On the possibility for synthesizing dihydrotriazolothiadiazoles by condensation of 4-amino-2,4-dihydro-3H-1,2,4-triazole-3-thiones with aromatic aldehydes

Article abstract of DOI:10.1134/S1070428016030210

Regardless of the conditions, the condensation of 4-amino-2,4-dihydro-3H-1,2,4-triazole-3-thiones with aromatic aldehydes afforded the corresponding hydrazones as the only product. Both initial amines and resulting hydrazones exist as the thione rather th

Full text of DOI:10.1134/S1070428016030210

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 3, pp. 421–428. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © A.Ya. Bespalov, T.L. Gorchakova, A.Yu. Ivanov, M.A. Kuznetsov, L.M. Kuznetsova, A.S. Pankova, L.I. Prokopenko,
A.F. Khlebnikov, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52, No. 3, pp. 441–448.
On the Possibility for Synthesizing Dihydrotriazolothiadiazoles
by Condensation of 4-Amino-2,4-dihydro-3H-1,2,4-triazole-
3-thiones with Aromatic Aldehydes
A. Ya. Bespalova, T. L. Gorchakovaa, A. Yu. Ivanovb, M. A. Kuznetsovb, L. M. Kuznetsovab,
A. S. Pankovab, L. I. Prokopenkoa, and A. F. Khlebnikovb
a Institute of Toxicology, Federal Medical and Biological Agency of the Russian Federation,
ul. Bekhtereva 1, St. Petersburg, 192019 Russia
b St. Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198504 Russia
e-mail: m.kuznetsov@spbu.ru
Received January 29, 2016
Abstract—Regardless of the conditions, the condensation of 4-amino-2,4-dihydro-3H-1,2,4-triazole-3-thiones
with aromatic aldehydes afforded the corresponding hydrazones as the only product. Both initial amines and
resulting hydrazones exist as the thione rather than thiol tautomer. In no case bicyclic 5,6-dihydro[1,2,4]tri-
azolo[3,4-b][1,3,4]thiadiazoles that are isomeric to the hydrazones were detected. DFT quantum chemical
calculations at the B3LYP/6-31+g(d,p) level of theory with full geometry optimization showed that the
hydrazone structure in methanol and DMF is more stable than the bicyclic isomer by 19–23 kcal/mol, which
completely excluded the possibility for such cyclization. The thione tautomer of the hydrazones is more stable
than the thiol structure by 11–13 kcal/mol.
DOI: 10.1134/S1070428016030210
Preparation of Schiff bases is one of the simplest
and reliably accomplishable synthetic procedures, and
the possibility for variation of substituents in both
amine and carbonyl component over a wide range has
made this reaction very popular for the preparation of
huge libraries of compounds for various purposes.
Over the past decades particular attention was given to
condensations with compounds containing heterocyclic
fragments, taking into account that the resulting prod-
ucts could exhibit various biological activities. They
are also used as analytical reagents, ligands for com-
plexation with metals, etc. The same equally applies to
4-amino-2,4-dihydro-3H-1,2,4-triazole-3-thiones 1 [1]
that are the subject of the present study. About
1500 products of their condensation with various
aldehydes have been reported, and only within the past
two years this reaction of aminotriazolethiones 1 has
been described in more than 30 publications, and the
products were tested for antioxidant [2], antibacterial
and antimicrobial [3, 4], insecticidal [5], nematicidal
[6], and other kinds of biological activity.
related to the structure of initial 4-amino-1,2,4-tri-
azole-3-thiones 1 (thione tautomer) for which thiol
structure 1-SH is also possible. In more than
1100 cases, just the thiol tautomers, 4-amino-4H-1,2,4-
triazole-3-thiols, were reported to react with carbonyl
compounds, and the thione tautomer was pointed out
as reagent in only ~400 reactions. The second problem
concerns the structure of the condensation products.
Although in most cases the products were assigned the
structure of Schiff bases (hydrazones) 2, the authors of
more than 30 publications contended that these hydra-
zones are capable of being converted into bicyclic
5,6-dihydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 3
under more severe conditions or on prolonged reaction
time (Scheme 1); moreover, the possibility for ring–
chain tautomerism 2
3 was assumed.
Insofar as such a simple synthetic route to dihydro-
triazolothiadiazoles 3 may be of great interest, the goal
of the present work was to study in detail the
possibility for the formation of compounds 3 in the
condensation of 1 with carbonyl compounds. However,
the first part of our study was aimed at elucidating the
structure of the initial 4-amino-1,2,4-triazole-3-thiones
On the other hand, analysis of published data
revealed at least two problems. The first problem is
421

BESPALOV et al.
422
Scheme 1.
H
H
N
N
N
NH
N
S
N
S
ArCHO
–H2O
N
R
N
R
R
SH
R
S
N
N
Ar
N
N
N
N
NH2
1-SH
NH2
1a–1g
H
Ar
2a–2h
3
1, R = H (a), i-Pr (b), Ph (c), 4-MeC6H4 (d), 3-ClC6H4 (e), 4-Me2NC6H4 (f), furan-2-yl (g); 2, Ar = 4-MeOC6H4, R = H (a), i-Pr (b),
Ph (c), 3-ClC6H4 (d); Ar = furan-2-yl, R = Ph (e), furan-2-yl (f); Ar = 4-ClC6H4, R = H (g), Ph (h).
1 and condensation products 2, i.e., whether they are
thione or thiol tautomers.
Analogous thiol–thione tautomerism is theoretically
possible for the condensation products of aminotri-
azoles 1 with carbonyl compounds, i.e., Schiff bases 2.
Zhang et al. [11] reliably showed by one- and two-
Although it has been known more than 20 years [7]
that compounds containing a thioamide fragment gen-
erally have thione structure, the thiol tautomer of
aminotriazolethiones 1 (1-SH) is traditionally believed
to be more stable due to aromatic character of the five-
membered heterocycle therein. Analogous dilemma
exists for other heterocycles with a thioamide frag-
ment, e.g., for benzimidazole-2-thiols; as we have
recently shown, these compounds have exclusively the
thione structure and are in fact 2,3-dihydro-1H-benz-
imidazole-2-thiones [8].
1
dimensional H and 13C NMR spectroscopy and X-ray
analysis that compounds 2 both in solution and in
crystal exist exclusively in the thione form. In full
1
agreement with this conclusion, the H–15N HSQC
spectrum of 2b clearly showed a correlation between
the NH proton (δ 13.73 ppm) and N2 (δN 198 ppm).
1
This correlation was confirmed by the H–15N HMBC
spectrum, where the following 15N/1H cross peaks
were observed (δ, ppm): N1 (265)/NH (13.73), N1/CH
(3.11), N4 (210)/NH (13.42), N4/N=CH (9.73), N4/CH
(3.11), N=CH (295)/N=CH, N=CH/o-H (7.85). Thus,
both aminotriazoles 1 and Schiff bases 2 derived
therefrom exist exclusively as thione tautomers, and
the presence of a downfield signal (D2O-exchangeable)
The problem of thiol–thione tautomerism of amino-
triazolethiones 1 has been explicitly raised by Mathew
et al. [9]. The data given in [9] largely characterized
the established situation. On the one hand, the IR
spectra indicated the thione structure of 1, and the most
1
1
in their H NMR spectra reliably indicates thioamide
downfield signal in their H NMR spectra (δ 13.5–
structure.
13.8 ppm) was that of the NH proton; on the other
hand, the same signal was assigned to SH in the
Experimental section [9]. We believe that thiol struc-
ture 1-SH can be unambiguously excluded even on the
basis of the 1H NMR spectra where, as in the spectra of
other thioamides [8], the D2O-exchangeable proton
signal is located in a much weaker field than δ 10 ppm,
whereas the SH signal of benzenethiols typically
appears as δ 2–4 ppm (δ 1–2 ppm for thiols) [10]. In
this work we assigned the downfield signal just to the
It was much more difficult to find out whether
bicyclic products, dihydrotriazolothiadiazoles 3, can be
formed in the condensation of aminotriazolethiones 1
with carbonyl compounds. The condensation is com-
monly carried out in the presence of an acid catalyst
under fairly mild conditions by heating (or irradiating
by microwaves) an equimolar mixture of the reactants
in benzene, toluene, alcohol, or DMF with a Dean–
Stark trap (or without it) or in some cases merely at
room temperature. As already noted, in most cases the
products were hydrazones 2 which were isolated in
high yields. The formation of bicyclic compounds 3
was declared fairly rarely, and analysis of published
data showed that in approximately a half of such cases
bicyclic structure was assigned to the products without
any grounds, while the given spectral data could not be
interpreted reasonably. There were clear inconsis-
tencies in some publications. For instance, Jubie et al.
[12] interpreted the triplet signal of CDCl3 in the
13C NMR spectra of some postulated bicycles as three
signals of carbon atoms in the phenyl substituent;
1
NH proton on the basis of the H–15N correlation
spectroscopy data for 4-amino-5-isopropyltriazole-
1
thione 1b. In the H–15N HSQC spectrum of 1b, the
proton resonating at δ 13.42 ppm showed direct
coupling with the N2 atom (δN 196 ppm), whereas the
NH2 protons (δ 5.50 ppm) were coupled with the
amino nitrogen atom (δN 65 ppm). These correlations
were confirmed by the 1H–15N HMBC spectrum which
displayed cross peaks between N1 (δN 265 ppm)
and protons resonating at δ 13.42 (NH), 3.06 (CH),
and 1.21 ppm (CH3, weak), as well as between N4
(δN 186 ppm) and NH (δ 13. 42 ppm), NH2
(δ 5.50 ppm), and CH protons (δ 3.06 ppm).
1
surprisingly identical H and 13C chemical shifts were
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ON THE POSSIBILITY FOR SYNTHESIZING DIHYDROTRIAZOLOTHIADIAZOLES
423
1
reported for a wide series of different compounds
(a bright example is recent publication [13]), etc.;
therefore, these data may not be taken into account.
The spectra given in [14–20] indicated the hydrazone
rather than bicyclic structure of the products.
the H NMR spectra of the products obtained in [27]
were generally uninterpretable; in the best case, the
spectral data were consistent with the hydrazone struc-
ture. Moreover, several years later the possibility of
tautomeric equilibrium 2-SH
3 involving the thiol
form of the hydrazone was discussed [14, 15] as
a particular case of a huge family of ring–chain tauto-
meric transformations. However, the spectral param-
eters of the condensation products given in [14, 15]
were also indicative of their hydrazone structure, and
the assertion that the cyclic tautomer is present in solu-
tion was not substantiated in any way (Scheme 2).
Thus we can state that only the IR and NMR
spectra reported in [9, 21–26] do not contradict the
proposed triazolothiadiazole structure 3. Nevertheless,
the spectral parameters of compounds with the same
bicyclic skeleton, given by different authors, are
strongly different. For instance, the N5H chemical shift
varies from δ 2.7–3.1 [25] to 13.4–14.0 ppm [26], and
the position of the C6 signal, from δC 60 [26] to 85–95
[23, 24] and even 160 ppm [22]. Relatively consistent
data were given only for the 6-H proton (a singlet at
δ 5.5–7.0 ppm).
Abdel-Rachman et al. [19] reported that hydrazones
formed in the condensation of 4-amino-5-(pyridin-
4-yl)-1,2,4-triazole-3-thione with 2,6-difluoro- and
2-chloro-6-fluorobenzaldehydes undergo cyclization to
dihydrotriazolothiadiazoles 3 on prolonged heating in
boiling toluene. However, this statement does not hold
In most studies [9, 21–26], “bicyclic” condensation
products were isolated after prolonged heating of the
reactant mixture in boiling DMF in the presence of
a strong acid as catalyst. Alternatively, the reactions
were carried out under microwave irradiation. In this
connection, it should be noted that many of the initial
heterocyclic aldehydes of the furan, pyrrole, and thio-
phene series are not very stable under the above con-
ditions; furthermore, DMF usually undergoes appre-
ciable decomposition on prolonged heating with
an acid. Therefore, we performed a series of condensa-
tions involving both those reactant pairs which were
reported to afford triazolothiadiazoles and other 5-aryl
(alkyl)-4-amino-1,2,4-triazole-3-thiones 1a–1g and
various aromatic and heteroaromatic aldehydes.
1
water. Judging by the melting points and H NMR
spectra of the products, the initial hydrazones were
merely purified by recrystallization from toluene. On
the other hand, Chidananda et al. [26] heated hydra-
zones derived from 4-amino-5-(2-bromo-5-methoxy-
phenyl)-1,2,4-triazole-3-thione (though 2-bromo-4-me-
thoxyphenyl substituent was shown in all reaction
schemes) for 10–12 h in boiling DMF containing
p-toluenesulfonic acid. The melting points and spectral
characteristics of the products considerably differed
from those of the initial hydrazones, so that they could
have the structure of triazolothiadiazoles 3. Therefore,
we also tried to effect cyclization of hydrazones 2 to
triazolothiadiazoles.
We found that hydrazones 2 remained unchanged
under fairly mild conditions (heating in boiling tolu-
ene), whereas harsh conditions (prolonged heating of
aminotriazolethiones 1 with aldehydes in DMFA) in-
duced appreciable tarring. In the latter case, apart from
expected hydrazones 2, we isolated and identified only
products of their decomposition via cleavage of the
exocyclic N–N bond, dihydrotriazolethiones 4. This
transformation, which is analogous to decomposition
of hydrazonium salts into amines and nitriles [28], was
first reported in 2005 [29]. The reaction mechanism
proposed therein is shown in Scheme 3.
Despite wide variation of the reactants and reaction
conditions, from the reaction mixtures we isolated in
all cases only hydrazones 2a–2h. Their structure was
1
confirmed by H and 13C NMR and high-resolution
mass spectra. The structure and signal assignment in
the NMR spectra of 2b (condensation product of
4-amino-5-isopropyl-1,2,4-triazole-3-thione with
4-methoxybenzaldehyde) were additionally confirmed
using 13C–1H and 15N–1H correlation techniques.
Shi et al. [27] assumed that the reaction begins with
formation of hydrazone 2 which then undergoes
cyclization to dihydrotriazolothiadiazole 3. However,
Scheme 2.
H
H
N
S
N
SH
N
S
N
R
N
R
N
R
Ar
N
N
N
N
N
N
H
Ar
Ar
2
2-SH
3
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BESPALOV et al.
424
Scheme 3.
H
N
S
N
NH
N
NH
N
R
∆
H
N
–ArCN
SH
S
R
R
N
N
N
H
Ar
2i, 2j
4a, 4b
2, Ar = 4-O2NC6H4, R = 4-MeC6H4 (i); Ar = furan-2-yl, R = 4-Me2NC6H4 (j); 4, R = 4-MeC6H4 (a), 4-Me2NC6H4 (b).
In order to rationalize our failure to synthesize di-
substituent (NO2) into the para position of one or both
phenyl rings also weakly affected the relative stability
of the hydrazone and bicyclic structures. The hy-
drazone derived from 5-phenyltriazolethione and
p-nitrobenzaldehyde was more stable by 14.6 kcal/mol,
and that derived from 5-(4-dimethylaminophenyl)-
triazolethione and benzaldehyde, by 17.1 kcal/mol.
Likewise, the hydrazone tautomer of the condensation
product of 4-amino-5-[4-(dimethylamino)phenyl]-
1,2,4-triazole-3-thione (1f) with furfural in methanol
was much more stable than the bicyclic structure: the
energy difference was estimated at 16.5 kcal/mol.
Furthermore, in keeping with the experimental data,
both hydrazones should exist exclusively as thione
tautomers which are more stable than the thiol struc-
tures by 12–13 kcal/mol.
hydrotriazolothiadiazoles 3, we estimated the energies
of the possible reaction products by DFT quantum
chemical calculations at the B3LYP/6-31+g(d,p) level
of theory for solutions in methanol and DMF with full
geometry optimization. The results (see figure) were
very consistent with our experimental data. The hydra-
zone structure of the condensation product of 4-amino-
5-phenyl-1,2,4-triazole-3-thione (1c) with benzalde-
hyde in methanol is more stable than the corresponding
cyclic structure, 3,6-diphenyl-5,6-dihydro[1,2,4]tri-
azolo[3,4-b][1,3,4]thiadiazole, by 15.3 kcal/mol. Re-
placement of methanol by DMF almost does not affect
the calculated relative energies of both isomers: the
differences did not exceed 0.1 kcal/mol. Introduction
of an electron-donor (Me2N) or electron-withdrawing
A, 0 kcal/mol
B, 11.78 kcal/mol
C, 15.32 kcal/mol
D, 0 kcal/mol
E, 12.98 kcal/mol
F, 16.51 kcal/mol
Optimized structures and relative Gibbs free energies of the condensation products of 4-amino-5-phenyl-1,2,4-triazole-3-thione with
benzaldehyde (A–C) and of 4-amino-5-[4-(dimethylamino)phenyl]-1,2,4-triazole-3-thione with furfural (D–F): hydrazone thione (A,
D), hydrazone thiol (B, E), and triazolothiadiazole (C, F).
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ON THE POSSIBILITY FOR SYNTHESIZING DIHYDROTRIAZOLOTHIADIAZOLES
425
Thus, the results of quantum chemical calculations
completely reject the possibility for cyclization of
hydrazones 2 to dihydrotriazolothiadiazoles 3 with
a fairly strained system consisting of two fused five-
membered heterocycles. Therefore, our unsuccessful
attempts to accomplish such cyclization are not sur-
prising. On the other hand, one cannot believe that the
existence of dihydrotriazolothiadiazoles 3 is forbidden
by the theoretical data. The structures of 3 correspond
to local minima on the potential energy surfaces, so
that their formation is theoretically possible, but cy-
clization of hydrazones 2 to dihydrotriazolothiadi-
azoles 3 is unambiguously ruled out. Moreover, it
becomes obvious that bicyclic compounds 3 could be
readily converted into hydrazones 2 since the position
of possible ring–chain tautomeric equilibrium should
be displaced completely toward the hydrazone struc-
ture. However, taking into account negative results
of our experiments, the real structure and/or way
of formation of compounds which were assigned in
[9, 21–26] dihydrotriazolothiadiazole structure remain
an open question.
(1H, CH, J = 7.0 Hz), 5.50 s (2H, NH2), 13.42 s (1H,
NH). 13C NMR spectrum, δC, ppm: 19.5 (CH3), 24.7
(CH), 156.3 (C5), 166.1 (C=S). 15N NMR spectrum,
δN, ppm: 65 (NH2), 186 (N4), 196 (N2), 265
(N1). Found: m/z 264.9676/266.9672 [M + Ag]+.
C5H10AgN4S. Calculated: m/z 264.9672/ 266.9667.
4-{[(4-Methoxyphenyl)methylidene]amino}-2,4-
dihydro-3H-1,2,4-triazole-3-thione (2a). Concentrat-
ed aqueous HCl, 0.1 mL, was added to a solution of
232 mg (2 mmol) of aminotriazole 1a and 272 mg
(2 mmol) of 4-methoxybenzaldehyde in 10 mL of
ethanol, and the mixture was heated for 2 h under
reflux (a solid separated almost immediately). The
mixture was cooled, and the precipitate was filtered
off, washed with ethanol, and dried in air. Yield
379 mg (74%), yellow crystals, mp 223–224°C.
1H NMR spectrum, δ, ppm: 3.84 s (3H, OCH3), 7.10 d
(2H, m-H, J = 8.8 Hz), 7.83 d (2H, o-H, J = 8.8 Hz),
8.87 s (1H, 5-H), 9.31 s (1H, N=CH), 13.88 s (1H,
NH). 13C NMR spectrum, δC, ppm: 55.5 (OCH3), 114.6
(Cm), 124.5 (Ci), 130.5 (Co), 138.3 (C5), 161.3
(N=CH), 162.6 and 162.7 (Cp, C=S). Found:
m/z 257.0453 [M + Na]+. C10H10N4NaO2S. Calculated:
m/z 257.0468.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
Compounds 2b–2h were synthesized in a similar
way.
a Bruker Avance III-400 spectrometer at 400.13 and
100.61 MHz, respectively, using DMSO-d6 as solvent
and reference (δ 2.50 ppm; δC 39.50 ppm). Signals in
the 13C NMR spectra were assigned using DEPT and
1H–13C HSQC techniques. The chemical shifts of
nitrogen nuclei were determined by the inverse 1H–15N
5-Isopropyl-4-{[(4-methoxyphenyl)methylidene]-
amino}-2,4-dihydro-3H-1,2,4-triazole-3-thione (2b).
1
Yield 76%, mp 156–158°C. H NMR spectrum, δ,
ppm: 1.24 d (6H, CH3, J = 6.9 Hz), 3.11 sept (1H, CH,
J = 6.9 Hz), 3.84 s (3H, OCH3), 7.09 d (2H, m-H, J =
8.7 Hz), 7.85 d (2H, o-H, J = 8.7 Hz), 9.73 s (1H,
N=CH), 13.73 s (1H, NH). 13C NMR spectrum, δC,
ppm: 19.4 (CH3), 25.1 (CH), 55.5 (OCH3), 114.6 (Cm),
124.6 (Ci), 130.5 (Co), 155.0 (C5), 161.4 (C=S), 162.8
(Cp), 163.9 (N=CH). 15N NMR spectrum, δN, ppm: 198
(N2), 210 (N4), 265 (N1), 295 (N=CH). Found:
m/z 299.0935 [M + Na]+. C13H16N4NaOS. Calculated:
m/z 299.0937.
HSQC and H–15N HMBC techniques and are given
1
relative to liquid ammonia. The high-resolution mass
spectra (electrospray ionization) were obtained on
a Bruker maXis HRMS-ESI-QTOF mass spectrometer.
The purity of the isolated compounds was checked by
TLC on Sorbfil UV 254 plates (Imid Ltd., Russia).
Commercially available benzaldehyde derivatives and
furfural (from Acrus) were used. 4-Amino-2,4-dihy-
dro-3H-1,2,4-triazole-3-thiones 1a–1f were synthe-
sized according to the procedures reported in [9, 25,
30–32]. DFT B3LYP/6-31+g(d,p) quantum chemical
calculations [33–35] were performed using Gaussian
09 [36]. Geometric parameters were optimized using
the polarizable continuum model (PCM) for metha-
nol and DMF. Stationary points were identified as
energy minima by calculating Hessian matrices.
4-{[(4-Methoxyphenyl)methylidene]amino}-5-
phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (2c).
1
Yield 85%, mp 209–211°C. H NMR spectrum, δ,
ppm: 3.85 s (3H, OCH3), 7.11 d (2H, m′-H, J =
8.8 Hz), 7.49–7.54 m (3H, m-H, p-H), 7.85–7.90 m
(4H, o-H, o′-H), 9.49 s (1H, N=CH), 14.18 s (1H, NH).
13C NMR spectrum, δC, ppm: 55.6 (OCH3), 114.7
(Cm′), 124.3 (Ci′), 125.6 (Ci), 128.1 and 128.7 (Cm, Co),
130.6 (Cp), 130.8 (Co′), 148.4 (C5), 162.4 and 163.1
(Cp′, C=S), 167.0 (N=CH). Found: m/z 333.0772
[M + Na]+. C16H14N4NaOS. Calculated: m/z 333.0781.
4-Amino-5-isopropyl-2,4-dihydro-3H-1,2,4-tri-
azole-3-thione (1b). mp 108–110°C. H NMR spec-
trum, δ, ppm: 1.21 d (6H, CH3, J = 7.0 Hz), 3.06 sept
1
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BESPALOV et al.
426
5-(3-Chlorophenyl)-4-{[(4-methoxyphenyl)-
ppm: 7.50–7.57 m (3H, m-H, p-H), 7.64 d (2H, m′-H,
J = 8.5 Hz), 7.84–7.88 m (2H, o-H), 7.91 d (2H, o′-H,
J = 8.5 Hz), 9.76 s (1H, N=CH), 14.26 s (1H, NH).
13C NMR spectrum, δC, ppm: 125.4 (Ci), 128.3 and
128.7 (Co, Cm), 129.4 and 130.4 (Co′, Cm′), 130.7 (Cp),
130.8 and 137.5 (Ci′, Cp′), 148.6 (C5), 162.3 (C=S),
165.4 (N=CH). Found: m/z 315.0451 [M + H]+.
C15H12ClN4S. Calculated: m/z 315.0466.
methylidene]amino}-2,4-dihydro-3H-1,2,4-triazole-
1
3-thione (2d). Yield 81%, mp 227–229°C. H NMR
spectrum, δ, ppm: 3.86 s (3H, OCH3), 7.11 d (2H,
m′-H, J = 8.8 Hz), 7.52–7.61 m (2H, 4-H, 5-H), 7.85 d
(3H, o′-H, 6-H, J = 8.8 Hz), 7.92 t (1H, 2-H, J =
1.6 Hz), 9.54 s (1H, N=CH), 14.25 s (1H, NH).
13C NMR spectrum, δC, ppm: 55.6 (OCH3), 114.8
(Cm′), 124.8 (Ci′), 126.6 (Carom), 127.5 (C1), 127.8
(Carom), 130.4 (Carom), 130.67 (Carom), 130.74 (Co′),
133.3 (C3), 147.1 (C5), 162.6 and 163.1 (Cp′, C=S),
166.8 (N=CH). Found: m/z 367.0379 [M + Na]+.
C16H13ClN4NaOS. Calculated: m/z 367.0391.
Attempted syntheses of dihydrotriazolothia-
diazoles 3 according to published procedures.
a. Heating in toluene [19]. A mixture of 1 mmol of
compound 2b or 2d (prepared as described above) and
10 mL of anhydrous toluene was heated for 12 h under
reflux. After cooling, the precipitate was filtered off
and dried in air. The product was almost pure initial
hydrazone 2b (recovery 90%) or 2d (80%), which was
identified by the melting point and chromatographic
and spectral data.
4-[(Furan-2-ylmethylidene)amino]-5-phenyl-2,4-
dihydro-3H-1,2,4-triazole-3-thione (2e). Yield 69%,
1
mp 205–206°C. H NMR spectrum, δ, ppm: 6.79 d.d
(1H, 4′-H, J = 3.5, 1.7 Hz), 7.37 d (1H, 3′-H, J =
3.5 Hz), 7.49–7.56 m (3H, m-H, p-H), 7.85–7.88 m
(2H, o-H), 8.07 d (1H, 5′-H, J = 1.7 Hz), 9.57 s (1H,
N=CH), 14.20 s (1H, NH). 13C NMR spectrum, δC,
ppm: 113.0 (C4′), 120.4 (C3′), 125.5 (Ci), 128.3 (2C,
b. Heating in DMF [9, 17, 18, 23–25]. Aminotri-
azole 1b, 316 mg (2 mmol) and 4-methoxybenzal-
dehyde, 272 mg (2 mmol), were dissolved in 10 mL of
DMF, 10 mg of p-toluenesulfonic acid was added, and
the mixture was heated for 12 h under reflux. The
mixture was cooled and evaporated by half, and the
residue was poured onto ice under stirring. The precip-
itate was filtered off, washed with water and alcohol,
and dried in air. The product, 280 mg (51%), yellow
crystals, mp 156–158°C, was identified by comparing
with an authentic sample of 2b. Likewise, in the reac-
tion of 453 mg (2 mmol) of aminotriazole 1e with
272 mg (2 mmol) of 4-methoxybenzaldehyde we
isolated 420 mg (61%) of hydrazone 2d.
C
arom), 128.7 (2C, Carom), 130.6 (Cp), 147.2 (C2′), 148.2
(C5′), 148.6 (C5), 154.6 (N=CH), 162.3 (C=S). Found:
m/z 271.0647 [M + H]+. C13H12N4OS. Calculated:
m/z 271.0648.
5-(Furan-2-yl)-4-[(furan-2-ylmethylidene)-
amino]-2,4-dihydro-3H-1,2,4-triazole-3-thione (2f).
1
Yield 71%, mp 196–197°C. H NMR spectrum, δ,
ppm: 6.73 d.d and 6.81 d.d (1H each, 4-H, J = 3.5,
1.8 Hz), 7.17 d.d (1H, 3-H, J = 3.0, 0.7 Hz), 7.43 d
(1H, 3-H, J = 3.2 Hz), 7.97 d.d (1H, 5-H, J = 1.7,
0.7 Hz), 8.12 d (1H, 5-H, J = 1.7 Hz), 9.76 s (1H,
N=CH), 14.21 s (1H, NH). 13C NMR spectrum, δC,
ppm: 112.1 and 113.1 (C4′), 114.7 and 120.6 (C3′),
139.4 and 141.6 (C2′), 145.6 and 148.4 (C5′), 147.2 (C5),
153.1 (N=CH), 161.7 (C=S). Found: m/z 261.0433
[M + H]+. C11H9N4O2S. Calculated: m/z 261.0441.
Heating of an equimolar mixture of 4-amino-5-(4-
methylphenyl)triazolethione 1d and 4-nitrobenzalde-
hyde under analogous conditions resulted in the forma-
tion of deamination product, triazolethione 4a (yield
26%). In the reaction of 4-amino-5-[4-(dimethyl-
amino)phenyl]triazolethione 1f with furfural we
succeeded in isolating only the deamination product,
triazolethione 4b (yield 34%). A mixture of furfural
with 4-amino-5-(furan-2-yl)triazolethione 1g rapidly
turned dark and underwent complete tarring.
4-{[(4-Chlorophenyl)methylidene]amino}-2,4-
dihydro-3H-1,2,4-triazole-3-thione (2g). Yield 77%,
1
mp 219–220°C. H NMR spectrum, δ, ppm: 7.62 d
(2H, m-H, J = 8.5 Hz), 7.88 d (2H, o-H, J = 8.5 Hz),
8.92 s (1H, 5-H), 9.47 s (1H, N=CH), 13.95 s (1H,
NH). 13C NMR spectrum, δC, ppm: 129.3 (2C, Carom),
130.1 (2C, Carom), 131.1 (Carom), 137.0 (Carom), 138.0
(C5), 159. 3 (N=CH), 163. 0 (C=S). Found:
m/z 239.0146 [M + H]+. C9H8ClN4S. Calculated:
m/z 239.0153.
5-(4-Methylphenyl)-2,4(1,2)-dihydro-3H-1,2,4-
1
triazole-3-thione (4a) [37]. mp 237–239°C. H NMR
spectrum, δ, ppm: 2.35 s (3H, CH3), 7.32 d (2H, m-H,
J = 7.8 Hz), 7.79 d (2H, o-H, J = 7.8 Hz), 13.60 s (1H,
2-H), 13.74 br.s (1H, 4-H or 1-H). 13C NMR spectrum,
δC, ppm: 21.0 (CH3), 122.7 (Ci), 122.6 and 129.6 (Co,
Cm), 140.5 (Cp), 150.3 (C5), 166.8 (C=S). Found:
4-{[(4-Chlorophenyl)methylidene]amino}-5-
phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (2h).
1
Yield 82%, mp 219–220°C. H NMR spectrum, δ,
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ON THE POSSIBILITY FOR SYNTHESIZING DIHYDROTRIAZOLOTHIADIAZOLES
427
m/z 192.0595 [M + H]+. C9H10N3S. Calculated:
m/z 192.0590.
2. Maddila, S., Momini, M., Gorle, S., Palakondu, L., and
Jonnalagadda, S.B., J. Chil. Chem. Soc., 2015, vol. 60,
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Chem., Sect. B, 2015, vol. 54, p. 228.
5-[4-(Dimethylamino)phenyl]-2,4(1,2)-dihydro-
3H-1,2,4-triazole-3-thione (4b). mp 284–288°C.
1H NMR spectrum, δ, ppm: 2.96 s (6H, CH3), 6.77 d
(2H, m-H, J = 8.7 Hz), 7.71 d (2H, o-H, J = 8.7 Hz),
13.37 s (1H, 2-H), 13.46 br.s (1H, 4-H or 1-H).
13C NMR spectrum, δC, ppm: 39.7 (CH3), 111.7 (Cm),
112.4 (Ci), 126.7 (Co), 150.8 and 151.5 (Cp, C5), 166.1
(C=S). Found: m/z 221.0860 [M + H]+. C10H13N4S.
Calculated: m/z 221.0855.
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c. Catalysis by benzyl(triethyl)ammonium chloride
[20]. A mixture of 350 mg (3 mmol) of 1a, 408 mg
(3 mmol) of 4-methoxybenzaldehyde, and 10 mg of
benzyl(triethyl)ammonium chloride in 5 mL of anhy-
drous DMF was heated for 8 h under reflux. After
cooling, the mixture was poured onto ice under
stirring, and the precipitate was filtered off, dried, and
recrystallized from ethanol. The product, 300 mg
(43%), colorless crystals, mp 223–224°C, was iden-
tified as hydrazone 2a by comparing with an authentic
sample. Likewise, from 350 mg (3 mmol) of amino-
triazole 1a and 420 mg (3 mmol) of 4-chlorobenzal-
dehyde we obtained 300 mg (42%) of hydrazone 2g
(identified by comparing with an authentic sample) as
colorless crystals with mp 213–214°C.
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d. Catalysis by L-(+)-tartaric acid [38]. A mixture
of 193 mg (1 mmol) of aminotriazole 1c, 136 mg
(1 mmol) of 4-methoxybenzaldehyde, and 30 mg of
L-(+)-tartaric acid in 5 mL of anhydrous ethanol was
heated for 2 h under reflux. After cooling, the precip-
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The product, 200 mg (64%), colorless crystals,
mp 209–211°C, was identified as 2c by comparing
with an authentic sample. Likewise, the reaction of
193 mg (1 mmol) of 1c with 96 mg (1 mmol) of
furfural gave 150 mg (55%) of off-white crystals with
mp 205–206°C, which were identified as 2e.
14. Moustafa, A.H., Haggam, R.A., Younes, M.E., and El
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19. Abdel-Rachman,
R.M., Al-Footy,
K.O.,
and
This study was performed under financial support
by the Russian Science Foundation (project no. 14-13-
00126). NMR experiments were carried out using the
equipment of the Magnetic Resonance Research
Center, and quantum chemical calculations were per-
formed at the Computing Center of the St. Petersburg
State University.
Aqlan, F.M., Int. J. ChemTech Res., 2011, vol. 3, p. 423.
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