocycles are structurally
related to purine and adenine [1, 2]. Triazolotriazines
have been reported to possess different biological
activities; in particular, herbicides [3], eosinophilia
inhibitors [4], and antitumor agents have been found in
the triazolotriazine series [5, 6]. Among triazole deriv-
atives, triazolothiadiazines have received considerable
attention due to their biological importance [7, 8].
Our recent interests were aimed at the synthesis and
chemical properties of [1,2,4]triazolo[4,3-a][1,3,5]tri-
azin-5-amines 2a–2c, [1,2,4]triazolo[4,3-c][1,3,5]thia-
diazine-5-thiones 3a–3c, and [1,2,4]triazolo[4,3-c]-
[1,3,5]thiadiazin-5-imines 4a–4c.
N-(4H-1,2,4-Triazol-3-yl) carboximidates 1a–1c
were synthesized by condensation of 4H-1,2,4-triazol-
3-amine with the corresponding ortho esters in the
presence of acetic acid. Imino esters 1a–1c were
selected as model substrates to react with cyanamide,
carbon disulfide, and sodium thiocyanate with the goal
of obtaining compounds 2–4 (Scheme 1, Table 1).
Treatment of 1a–1c with cyanamide in methanol under
reflux gave triazolotriazinamines 2a–2c whose IR,
1H and 13C NMR, and mass spectra and elemental
analyses were in good agreement with the assigned
structures (see Experimental). The IR spectra of 2
exhibited absorption bands at 3130–3200 (NH2) and
1
1618 cm–1 (C=N). The H NMR spectrum of 2c
showed signals of aromatic protons in the region
δ 7.10–7.65 ppm. The presence of an amino group in
molecules 2a–2c was confirmed by the disappearance
of signals at δ 7.32 (2a), 7.12 (2b), and 7.52 ppm (2c)
after addition of D2O. Furthermore, neither NH nor
EtO signals typical of initial esters 1 were observed.
The 13C NMR spectra of 2 were also consistent with
the proposed structure.
The reaction of 1 with carbon disulfide is likely to
involve initial proton elimination from the N4H group
by pyridine. The second step is nucleophilic attack of
the N4 nitrogen atom of 1 on the C=S carbon atom.
Finally, intramolecular cyclization affords triazolothia-
diazinethione 3 (Scheme 1). The IR spectra of 3a–3c
showed absorption bands corresponding to C=N and
C=S bonds at 1615 and 1250 cm–1, whereas no N–H
1580

CONVENIENT SYNTHESIS OF [1,2,4]TRIAZOLO[4,3-a][1,3,5]TRIAZIN-5-AMINES
1581
Scheme 1.
NH2
NH2CN/MeOH
reflux, 48 h
N
N
S
S
N
N
N
N
N
N
N
R
R
R
2a–2c
S
R
CS2, Py/EtOH
reflux, 24 h
N
N
NH
RC(OEt)3/AcOH
N
OEt
N
NH2
N
N
N
N
H
1a–1c
3a–3c
NH
N
NaSCN, EtOH/H2O
reflux, 12 h
N
4a–4c
R = Me (a), Et (b), Ph (c).
stretching band was present. In the 13C NMR spectra of
3a–3c, the C=S carbon atom resonated at δC 172.2
(3a), 173.5 (3b), and 171.1 ppm (3c) in addition to
other characteristic carbon signals.
performed on a Perkin Elmer 2400 Series II CHNS/O
analyzer (USA). The mass spectra (positive electron
spray ionization) were recorded on a Bruker Daltonics
LC/MS instrument (USA). All chemicals, reagents,
and solvents were obtained from Sigma–Aldrich and
were used without any purification. The yields and
melting points of compounds 1a–1c, 2a–2c, 3a–3b,
and 4a–4c are given in Table 1.
The reaction of 1a–1c with an equimolar amount of
sodium thiocyanate (NaSCN) in ethanol under reflux
for 12 h afforded [1,2,4]triazolo[4,3-c][1,3,5]thiadi-
azin-5-imines 4a–4c. The IR spectra of 4 showed
absorption bands in the regions 1628–1622 (C=N) and
3450–3440 cm–1 (=N–H). The 1H NMR spectrum of 4c
displayed two multiplets in the region δ 7.3–7.8 ppm
due to aromatic protons and a broadened singlet at
δ 4.83 ppm due to =NH.
N-(4H-1,2,4-Triazol-3-yl) carboximidates 1a–1c
were synthesized by heating 4H-1,2,4-triazol-3-amine
with excess triethyl orthoacetate, triethyl orthopro-
pionate, or triethyl orthobenzoate in the presence of
In conclusion, the proposed method seems to be
economically feasible because the products can be
obtained through a facile two-step reaction from
commercially available and relatively inexpensive
chemicals. Further research on biological activity of
heterocyclic compounds 2a–2c, 3a–3b, and 4a–4c is
needed.
Table 1. Yields and melting points of compounds 1a–1c,
2a–2c, 3a–3c, and 4a–4c
Compound no.
Yield, %
mp, °C
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
65
68
74
66
55
75
60
65
70
48
53
67
150–152
162–164
148–150
280–282
290–292
275–277
180–182
195–197
205–208
230–233
217–219
286–288
EXPERIMENTAL
The IR spectra were recorded with a Nicolet IR200
1
FT-IR spectrometer (USA). The H and 13C NMR
spectra were recorded on a on a Bruker AC 300 spec-
1
trometer (USA; 300 MHz for H) using DMSO-d6 as
solvent and tetramethylsilane as internal standard. The
melting points were determined on an Electrothermal
9100 melting point apparatus (Weiss-Gallenkamp,
Loughborough, UK). Elemental micro analysis was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

HAJRI, MARZOUKI
1582
acetic acid under reflux for 3 h. The solvent was
evaporated under reduced pressure, and the residue
was recrystallized from ethanol.
m/z 165 [M + H]+. Found, %: C 43.97; H 4.95;
N 51.23. C6H8N6. Calculated, %: C 43.90; H 4.91;
N 51.19.
7-Phenyl[1,2,4]triazolo[4,3-a][1,3,5]triazin-5-
Ethyl N-(4H-1,2,4-triazol-3-yl)acetimidate (1a).
amine (2c). IR spectrum, ν, cm–1: 3130–3200 (NH2),
1
IR spectrum: ν 1660 cm–1 (C=N). Н NMR spectrum,
1
1618 (C=N). Н NMR spectrum, δ, ppm: 7.15–7.65 m
δ, ppm: 1.42 t (3H, CH3CH2), 2.30 s (3H, CH3C=N),
4.18 q (2H, CH2O), 8.82 s (1H, 5-H), 10.80 s (1H,
NH). 13C NMR spectrum, δC, ppm: 16.4, 23.2, 62.2,
152.9, 154.1, 161.2. Found, %: C 46.85; H 6.68;
N 36.40. C6H10N4O. Calculated, %: C 46.74; H 6.54;
N 36.34.
(5H, Harom), 9.12 s (1H, 3-H), 7.52 br.s (2H, NH2, D2O
exchangeable). 13C NMR spectrum, δC, ppm: 113.1,
115.3, 115.8, 126.3, 126.9, 131.7, 152.2, 154.1, 155.6,
162.4. Mass spectrum: m/z 213 [M + H]+. Found, %:
C 56.63; H 3.82; N 39.64. C10H8N6. Calculated, %:
C 56.60; H 3.80; N 39.60.
Ethyl N-(4H-1,2,4-triazol-3-yl)propanimidate
(1b). IR spectrum, ν, cm–1: 3425 (N–H), 1664 (C=N).
1Н NMR spectrum, δ, ppm: 1.12 t (3H, CH3CH2C),
1.52 q (2H, CH3CH2C), 1.44 t (3H, CH3CH2O), 4.20 q
(2H, CH2O), 8.75 s (1H, 5-H), 10.65 s (1H, NH).
13C NMR spectrum, δC, ppm: 12.4, 16.1, 24.4,
61.6, 151.8, 155.5, 160.8. Found, %: C 50.12;
H 7.23; N 33.38. C7H12N4O. Calculated, %: C 49.99;
H 7.19; N 33.31.
[1,2,4]Triazolo[4,3-c][1,3,5]thiadiazine-5-thiones
3a–3c (general procedure). A mixture of 1a–1c
(3 mmol) and carbon disulfide (3.2 mmol) in anhy-
drous ethanol (10 mL) containing pyridine (3.2 mmol)
was refluxed for 24 h. After cooling, the solvent was
evaporated under reduced pressure, and the resulting
solid was collected by filtration, washed with ether,
and recrystallized from methanol.
7-Methyl-5H-[1,2,4]triazolo[4,3-c][1,3,5]thiadi-
azine-5-thione (3a). IR spectrum, ν, cm–1: 1615
(C=N), 1250 (C=S). 1Н NMR spectrum, δ, ppm: 1.71 s
(3H, CH3), 10.01 s (1H, 3-H). 13C NMR spectrum, δC,
ppm: 19.3, 150.3, 152.1, 166.53, 172.2. Mass spec-
trum: m/z 185 [M + H]+. Found, %: C 32.61; H 2.21;
N 30.43. C5H4N4S2. Calculated, %: C 32.59; H 2.19;
N 30.41.
Ethyl N-(4H-1,2,4-triazol-3-yl)benzimidate (1c).
IR spectrum, ν, cm–1: 3422 (N–H), 1661 (C=N).
1Н NMR spectrum, δ, ppm: 1.42 t (3H, CH3CH2),
4.21 q (2H, CH2O), 7.14–7.52 m (5H, Harom), 9.63 s
(1H, 5-H), 10.77 s (1H, NH). 13C NMR spectrum, δC,
ppm: 16.4, 62.4, 130.1, 129.2, 128.2 (2C), 127.6 (2C),
153.2, 156.5, 162.1. Found, %: C 61.07; H 5.47;
N 25.93. C11H12N4O. Calculated, %: C 61.10; H 5.59;
N 25.91.
7-Ethyl-5H-[1,2,4]triazolo[4,3-c][1,3,5]thiadi-
azine-5-thione (3b). IR spectrum, ν, cm–1: 1615
(C=N), 1250 (C=S). 1Н NMR spectrum, δ, ppm: 1.10 t
(3H, J = 9.0 Hz, CH3CH2), 2.28 q (2H, J = 9.0 Hz,
CH3CH2), 10.09 s (1H, 3-H). 13C NMR spectrum, δC,
ppm: 11.3, 18.20, 151.8, 152.5, 165.6, 173.5. Mass
spectrum: m/z 199 [M + H]+. Found, %: C 36.37;
H 3.08; N 28.29. C6H6N4S2. Calculated, %: C 36.35;
H 3.05; N 28.26.
[1,2,4]Triazolo[4,3-a][1,3,5]triazin-5-amines 2a–
2c (general procedure). A mixture of compound 1a–1c
(2 mmol) and cyanamide (2 mmol) in methanol
(15 mL) was refluxed for 48 h. The solvent was
removed under reduced pressure, and the solid product
was filtered off and recrystallized from ethanol.
7-Methyl[1,2,4]triazolo[4,3-a][1,3,5]triazin-5-
amine (2a). IR spectrum, ν, cm–1: 3130–3200 (NH2),
1
7-Phenyl-5H-[1,2,4]triazolo[4,3-c][1,3,5]thiadi-
azine-5-thione (3c). IR spectrum, ν, cm–1: 1615
(C=N), 1250 (C=S). 1Н NMR spectrum, δ, ppm: 9.95 s
(1H, 3-H), 7.11–7.91 m (5H, Harom). 13C NMR spec-
trum, δC, ppm: 112.6, 115.2, 115.8, 127.3, 127.5,
132.1, 151.2, 152.2, 164.9, 170.1. Mass spectrum:
m/z 247 [M + H]+. Found, %: C 48.79; H 2.48;
N 22.77. C10H6N4S2. Calculated, %: C 48.76; H 2.46;
N 22.75.
1618 (C=N). Н NMR spectrum, δ, ppm: 2.20 s (3H,
CH3), 8.72 s (1H, 3-H), 7.32 br.s (2H, NH2, D2O ex-
changeable). 13C NMR spectrum, δC, ppm: 23.2, 151.7,
152.9, 154.1, 161.2. Mass spectrum: m/z 151 [M + H]+.
Found, %: C 40.05; H 4.08; N 55.99. C5H6N6.
Calculated, %: C 40.00; H 4.03; N 55.97.
7-Ethyl[1,2,4]triazolo[4,3-a][1,3,5]triazin-5-
amine (2b). IR spectrum, ν, cm–1: 3130–3200 (NH2),
1
1618 (C=N). Н NMR spectrum, δ, ppm: 1.15 t (3H,
[1,2,4]Triazolo[4,3-c][1,3,5]thiadiazin-5-imines
4a–4c (general procedure). Equimolecular amounts
(1 mmol) of compound 1a–1c and sodium thiocyanate
were dissolved under vigorous stirring in a mixture of
J = 7.2 Hz, CH3CH2), 2.25 q (2H, J = 7.2 Hz,
CH3CH2), 8.60 s (1H, 3-H), 7.12 br.s (2H, NH2, D2O
exchangeable). 13C NMR spectrum, δC, ppm: 10.8,
20.6, 150.1, 152.1, 153.8, 163.7. Mass spectrum:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

CONVENIENT SYNTHESIS OF [1,2,4]TRIAZOLO[4,3-a][1,3,5]TRIAZIN-5-AMINES
1583
ethanol (17 mL) and water (3 mL). After complete
CONFLICT OF INTERESTS
The authors declare no conflict of interests.
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The organic phase was dried over anhydrous Na2SO4,
the solvent was evaporated under reduced pressure,
and the residue was recrystallized from methanol.
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