Synthesis of bis[1,2,4]triazolo[4,3-b:1′,5′-d][1,2,4]triazine, a novel polynitrogenated heterocyclic system

Article abstract of DOI:10.1007/s00706-016-1810-y

Abstract: 2-Aryl [1,2,4]triazolo[1,5-d][1,2,4]triazine-5(6H)-thiones were methylated using methyl iodide in the presence of NaOH to give the corresponding 5-methylthio derivatives. Upon treatment with hydrazine hydrate, the latter were transformed to the corresponding 5-hydrazino derivatives via nucleophilic displacement. The 5-hydrazino compounds were reacted with orthoesters to furnish a novel heterocyclic system, bis[1,2,4]triazolo[4,3-b:1′,5′-d][1,2,4]triazines. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-016-1810-y

Monatsh Chem
DOI 10.1007/s00706-016-1810-y
ORIGINAL PAPER
Synthesis of bis[1,2,4]triazolo[4,3-b:10,50-d][1,2,4]triazine, a novel
polynitrogenated heterocyclic system
Nasser Montazeri1 Majid M. Heravi2 Farzaneh Tajfirooz1 Niousha Nazari2
•
•
•
Received: 2 April 2016 / Accepted: 26 June 2016
Ó Springer-Verlag Wien 2016
Abstract 2-Aryl [1,2,4]triazolo[1,5-d][1,2,4]triazine-5(6H)-
thiones were methylated using methyl iodide in the presence of
NaOH to give the corresponding 5-methylthio derivatives.
Upon treatment with hydrazine hydrate, the latter were trans-
formed to the corresponding 5-hydrazino derivatives via
nucleophilic displacement. The 5-hydrazino compounds were
reacted with orthoesters to furnish a novelheterocyclic system,
bis[1,2,4]triazolo[4,3-b:10,50-d][1,2,4]triazines.
Introduction
Fused 1,2,4-triazines constitute an important group of
heterocycles with diverse and interesting biological
activities [1]. Various members of these compounds
were reported to possess anti-HIV [2], anticancer, anti-
hypertensive, anesthetic, antidepressant, and antiviral
activities [3–5]. In addition, the 1,2,4-triazine ring sys-
tem is a key fragment of several commercial dyes,
herbicides, insecticides, and pharmaceutical compounds
[6, 7]. The great interest in the synthesis of fused 1,2,4-
triazine ring systems is partially due to the biological
properties of azolotriazines, which may be regarded as
structural analogs of naturally occurring purine bases.
Some representatives of these heterocycles were found
to exhibit antitumor and antiviral activities [8, 9]. The
chemistry of 1,2,4-triazines has been extensively
investigated and the biological properties and potencies
Graphical abstract
Keywords Bis-triazolotriazine Á Triazolotriazine Á
Orthoester Á Cyclizations Á Heterocycles
of compounds bearing 1,2,4-triazine moiety as
a
framework in their structures have also been recognized
[10, 11]. Although several approaches have been
reported for the synthesis of azolotriazines in which an
azole ring was built on a pre-prepared triazine ring [12],
the synthesis of bis-triazolotriazines remains scarcely
studied [13].
We are interested in heterocyclic chemistry [14–24],
and in particular bicyclic compounds derived from
1,2,4-triazines. Our group has been engaged on the
chemistry of 1,2,4-triazines, studying it from different
points of view (synthesis of novel heterocyclic sys-
tems, developments, catalysis, green chemistry,
electrochemical synthesis, and computational) [25–28].
Armed with these experience and in the context of
ongoing research linking to our interest in the synthesis
of heterocyclic compounds derived from 1,2,4-triazine,
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-016-1810-y) contains supplementary
material, which is available to authorized users.
& Majid M. Heravi
mmh1331@yahoo.com
1
Department of Chemistry, Islamic Azad University,
Tonekabon Branch, Tonekabon, Iran
2
Department of Chemistry, School of Science, Alzahra
University, Vanak, Tehran, Iran
123

N. Montazeri et al.
Scheme 1
herein, we wish to report a facile and efficient
approach leading to a novel polynitrogenated hetero-
cyclic system, bis[1,2,4]triazolo[4,3-b:10,50-d][1,2,4]
triazine (4) (Scheme 1).
spectrum of 4a lacked the signal of the methylthio group,
whereas this signal was seen in the spectrum of precursor
compound 2a at d = 2.96 ppm. Moreover, a characteristic
1
sharp H NMR signal at 8.92 ppm was observed for 4a,
which could be assigned to the singular heteroaromatic
proton of the newly formed triazole ring, and consequently,
evidenced the formation of the tricyclic compound 4a.
The extreme downfield shift of this proton was due to
the anisotropic and strong inductive effect of the aromatic
triazole ring. Likewise, the IR spectrum of this compound
confirmed the assigned structure for 4a as it was devoid of
Results and discussion
To approach the synthesis, we extended our previously
reported procedure for the construction of [1,2,4]tria-
zolo[1,5-d][1,2,4]triazine-5-thiones 1a–1c [29]. The
required [1, 2, 4] triazolo[1,5-d][1,2,4]triazine-5-thiones
1a–1c were prepared according to our reported method for
the cyclocondensation of 6-methyl-4-amino[1,2,4]triazine-
5-one-3-thiones with aromatic nitriles in basic alcoholic
medium. Treatment of compounds 1a–1c with methyl
iodide in an aqueous solution of sodium hydroxide at room
temperature afforded the required precursors which were
fully characterized as 8-methyl-5-methylthio-2-aryl-6H-
[1,2,4]triazolo[1,5-d][1,2,4]triazines 2a–2c. Nucleophilic
displacement of the methylthio group with hydrazine
hydrate furnished 5-hydrazino derivatives 3a–3c. Com-
pounds 3a–3c were subjected to cyclocondensation with
triethylorthoesters under heating in ethanol to give the
desired tricyclic products bis[1,2,4]triazolo[4,3-b:10,50-
d][1,2,4]triazines 4a–4e. Although small amounts of
unidentified by-products were detected on TLC, the desired
products 4a–4e were obtained in pure form after crystal-
lization in satisfactory yields. The products 4a–4e were
easily separated as solids upon cooling of the reaction
mixtures to room temperature. The crude purified by
recrystallization from ethanol to afford the desired com-
pounds in pure form.
NH absorption bands at around 3400 cm-1
exhibiting a distinctive absorption band at 1627 cm-1
, while
,
characteristic for the vibration of C=N bonds. The 13C
NMR spectra of all products displayed distinct signals at
appropriate chemical shifts.
Conclusion
In summary, we have established a facile and efficient
route for the uncatalyzed synthesis of some novel bis-tri-
azolotriazine compounds. We anticipate that these
polynitrogenated new ring system attracts the attention of
medicinal chemists and pharmacologist for further bio-
logical investigation, due to their structural similarity with
biologically active purine bases.
Experimental
Melting points were recorded on an Electrothermal type
9100 melting point apparatus. The IR spectra were
obtained on a Shimadzu 4300 spectrophotometer in KBr
disks. The 1H NMR (400.22 MHz) and 13C NMR
The structural assignments for all the new compounds
4a–4e were based on the interpretation of 1H NMR and 13
1
NMR as well as elemental microanalyses. The H NMR
C
(100.63 MHz) spectra were recorded on a Bruker
123

Synthesis of bis[1,2,4]triazolo[4,3-b:10,50-d][1,2,4]triazine, a novel polynitrogenated…
6-Methyl-8-phenylbis[1,2,4]triazolo[4,3-b:10,50-d][1,2,4]-
AVANCE-400 spectrometer. Elemental analyses were
performed on a Thermo Finnigan Flash EA microanalyzer
and the results were found to agree satisfactorily with the
calculated values.
triazine (4a, C12H9N7)
Yield 63 %; m.p.: 276–278 °C; 1H NMR (400.2 MHz,
CDCl3): d = 8.92 (s, 1H), 8.39 (m, 2H), 7.53 (m, 3H), 2.95
(s, 3H) ppm; 13C NMR (100.63 MHz, CDCl3): d = 166.5,
147.4, 144.4, 140.2, 138.8, 131.3, 128.9, 128.5, 127.7,
General procedure for the synthesis of compounds 2a–2c
To a solution of the 2-aryl[1,2,4]triazolo[1,5-d][1,2,4]tri-
azine-5(6H)-thiones 1a–1c (5 mmol) and sodium
hydroxide (13.04 mmol) in 15 cm3 water was added
methyl iodide (5 mmol). The reaction mixture was stirred
at room temperature for 4 h. Then, the crude product was
collected and recrystallized from ethanol to give com-
pounds 2a–2c in 65–72 % yields.
17.9 ppm; IR (KBr): mꢀ = 3130, 2975, 1627 cm-1
.
3,6-Dimethyl-8-phenylbis[1,2,4]triazolo-
[4,3-b:10,50-d][1,2,4] triazine (4b, C13H11N7)
Yield 67 %; m.p.: 273–275 °C; 1H NMR (400.2 MHz,
CDCl3): d = 8.32 (m, 2H), 7.47 (m, 3H), 2.91 (s, 3H), 2.78
(s, 3H) ppm; 13C NMR (100.63 MHz, CDCl3): d = 166.1,
147.7, 146.2, 143.9, 139.9, 131.1, 128.9, 128.6, 127.5,
-1
8-Methyl-5-methylthio-2-phenyl-6H-[1,2,4]triazolo-
[1,5-d][1,2,4]triazine (2a, C12H11N5S)
ꢀ
17.9, 10.1 ppm; IR (KBr): m = 3056, 2974, 1625 cm
.
Yield 67 %; m.p.: 157–158 °C; 1H NMR (400.2 MHz,
CDCl3): d = 8.29 (m, 2H), 7.41 (m, 3H), 2.94 (s, 3H), 2.85
(s, 3H) ppm; 13C NMR (100.63 MHz, CDCl3): d = 165.3,
152.0, 150.0, 144.4, 131.1, 129.0, 128.7, 127.9, 17.8,
6-Methyl-8-(3-methylphenyl)bis[1,2,4]triazolo[4,3-b:10,50-d]-
[1,2,4]triazine (4c, C13H11N7)
Yield 51 %; m.p.: 219–221 °C; 1H NMR (400.2 MHz,
CDCl3): d = 9.60 (s, 1H), 8.15 (d, J = 6.4 Hz, 1H), 8.12
(s, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H),
3.07 (s, 3H), 2.49 (s, 3H) ppm; 13C NMR (100.63 MHz,
CDCl3): d = 166.4, 154.9, 145.2, 138.8, 138.4, 132.3,
ꢀ
13.2 ppm; IR (KBr): m = 3070, 2830, 1524, 1438, 1393,
1320, 719 cm-1
.
8-Methyl-2-(3-methylphenyl)-5-methylthio-6H-[1,2,4]-
triazolo[1,5-d][1,2,4]triazine (2b, C13H13N5S)
128.9, 128.8, 128.5, 125.1, 21.4, 18.4 ppm; IR (KBr):
-1
ꢀ
m = 3093, 2910, 1598 cm
.
Yield 65 %; m.p.: 164–167 °C; 1H NMR (400.2 MHz,
CDCl3): d = 8.17 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.43
(t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 2.99 (s, 3H),
2.90 (s, 3H), 2.49 (s, 3H) ppm; 13C NMR (100.63 MHz,
CDCl3): d = 165.6, 152.1, 150.0, 144.4, 138.7, 132.1,
3,6-Dimethyl-8-(3-methylphenyl)bis[1,2,4]triazolo-
[4,3-b:10,50-d][1,2,4]triazine (4d, C14H13N7)
Yield 63 %; m.p.: 225–227 °C; 1H NMR (400.2 MHz,
CDCl3): d = 7.28–8.16 (m, 4H), 2.91 (s, 3H), 2.49 (s, 3H),
1.92 (s, 3H) ppm; 13C NMR (100.63 MHz, CDCl3):
d = 165.5, 146.5, 145.9, 138.7, 131.9, 129.1, 128.8,
128.9, 128.8, 128.5, 125.2, 21.4, 17.9, 13.3 ppm; IR (KBr):
-1
ꢀ
m = 3100, 2860, 1520, 1440, 1402, 1320 cm
.
128.5, 127.0, 124.9, 123.5, 21.4, 17.8, 16.6 ppm; IR
-1
8-Methyl-2-(4-methylphenyl)-5-methylthio-6H-[1,2,4]-
triazolo[1,5-d][1,2,4]triazine (2c, C13H13N5S)
ꢀ
(KBr): m = 3095, 2950, 1623 cm
.
Yield 72 %; m.p.: 171–174 °C; 1H NMR (400.2 MHz,
CDCl3): d = 8.25 (d, J = 8.0 Hz, 2H), 7.35 (d,
J = 8.0 Hz, 2H), 2.99 (s, 3H), 2.90 (s, 3H), 2.47 (s, 3H)
ppm; 13C NMR (100.63 MHz, CDCl3): d = 165.6, 152.0,
150.0, 144.4, 141.7, 129.6, 127.9, 126.3, 21.6, 17.9,
6-Methyl-8-(4-methylphenyl)bis[1,2,4]triazolo[4,3-b:10,50-d]-
[1,2,4]triazine (4e, C13H11N7)
Yield 56 %; m.p.: 241–243 °C; 1H NMR (400.2 MHz,
CDCl3): d = 9.59 (s, 1H), 8.23 (d, J = 7.8 Hz, 2H), 7.36
(d, J = 7.8 Hz, 2H), 3.06 (s, 3H), 2.47 (s, 3H) ppm; 13C
NMR (100.63 MHz, CDCl3): d = 166.4, 154.8, 146.8,
ꢀ
13.3 ppm; IR (KBr): m = 3080, 2940, 1518, 1438, 1396,
1323 cm-1
.
145.2, 141.9, 138.4, 129.7, 127.9, 126.1, 21.6, 18.4 ppm;
-1
ꢀ
IR (KBr): m = 3098, 2960, 2925, 1620 cm
.
General procedure for the synthesis of compounds 4a–4e
A mixture of compound 2a–2c (5 mmol) and hydrazine
hydrate (15 mmol) in 150 cm3 ethanol was heated under
reflux condition for 3 h. Upon completion of the reaction
(monitored by TLC on silica gel using chloro-
form:methanol, 95:5, as eluent), the volatiles (ethanol and
excess hydrazine hydrate) were removed under reduced
pressure. To the crude residue (cooled to room tempera-
ture) 5.5 cm3 triethylorthoester was added in three portions
and this mixture was stirred for 8 h. The precipitates were
filtered and recrystallized from EtOH.
Acknowledgments We acknowledge the financial support from
Research Council of Islamic Azad University, Tonekabon branch and
Alzahra University, Tehran, Iran.
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