Thiazolo[3,2-b][1,2,4]triazol-7-ium salts: Synthesis, properties and structural studies

Article abstract of DOI:10.1515/hc-2018-0048

The reactions of [1,3]thiazolo[3,2-b][1,2,4]triazol-7-ium salts with nucleophiles were investigated. Theoretical investigation of reactivity descriptors and structural parameters of [1,3]thiazolo[3,2-b][1,2,4]triazol-7-ium cation was carried out, and the

Full text of DOI:10.1515/hc-2018-0048

Heterocycl. Commun. 2018; aop
Mikhailo Slivka*, Nataliya Korol, Maksym Fizer, Vjacheslav Baumer and Vasil Lendel
[
1,3]Thiazolo[3,2-b][1,2,4]triazol-7-ium salts:
synthesis, properties and structural studies
https://doi.org/10.1515/hc-2018-0048
Received March 21, 2018; accepted June 1, 2018
Herein, we discuss the reactivity of the [1,3]thiazolo[3,2-b]
1,2,4]triazol-7-ium salts using quantum chemical calcula-
[
tions followed by experimental studies on the reactions of
these salts with O,N-nucleophiles, leading to the forma-
tion of new polyfunctional derivatives of 1,2,4-triazole.
Abstract: The reactions of [1,3]thiazolo[3,2-b][1,2,4]triazol-
7
-ium salts with nucleophiles were investigated. Theoreti-
cal investigation of reactivity descriptors and structural
parameters of [1,3]thiazolo[3,2-b][1,2,4]triazol-7-ium cation
was carried out, and the reactivity centers of the model
salts were located. An efficient general method for the Results and discussion
synthesis of novel poly-functional derivatives of symmet-
ric triazoles from [1,3]thiazolo[3,2-b][1,2,4]triazol-7-ium Previously, we reported on the synthetic approach to
halides was developed. The structures of the synthesized the [1,3]thiazolo[3,2-b][1,2,4]triazol-7-ium salts via elec-
compounds were confirmed using proton nuclear mag- trophilic heterocyclization [16, 17]. The literature also
1
netic resonance ( H NMR), carbon-13 nuclear magnetic contains a limited number of sources that describe the
13
resonance ( C NMR), Fourier-transform infrared spectros- chemical properties of azolinium cations; however, these
copy (FTIR) and single-crystal X-ray analysis.
data are contradictory [16, 18–22]. In order to investigate
the reactivity of the [1,3]thiazolo[3,2-b][1,2,4]triazol-7-ium
cation in more detail, in this work we used a combination
of theoretical and experimental approaches.
The bromides 1 and 2 (Figure 1) were used as model
salts. The starting geometries of the cations 1 and 2 were
pre-optimized using the semiempirical PM7 approach [23],
which is one of the best neglect of differential diatomic
overlap (NDDO) methods and describes triazole systems
Keywords: functionalization; nucleophiles; reactivity
descriptor; regioselectivity; [1,3]thiazolo[3,2-b][1,2,4]tria-
zol-7-ium salts.
Introduction
Thiazolo[3,2-b][1,2,4]triazoles and other derivatives of well [24]. The re-optimization of the geometries of 1 and 2
1
,2,4-triazoles show diverse biological activity [1–7]. with the DFT PBE/6-311G(d,p) level of theory [25] was the
The most recent approaches toward the synthesis of the next step. This decision was based on our previous studies,
thiazolo[3,2-b][1,2,4]triazole system have been described where it was found that the PBE functional can model
8], but only the C-5 substitution in this fused system has similar C, H, N, S containing organic compounds very well
[
been studied as regards the chemical properties [9–15]. [26, 27]. Table 1 shows the comparison of selected bonds
Recently there has been significant interest in developing of the optimized geometries of cations 1 and 2 with similar
reactions for thiazolo[3,2-b][1,2,4]triazole and [1,2,4]tria- experimental data. Most of the calculated parameters are
zole systems’ functionalizations with the aim of expand- in good agreement with the experimental parameters and
ing the range of potential bio-active compounds [1–7]. lie within single standard deviations of the experimentally
determined values. The only exception is the C33-C34 bond,
where the DFT computed length is slightly overestimated as
*
Corresponding author: Mikhailo Slivka, Department of Organic
compared with variability range of the experimental bond
length (Table 1). This discrepancy can be explained by the
fact that none of the presented experimental geometries
contain a fragment with the set of bonds chemically and
Chemistry, Organic Synthesis Laboratory, Uzhhorod National
University, Uzhhorod 88000, Ukraine; and Department of Ecology,
Faculty of Humanity and Natural Sciences, University of Prešov,
Prešov 08116, Slovak Republic, e-mail: mikhailslivka@gmail.com
Nataliya Korol, Maksym Fizer and Vasil Lendel: Department of
Organic Chemistry, Organic Synthesis Laboratory, Uzhhorod
National University, Uzhhorod 88000, Ukraine
+
structurally equivalent to the N4 -C33-C34 bonds.
The Fukui function [32] and molecular electrostatic
potential [33] are well-established reactivity descriptors
that can explain the regioselectivity of the reaction [24,
27]. The wavefunction for the production and analysis
Vjacheslav Baumer: Department of X-ray Diffraction Studies and
Quantum Chemistry, Institute for Single Crystals, NASU, Nauky
ave. 60, Kharkiv 61001, Ukraine
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ꢀꢀꢀꢀꢁꢀM. Slivka et al.: Properties of [1,3]thiazolo[3,2-b][1,2,4]triazoles
Figure 1ꢀThe general view of optimized cations 1 and 2 with numbering. R equals H in cation 1, and R is CH in cation 2.
3
Table 1ꢀSelected bond lengths of PBE/6-311G(d,p) geometries of cations 1 and 2 and similar experimental data (in Å).
Bond
Cation ꢁ/Cation ꢂ
Exp. Bond
Cation ꢁ/Cation ꢂ
Exp. Bond
Cation ꢁ/Cation ꢂ
Exp.
Nꢂ-Nꢃ
ꢄ.ꢂꢅ9/ꢄ.ꢂꢅꢆ ꢄ.ꢂꢃꢄ(ꢆ) [ꢇꢆ] Nꢃ-Cꢂꢂ
ꢄ.ꢂ9ꢅ(ꢅ) [ꢇ9]
ꢄ.ꢃ7ꢅ/ꢄ.ꢃ9ꢈ ꢄ.ꢃ7ꢈ(ꢆ) [ꢇꢆ] Nꢅ-C7
ꢄ.ꢃꢅꢄ(ꢉ) [ꢇ9]
ꢄ.ꢃꢇꢈ/ꢄ.ꢃꢄ9 ꢄ.ꢂ7ꢇ(9) [ꢇꢆ]
ꢄ.ꢂꢃ9(ꢉ) [ꢂꢈ]
ꢄ.ꢂꢆꢃ(ꢅ) [ꢂꢈ]
ꢄ.ꢂ7ꢅ(ꢂ)a
a
ꢄ.ꢂ9ꢆ(ꢂ)
Nꢂ-C7
Nꢃ-Cꢉ
ꢄ.ꢂꢇꢆ/ꢄ.ꢂꢇꢆ ꢄ.ꢂꢂꢂ(ꢆ) [ꢇꢆ] Nꢅ-Cꢉ
ꢄ.ꢇꢆꢃ(ꢉ) [ꢇ9]
ꢄ.ꢂꢅꢅ/ꢄ.ꢂꢅꢉ ꢄ.ꢂꢄꢅ(ꢆ) [ꢇꢆ] Cꢂꢂ-Cꢂꢃ
ꢄ.ꢂ77(ꢅ) [ꢇ9]
ꢄ.ꢅꢂꢇ/ꢄ.ꢅꢃꢅ ꢄ.ꢅꢈ9(ꢆ) [ꢇ9]
ꢄ.ꢃꢉ7(ꢆ) [ꢂꢄ]
ꢄ.ꢂꢈꢅ(ꢉ) [ꢂꢈ]
ꢄ.ꢂ77(ꢅ) [ꢂꢈ]
ꢄ.ꢅꢈꢄ(ꢅ)a
a
a
ꢄ.ꢇ99(ꢂ)
ꢄ.ꢂꢉꢉ(ꢂ)
ꢄ.ꢂꢂꢆ/ꢄ.ꢂꢂꢉ ꢄ.ꢂꢇꢂ(9) [ꢇꢆ] Sꢇ-Cꢉ
ꢄ.ꢂꢂꢅ(ꢅ) [ꢇ9]
ꢄ.7ꢇꢈ/ꢄ.7ꢇꢈ ꢄ.ꢉꢆꢈ(ꢉ) [ꢇꢆ] Brꢄ-Cꢂꢃ
ꢄ.7ꢂꢆ(ꢅ) [ꢇ9]
ꢄ9ꢉꢇ/ꢄ.9ꢉꢂ ꢄ.9ꢉꢄ(ꢅ) [ꢇ9]
ꢄ.9ꢉꢅ(ꢅ) [ꢂꢄ]
ꢄ.ꢇ9ꢈ(ꢉ) [ꢂꢈ]
ꢄ.7ꢇ7(ꢅ) [ꢂꢈ]
ꢄ.9ꢄꢃ(ꢃ)a
a
a
ꢄ.ꢇ9ꢆ(ꢃ)
ꢄ.7ꢃꢃ(ꢇ)
aThe dibromide 7 in this work.
of reactivity descriptors was generated at the B3LYP/6- less probable is the substitution of Br1 atom by nucleo-
11G(d,p) level. It was demonstrated that the B3LYP func- philes. These data strongly suggest breaking of the S2-C6
tional [34] produces relatively good electron densities thiazoline bond under the action of nucleophiles.
3
[
35]. Moreover, the predictive power of reactivity descrip-
Thesetheoreticalresultspromptedfurtherexperimental
tors, obtained by this approach and natural population studies on the behavior of the model salts 1, 2 under the
analysis (NPA) partial charges, [36] is satisfactory [37]. action of nucleophiles (Scheme 1). The reactions between
−
The 6-311G(d,p) basis set [38] was chosen as it generates salts 1, 2 and OH nucleophile in aqueous solutions of
a reliable electrostatic potential [33]. Table 2 presents NaOH, Na CO , Na SO at room temperature were studied.
2
3
2
3
the computed reactivity indexes of the condensed Fukui The cleavage of the thiazoline moiety with the formation
function (CFF) for the nucleophilic attack of cations 1 and of poly-functional symmetric triazoles 3, 4 was observed
2
. As can be seen from Table 2, the most reactive atom for in all cases. Also, as was shown previously [16], the use of
both cations is C6. The reactivity order S2ꢀ>ꢀN5ꢀ>ꢀC7 can more concentrated solutions of reagents and longer reac-
also be noted. The rearrangement of 1,2,4-triazole system tion times lead to the formation of the elimination product
under the action of bases to 1,3,4-thiadiazole system has 5 in the case of salt 1. The reaction is believed to proceed
been described in the literature [31]. Less plausible is the through the cleavage of the S2-C6 thiazoline bond by nucle-
attack at para-carbon in the C19-H29 phenyl ring. Even ophile action with the subsequent substitution of bromine.
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M. Slivka et al.: Properties of [1,3]thiazolo[3,2-b][1,2,4]triazolesꢊꢁꢀꢀꢀꢊ3
Table 2ꢀCFF reactivity indexes for nucleophilic attack on cations 1 and 2, computed with NPA partial charges at the B3LYP/6-311G(d,p) level.
Atom
ꢁ
ꢂ
Atom
ꢁ
ꢂ
Atom
ꢁ
ꢂ
Atom
ꢁ
ꢂ
Brꢄ
Sꢇ
Nꢂ
Nꢃ
Nꢅ
Cꢉ
0.069
0.ꢁ0ꢄ
ꢈ.ꢈꢂ9
ꢈ.ꢈꢄꢆ
0.05ꢄ
0.ꢁꢄꢄ
0.0ꢃ6
−ꢈ.ꢈꢄꢇ
ꢈ.ꢈꢇꢃ
ꢈ.ꢈꢄꢈ
0.06ꢃ
0.098
ꢈ.ꢈꢃꢄ
ꢈ.ꢈꢄꢉ
0.05ꢁ
0.ꢁꢂ8
0.0ꢃ9
−ꢈ.ꢈꢄꢄ
ꢈ.ꢈꢇꢂ
ꢈ.ꢈꢈ9
Cꢄꢄ
Hꢄꢇ
Cꢄꢂ
Hꢄꢃ
Cꢄꢅ
Hꢄꢉ
Cꢄ7
Hꢄꢆ
Cꢄ9
Cꢇꢈ
ꢈ.ꢈꢄꢇ
ꢈ.ꢈꢇꢄ
ꢈ.ꢈꢉꢈ
ꢈ.ꢈꢇꢇ
ꢈ.ꢈꢄꢆ
ꢈ.ꢈꢇꢄ
ꢈ.ꢈꢄ9
ꢈ.ꢈꢄꢈ
−ꢈ.ꢈꢈ9
ꢈ.ꢈꢂꢅ
ꢈ.ꢈꢄꢂ
ꢈ.ꢈꢇꢄ
ꢈ.ꢈꢉꢈ
ꢈ.ꢈꢇꢇ
ꢈ.ꢈꢄ7
ꢈ.ꢈꢇꢄ
ꢈ.ꢈꢇꢄ
ꢈ.ꢈꢄꢈ
−ꢈ.ꢈꢈ7
ꢈ.ꢈꢂꢉ
Hꢇꢄ
Cꢇꢇ
Hꢇꢂ
Cꢇꢃ
Hꢇꢅ
Cꢇꢉ
Hꢇ7
Cꢇꢆ
Hꢇ9
Cꢂꢈ
ꢈ.ꢈꢄꢂ
ꢈ.ꢈꢄꢉ
ꢈ.ꢈꢇꢂ
0.0ꢃꢄ
ꢈ.ꢈꢇꢂ
ꢈ.ꢈꢈ9
ꢈ.ꢈꢇꢄ
ꢈ.ꢈꢂꢉ
ꢈ.ꢈꢈꢉ
ꢈ.ꢈꢈꢉ
ꢈ.ꢈꢄꢂ
ꢈ.ꢈꢄꢉ
ꢈ.ꢈꢇꢂ
0.0ꢃ5
ꢈ.ꢈꢇꢂ
ꢈ.ꢈꢈ9
ꢈ.ꢈꢇꢄ
ꢈ.ꢈꢂꢉ
ꢈ.ꢈꢈ7
ꢈ.ꢈꢈꢅ
Hꢂꢄ
Hꢂꢇ
Cꢂꢂ
Cꢂꢃ
Hꢂꢅ
ꢈ.ꢈꢇꢈ
ꢈ.ꢈꢄ7
−ꢈ.ꢈꢈꢃ
−ꢈ.ꢈꢄꢂ
ꢈ.ꢈꢈꢆ
ꢈ.ꢈꢇꢈ
ꢈ.ꢈꢈꢂ
–
ꢈ.ꢈꢄ9
ꢈ.ꢈꢄꢅ
−ꢈ.ꢈꢈꢄ
−ꢈ.ꢈꢄꢇ
ꢈ.ꢈꢈꢆ
a
X
−ꢈ.ꢈꢈꢃ
ꢈ.ꢈꢈꢆ
C7
Hꢂ7
Hꢂꢆ
Hꢂ9
Hꢃꢈ
Cꢆ
ꢈ.ꢈꢈꢉ
C9
–
ꢈ.ꢈꢄꢆ
Hꢄꢈ
–
−ꢈ.ꢈꢈꢄ
a
Largest values are shown in bold. In the case of cation 1, Xꢅ=ꢅH36ꢁ=ꢁR (see Figure 1), for cation 2, Xꢅ=ꢅC36, which is part of R.
HO
R1
S
N
N
1
Ph
O
3: R = H
4
N
1
: R = Me
Ph
2
NaOH
or
Na2CO3
or
H2O
O2 (atmosphere)
O
Na2SO3
N
(
for 1)
(for 2)
R1 CH2Br
Me
Br
i, morpholine
i, morpholine
S
N
N
N N
S
ii, H O
N
N
S
ii, H O
2
2
Ph
O
Ph
O
N
Ph
N
O2 (atmosphere)
N
O2 (atmosphere)
Ph
Ph
2
Ph
2
5
6
1
1
2
: R = H
1
: R = Me
Scheme 1ꢀ
−1
Oxidation of the thiol to a disulfide probably occurs in the strong band at 1700 cm (C=O group) is present in the infra-
−1
presence of atmospheric oxygen and gives the correspond- red (IR) spectrum of triazole 4; a wide signal at 3400 cm
ing target triazoles 3, 4. It should be noted that performing (OH group) is also seen. The different behavior of salts 1 and
these reactions under heating or in different solvents leads 2 is observed for the reaction of an N-nucleophile such as
to a decrease in selectivity [according to the nuclear mag- morpholine at room temperature with further dilution of
netic resonance (NMR) spectrum of the reaction mixture].
the mixture by water (Scheme 1). Specifically, the methyl-
1
The proton nuclear magnetic resonance ( H NMR), substituted salt 2 is transformed into amino-substituted
spectrum of compound 3 contains the characteristic signals product 6, whereas a similar treatment of the salt 1 gives
of exocyclic saturated fragment – the multiplet at 4.79– the elimination product 5, as earlier described by us [16]. In
4
.87 ppm for methine proton, the multiplet for oxi-methyl- addition to the signals of the CH , SCH and NCH groups,
3 2 2
1
ene protons at 4.01–4.08 ppm and the doublet of doublets the H NMR spectrum of triazole 6 also contains the triplets
for thiomethylene protons at 3.78 ppm, which (together for protons of methylene groups at 3.05 ppm and 3.45 ppm
−1
with the signals of the OH group at 3370 cm and the C=O (morpholine moiety). By contrast, there are only signals of
−1
1
group at 1695 cm in IR spectrum) confirm the structure. A the thiopropenyl moiety in the H NMR spectrum of triazole
1
similar pattern is observed in the case of triazole 4. The H 5, namely the singlet for the SCH group at 4.20 ppm and
2
NMR spectrum of triazole 4 contains the multiplet for SCH the singlets for cis and trans protons of the =CH group at
2
2
at 3.10–3.19 ppm, the multiplet for OCH at 4.15–4.21 ppm 6.00 ppm and 5.57 ppm, respectively. The IR spectra of tria-
2
−1
and a singlet for the methyl group protons at 1.76 ppm. The zoles 5 and 6 also show a strong band at 1700 cm (C=O
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ꢀꢀꢀꢀꢁꢀM. Slivka et al.: Properties of [1,3]thiazolo[3,2-b][1,2,4]triazoles
group); whereas the signal of the OH group is absent. In the of cation 1, the maxima on the ESP surface A, B and C
1
3
C NMR spectra of compounds 3–6, all signals of carbons with the corresponding values of 97, 86 and 88 kcal/mol,
3
2
belong to sp - and sp -hybridized carbons. The yields of the respectively, are closest to C33. In the case of the S 2 reac-
N
triazoles 3–6 are in the range of 64–78%, which indicates tion, the attack of a nucleophile must go opposite to the
regioselectivity of these reactions.
leaving group (the N4 atom), but in the case of cation 1
An interesting fact for significantly different sta- there is no maximum in the region opposite to N4, and
bilities of salts 1 and 2 toward heating can be noted. the angles N4-C33-X, where X can be A, B or C, are 71°,
Thus, salt 1 is stable upon heating in alcohol or acetic 91° and 105°, respectively. Obviously, the reaction is not
acid medium, whereas the heating of salt 2 in ethanol favorable for cation 1. By contrast, in the case of cation
leads to the destruction of the thiazoline ring with the 2, there is a maximum D (83 kcal/mol) located opposite
formation of dibromide 7 (Scheme 2). This difference in to N4 at the distance of 2.50 Å from C33. The N4-C33-D
stability of the N4-C33 bond in cations 1 and 2 is con- angle is 141°, which makes possible the attack of bromide
sistent with the following computational results. First, anion with cleavage of thiazoline system possible.
the N4-C33 bond in cation 2 is 0.015 Å longer than that
The formation of linear dibromide 7 was confirmed
of cation 1 (Table 1). Furthermore, a comparison of the by analysis of the NMR spectra and the structure was
NPA partial charges shows that the N4-C33 bond is more resolved using single-crystal X-ray diffraction analysis.
ionic in cation 2 than in 1. Thus, the partial charges of All calculations relevant to crystal structure determina-
N4/C33 in cation 1 are −0.204/−0.032, whereas in the case tion were performed using the SHELX-97 package [39].
of cation 2, the N4/C33 partial charges are −0.216/0.149. The program OLEX2 1.1 [40] was used for the analysis and
The Fukui function is not applicable in the case of Br− visualization of the structure and for rendering the illus-
attack (Table 2), as it shows the absence of any reactiv- trations. As salt 2 is a mixture of R- and S-enantiomers,
ity of C33 atom. We already faced similar limitations of
the CFF [24, 26, 27], and for correct treatment of ionic
reactions with the participation of hard nucleophiles
the electrostatic forces must be considered. Hence, the
electrostatic potential (ESP) is expected to be a useful
descriptor for understanding the reaction selectivity
between cations 1 and 2 (Figure 2). Thus, in the case
Me CH2Br
N
S
N
Br
Me
CH2Br
N
N
EtOH
N
Ph
S
N
Br
Ph
∆
Ph
Ph
2
7
Figure 3ꢀCrystal structure of the superimposed R- and S-enantiom-
ers of the molecule 7.
Scheme 2ꢀ
Figure 2ꢀThe electrostatic potential of cations 1 (A) and 2 (B). The maxima in the N4-C33 region are shown as letters with corresponding
values in parentheses (kcal/mol).
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M. Slivka et al.: Properties of [1,3]thiazolo[3,2-b][1,2,4]triazolesꢊꢁꢀꢀꢀꢊꢆ
the resulting dibromide 7 is also obtained in the form of a 6-(Bromomethyl)-6-methyl-2,3-diphenyl-5,6-dihydro-3H-[1,3]
thiazolo[3,2-b][1,2,4]triazol-7-ium bromide (2)ꢁThis compound
racemic mixture. Figure 3 presents the structure of dibro-
was synthesized according to the procedure [17]; yield 80% of white
mide 7 that was obtained by superimposition of R- and
powder; mp 284–286°C (lit. [17] mp 285–287°C).
S-enantiomers.
The 1,2,4-triazole-3-thiol moiety is almost planar
as in similar triazole systems that we have investigated General procedure for reaction of [1,3]thiazolo[3,2-b]
−
previously [28–30]. The angles between the plane of the [1,2,4]triazol-7-ium salts 1 and 2 with OH nucleophile
1,2,4-triazole-3-thiol fragment and C6-C11/C12-C17 phenyl
rings are 67.4°/33.0°, respectively. Intermolecular forces in A solution of salt 1 or 2 (1.0 mmol) in DMF (10 mL) was treated with
a solution of a – NaOH, b – Na CO or c – Na SO (2.0 mmol) in water
the crystal are formed by the weak interaction of the N1
atom with the H-CHS group, and by the weak interactions
between the 2,3-dibromopropyl fragments through the
Brꢀ·ꢀ·ꢀ·ꢀH-C attraction.
2
3
2
3
(
10 mL). The mixture was stirred for 2 h at room temperature and then
treated with water (50 mL). The resultant precipitate of 3 or 4 was
filtered, washed with water, dried and crystallized from acetone.
1
-2-Hydroxy-1-[3-hydroxy-2-(5-oxo-3,4-diphenyl-4,5-dihydro-
1
H-1,2,4-triazol-1-yl)propyldisulfanylmethyl]ethyl-3,4-diphe-
nyl-4,5-dihydro-1H-1,2,4-triazol-5-one (3)ꢁThis compound was
obtained by reaction of 1 with the reagent a–c; yields 58% (a),
Conclusions
6
4% (b) and 52% (c); white powder; mp 108–110°C; IR: 3370 (OH),
695 cm− (C=O); H NMR: δ 7.34–7.76 (m, 10H); 4.79–4.87 (m, 1H, CH),
1
1
1
The reactivity of [1,3]thiazolo[3,2-b][1,2,4]triazol-7-ium
cation toward nucleophiles was analyzed using a combi-
nation of theoretical and experimental approaches. As a
result, an efficient general synthesis of functional deriva-
tives of 1,2,4-triazole was developed.
1
3
4
.01–4.08 (m, 2H, CH O), 3.78 (dd, 2H, Jꢀ=ꢀ10.4, 3.2 Hz, CH S); C NMR:
2
2
δ 153.2, 151.0, 135.0, 131.7, 130.9, 129.6, 128.8, 128.2, 125.3, 123.2, 62.6,
5
9.1, 28.7. Anal. Calcd for C H N O S : C, 62.56; H, 4.94; N, 12.87; S,
34 32 6 4 2
9
.82. Found: C, 62.67; H, 5.11; N, 12.59; S, 9.77.
1-2-Hydroxy-1-[3-hydroxy-2-methyl-2-(5-oxo-3,4-diphenyl-4,5-
dihydro-1H-1,2,4-triazol-1-yl)propyldisulfanylmethyl]-1-methyl-
ethyl-3,4-diphenyl-4,5-dihydro-1H-1,2,4-triazol-5-one (4)ꢁThis
compound was obtained from salt 2 with the reagent a–c (see above);
yield 72% (a), 78% (b), 63% (c) (white powder); mp 88–90°C; IR:
Experimental
3400 (OH); 1700 cm− (C=O); H NMR: δ 7.17–7.47 (m, 10H); 4.15–4.21
1
1
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded
1
3
(
m, 2H, CH O), 3.10–3.19 (m, 2H, CH S), 1.76 (s, 3H, CH ); C NMR: δ
in hexadeutero dimethyl sulfoxide (DMSO-d ) as a solvent and with
2
2
3
6
1
53.0, 150.6, 134.2, 131.8, 130.2, 129.0, 128.6, 128.2, 126.6, 126.0, 64.8,
3.7, 36.9, 24.8. Anal. Calcd for C H N O S : C, 63.51; H, 5.33; N, 12.34;
tetramethylsilane (TMS) as an internal standard on a Varian VXR
6
4
00 spectrometer. Melting points were determined on a Stuart SMP30
36 36 6 4 2
S, 9.42. Found: C, 63.41; H, 5.72; N, 12.27; S, 9.18.
instrument. IR spectra were recorded on a Shimadzu FTIR Prestige 21
instrument with an attenuated total reflection (ATR) accessory. Ele-
mental analyses were performed on an Elementar Vario MICRO cube
analyzer. All crystallographic measurements were performed at room
temperature [293(2) K] on a single-crystal diffractometer, Oxford Dif-
fraction Xcalibur.
General procedure for the reaction of [1,3]thiazolo[3,2-b]
[
1,2,4]triazol-7-ium salts 1 and 2 with morpholine
A solution of salt 1 or 2 (1.0 mmol) and morpholine (2 mL) in DMF
(
5 mL) was stirred for 2 h at room temperature and then treated with
Computational software
water (100 mL). The resultant precipitate of 5 (from 1) or 6 (from 2)
was filtered, washed with water, dried and crystallized from acetone.
MOPAC2016 was used for the PM7 pre-optimization [41]. The PRIRODA
program was used for density functional theory (DFT) calculations 1-1-[2-(5-Oxo-3,4-diphenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)
[
42]. To reduce the computational time, the density fitting technique allyldisulfanylmethyl]vinyl-3,4-diphenyl-4,5-dihydro-1H-1,2,4-
was used [43]. Calculations of electrostatic potential were performed triazol-5-one (5)ꢁThis compound was obtained from 1; yield 70%
with Multiwfn 3.3.8 [44]. The JANPA program [45] was used for compu- (lit. [16] yield 76%) of white powder; mp 152–153°C (lit. [16] mp 106–
−1
1
tation of the NPA charges. Input files preparation and visualization of 108°C); IR: 1700 cm (C=O); H NMR: δ 7.32–7.60 (m, 10H); 6.00 (s, 1H,
the structures were made using the programs Avogadro [46], VMD [47] =CH -cis), 5.57 (s, 1H, =CH -trans), 4.20 (s, 2H, SCH ). Anal. Calcd for
2
2
2
and Jmol (Jmol: an open-source Java viewer for chemical structures C H N O S : C, 66.21; H, 4.58; N, 13.63; S, 10.40. Found: C, 66.35; H,
3
4
28
6
2 2
in 3D. http://www.jmol.org/).
4.56; N, 13.54; S, 10.28.
6
-(Bromomethyl)-2,3-diphenyl-5,6-dihydro-3H-[1,3]thiazolo[3,2- 1-1-Methyl-2-[2-methyl-3-morpholino-2-(5-oxo-3,4-diphenyl-4,5-
b][1,2,4]triazol-7-ium bromide (1)ꢁThis compound was synthe- dihydro-1H-1,2,4-triazol-1-yl)propyldisulfanyl]-1-morpholino-
sized according to the procedure [16]; yield 82% of white powder; mp methylethyl-3,4-diphenyl-4,5-dihydro-1H-1,2,4-triazol-5-one
1
95–196°C (lit. [16] mp 195°C).
(6)ꢁThis compound was obtained from salt 2; yield 68% (white
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ꢇꢀꢀꢀꢀꢁꢀM. Slivka et al.: Properties of [1,3]thiazolo[3,2-b][1,2,4]triazoles
−
1
1
powder); mp 122°C; IR: 1700 cm (C=O); H NMR: δ 7.38–7.80 (m, 10H);
.26–4.29 (m, 2H, NCH ), 3.45 (t, 4H, Jꢀ=ꢀ3.6 Hz, O(CH ) -morph), 3.38–
[5] Assarzadeh, V. J.; Almasirad, A.; Shafiee, A.; Koopaei, M. N.;
Abdollahi, M. Synthesis of new thiazolo[3,2-b][1,2,4]triazole-
6(5H)-one derivatives as potent analgesic and anti-inflamma-
tory agents. Med. Chem. Res. 2ꢈ14, 23, ꢋ48–ꢋ5ꢌ.
[6] Korol, N. I.; Pantyo, V. V.; Slivka, M. V.; Kryvovyaz, A. O.; Koval,
G. M.; Lendel, V. G. The usage of selenium and tellurium-con-
taining derivatives of 1,2,4-triazole-3-thiol as bactericides and
fungicides. UA Patent 114460 UA, 201ꢌ.
[ꢌ] Küçükgüzel, Ş. G.; Çıkla-Süzgün, P. Recent advances bioac-
tive 1,2,4-triazole-3-thiones. Eur. J. Med. Chem. 2ꢈ1ꢆ, 97,
830–8ꢌ0.
[8] Korol, N. I.; Slivka, M. V. Recent progress in the synthesis of
thiazolo[3,2-b][1,2,4]triazoles. Chem. Heterocycl. Compd. 2ꢈ17,
58, 852–854.
4
3
2
2 2
.42 (m, 2H, CH S), 3.05 (t, 4H, Jꢀ=ꢀ3.6 Hz, N(CH ) -morph), 1.74 (s, 3H,
2
2
2
1
3
CH ); C NMR: δ 153.3, 148.6, 129.9, 129.3, 129.1, 129.0, 128.2, 128.1, 127.6,
3
1
27.0, 63.7, 63.0, 62.3, 43.3, 36.8, 25.3. Anal. Calcd for C H N O S :
44 50 8 4 2
C, 64.52; H, 6.15; N, 13.68; S, 7.83. Found: C, 64.63; H, 6.12; N, 13.55;
S, 7.98.
3
1
-[(2,3-Dibromo-2-methylpropyl)sulfanyl]-4,5-diphenyl-4H-
,2,4-triazole (7)ꢁA solution of salt 2 (1.0 mmol) in ethanol (40 mL)
was heated under reflux for 15 min. After cooling, the resultant pre-
cipitate of 7 was filtered, washed with water and crystallized from
ethanol as fine colorless needles suitable for X-ray crystal structure
1
analysis; yield 88%; mp 186°C; H NMR: δ 7.32–7.62 (m, 10H), 4.09
(
s, 2H, CH Br), 3.90–4.01 (m, 2H, SCH ), 1.87 (s, 3H). Anal. Calcd for
[ꢋ] Kazzouli, S. L.; Koubachi, J.; Brahmi, N. E.; Guillaumet, G.
Advances in direct C-H arylation of 5,5-, 6,5- and 6,6-fused
heterocycles containing heteroatoms (N, O, S). RSC Adv. 2ꢈ1ꢆ,
5, 152ꢋ2–153ꢋꢌ.
2
2
C H Br N S: C, 46.27; H, 3.67; Br, 34.20; N, 8.99; S, 6.86. Found: C,
1
8
17
2
3
4
6.22; H, 3.65; Br, 34.03; N, 8.89; S, 6.91.
For X-ray crystallographic analysis, a single crystal of 7 (from
ethanol) was mounted in inert oil and transferred to the cold gas [10] Le Meur, M.; Bourg, S.; Massip, S.; Marchivie, M.; Jarry, C.; Guil-
stream of the diffractometer. X-ray crystal data: M 467.23, color-
less crystal, crystal size 0.20 mm–0.05 mm–0.04 mm; triclinic,
laumet, G.; Routier, S. First palladium-catalyzed direct regioselec-
tive C-5 (het)arylation of mono- or disubstituted thiazolo[3,2-b]
[1,2,4]triazoles. Eur. J. Org. Chem. 2ꢈ14, 2014, 3ꢌ04–3ꢌ14.
space group P1 (no. 2), Zꢀ=ꢀ2, μ(Mo Kα)ꢀ=ꢀ4.600, aꢀ=ꢀ5.9160(5) Å,
̅
bꢀ=ꢀ10.7456(6) Å, cꢀ=ꢀ14.3759(10) Å, αꢀ=ꢀ84.389(5)°, βꢀ=ꢀ89.460(6)°, [11] Wang, S.-H.; Liu, W.-J.; Zhan, H.-Y.; Zhang, H.; Liang, Y.; Tian,
3
3
γꢀ=ꢀ84.138(6)°, Uꢀ=ꢀ904.76(11) Å , Tꢀ=ꢀ293(2), Vꢀ=ꢀ904.76(11) A , Zꢀ=ꢀ2,
Y. Ligandless microwave-assisted Pd(OAc) -catalyzed direct
2
−3
−1
ρcalcꢀ=ꢀ1.715 mg mm , μꢀ=ꢀ4.600 mm , F(000)ꢀ=ꢀ464. The intensity
data were collected within the range of 6.54ꢀ≤ꢀθꢀ≤ꢀ57.1°, using Mo-Kα
arylation of thiazolo[3,2-b]-1,2,4-triazoles. RSC Adv. 2ꢈ13, 3,
23ꢋꢌ2–23ꢋꢌ5.
radiation (λꢀ=ꢀ0.71078 Å). The intensities of 6273 reflections were [12] Liu, W.; Wang, S.; Lin, J.; Jiang, Y.; Zhang, Q.; Zhong, Y.
collected (3871 unique reflections). The final wR(F ) was 0.1530.
Palladium-catalyzed direct and regioselective C-5 desulfita-
tive arylation of thiazolo[3,2-b]-1,2,4-triazoles with sodium
sulfinates. Synlett 2ꢈ14, 25, 586–5ꢋ0.
2
2
Convergence was obtained at R ꢀ=ꢀ0.0504 and wR ꢀ=ꢀ0.1344 for all
F
2
reflections, R ꢀ=ꢀ0.0760, wR ꢀ=ꢀ0.1530, GOFꢀ=ꢀ0.985.
F
[
[
13] Liu, W.; Wang, S.; Li, Z.; Huang, Y.; Li, S.; Wang, A.
Silver-catalyzed direct regioselective phosphonation of
thiazolo[3,2-b]-1,2,4-triazoles with dialkyl phosphites. Synlett
2ꢈ1ꢆ, 26, 2561–2566.
14] Liu, W.; Wang, S.; Zhan, H.; Lin, J.; He, P.; Jiang, Y. Highly
regioselective palladium-catalyzed direct alkenylation of
thiazolo[3,2-b]-1,2,4-triazoles via CH activation. Tetrahedron
Lett. 2ꢈ14, 55, 354ꢋ–3552.
Supplementary material
X-ray crystallographic data.
Acknowledgments: This study was partially supported by
the National Scholarship Program of the Slovak Republic.
[
[
15] Wang, S.; Liu, W.; Cai, Z.; Li, S.; Liu, J.; Wang, A. Copper-
catalyzed regioselective sulfenylation of thiazolo [3,2-b]-1,2,4-
triazoles with thiols. Synlett 2ꢈ1ꢇ, 27, 2264–2268.
16] Usenko, R. M.; Slivka, M. V.; Lendel, V. G. Electrophilic hetero-
cyclization of 4,5-disubstituted 3-allylthio-4H-1,2,4-triazoles
by the action of halogens. Chem. Heterocycl. Compd. 2ꢈ11, 47,
References
1
02ꢋ–1036.
[
1] Zaharia, V.; Silvestru, A.; Palibroda, N.; Mogoşan, C. Hetero-
cycles 28. Synthesis and characterization of some bis and
polyhetererocyclic compounds with anti-inflammatory potential.
Farmacia 2ꢈ11, 59, 624–635.
[1ꢌ] Slivka, M. V.; Korol, N. I.; Rusin, I. F.; Lendel, V. G. Synthesis of
[1,3]thiazolo[3,2-b][1,2,4]triazol-ꢌ-ium and [1,2,4]triazolo[5,1-b]
[1,3]thiazin-4-ium salts via regioselective electrophilic cycliza-
tion of 3-[(2-alken-1-yl)sulfanyl]-4H-1,2,4-triazoles. Heterocycl.
Cоmmun. 2ꢈ1ꢇ, 21, 3ꢋꢌ–401.
[18] Korotkikh, N. I.; Aslanov, A. F.; Raenko, G. F.; Shvaika, O. P.
Halocyclization reactions of recyclization for synthesis of thier-
ane, thioethane and selenethane derivatives of azolones. Russ.
J. Org. Chem. 1ꢉꢉꢉ, 35, ꢌ52–ꢌ5ꢋ.
[1ꢋ] Slivka, M. V.; Khripak, S. M.; Britcun, V. M.; Staninetc, V. I. Syn-
thesis of 3-substituted 1,2,4-triazolo[3,4-b]thiazolium halides.
Russ. J. Org. Chem. 2ꢈꢈꢈ, 36, 1064–106ꢋ.
[20] Korotkikh, N. I.; Shvayka, O. P.; Gorbunov, L. A. Synthesis of
1,3,4-oxadiazole and xanthen-2-one luminophoric epoxide
monomers. Chem. Heterocycl. Compd. 1ꢉꢉꢉ, 35, 358–362.
[
2] Barbuceanu, S. F.; Draghici, C.; Barbuceanu, F.; Bancescu, G.;
Saramet, G. Design, synthesis, characterization and antimicro-
bial evaluation of some heterocyclic condensed systems with
bridgehead nitrogen from thiazolotriazole class. Chem. Pharm.
Bull. 2ꢈ1ꢆ, 63, 6ꢋ4–ꢌ00.
[
3] Tozkoparan, B.; Aytaç, S. P.; Gürsoy, S.; Aktay, G. Design and
synthesis of some thiazolotriazolyl esters as anti-inflammatory
and analgesic agents. Med. Chem. Res. 2ꢈ12, 21, 1ꢋ2–201.
4] Lesyk, R.; Vladzimirska, O.; Holota, S.; Zaprutko, L.; Gzella, A.
New 5-substituted thiazolo[3,2-b][1,2,4]triazol-6-ones: synthesis
and anticancer evaluation. Eur. J. Med. Chem. 2ꢈꢈ7, 42, 641–648.
[
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M. Slivka et al.: Properties of [1,3]thiazolo[3,2-b][1,2,4]triazolesꢊꢁꢀꢀꢀꢊ7
[
21] Khripak, S. M.; Slivka, M. V.; Zborovskii Yu. L.; Staninets, V. I. The [33] Riley, K. E.; Tran, K.; Lane, P.; Murray, J. S.; Politzer, P. Com-
interaction of derivatives of 3-S-substituted 4-bromomethyl-ꢌ-p-
nitrophenyl-4,5H-1.2.4-triazolo[3,4-b]thiazol-3-ium bromide with
secondary amines. Ukrainian Chem. J. 2ꢈꢈ1, 67, 40–43.
parative analysis of electrostatic potential maxima and minima
on molecular surfaces, as determined by three methods and a
variety of basis sets. J. Comp. Sci. 2ꢈ1ꢇ, 17, 2ꢌ3–284.
[
22] Khripak, S. M.; Slivka, M. V.; Slivka, M. V.; Lendel, V. G. Thien-
ooxazolopyrimidinium salts. Reaction of 1-bromomethyl-5-oxo-
[34] Becke, A. D. A new mixing of Hartree-Fock and local density
functional theories. J. Chem. Phys. 1ꢉꢉ3, 98, 13ꢌ2–13ꢌꢌ.
[35] Medvedev, M. G.; Bushmarinov, I. S.; Sun, J.; Perdew, J. P.;
Lyssenko, K. A. Density functional theory is straying from the
path toward the exact functional. Science 2ꢈ17, 355, 4ꢋ–52.
[36] Reed, A. E.; Weinstock, R. B.; Weinhold, F. Natural population
analysis. J. Chem. Phys. 1ꢉꢊꢆ, 83, ꢌ35–ꢌ46.
[3ꢌ] Cao, J.; Ren, Q.; Chen, F.; Lu, T. Comparative study on the meth-
ods for predicting the reactive site of nucleophilic reaction. Sci.
China: Chem. 2ꢈ1ꢆ, 58, 1845–1852.
4
-phenyl-1,2,4,5,6,ꢌ,8,ꢋ-octahydro[1]benzothieno-[3,2-e][1,3]
oxazolo[3,2-a] pyrimidin-11-ium bromide with oxygen-centered
nucleophiles. Russ J. Org. Chem. 2ꢈꢈ7, 43, 43ꢋ–442.
[
[
23] Stewart, J. J. P. Optimization of parameters for semiempirical
methods VI: more modifications to the NDDO approximations
and re-optimization of parameters. J. Mol. Model. 2ꢈ13, 19,
1
–32.
24] Fizer, M.; Sukharev, S.; Slivka, M.; Mariychuk, R.; Lendel, V.
Preparation of bisthiourea and 5-amino-4-benzoyl-1,2,4-triazol- [38] Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. Self-consist-
3
-thione complexes of copper(II), nickel and zinc and their
ent molecular orbital methods. XX. A basis set for correlated
wave functions. J. Chem. Phys. 1ꢉꢊꢈ, 72, 650–654.
[3ꢋ] Sheldrick, G. M. A short history of SHELX. Acta Crystallogr.
2ꢈꢈꢊ, 64A, 112–122.
[40] Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. OLEX2: a complete structure solution, refinement
and analysis program. J. Appl. Crystallogr. 2ꢈꢈꢉ, 42, 33ꢋ–341.
[41] Stewart, J. J. P. MOPAC2016 version 16.060W, 2016. Stewart
Computational Chemistry, http://OpenMOPAC.net.
[42] Laikov, D. N.; Ustynyuk, A. Yu. PRIRODA-04: a quantum-chem-
ical program suite. New possibilities in the study of molecular
systems with the application of parallel computing. Russ.
Chem. Bull. 2ꢈꢈꢆ, 54, 820–826.
biological evolution. J. Organomet. Chem. 2ꢈ1ꢇ, 804, 6–12.
25] Perdew, J. P.; Burke, K.; Ernzerhof, M. Generalized gradi-
ent approximation made simple. Phys. Rev. Lett. 1ꢉꢉꢇ, 77,
[
[
3
865–3868.
26] Bevziuk, K.; Chebotarev, A.; Snigur, D.; Bazel, Y.; Fizer, M.;
Sidey, V. Spectrophotometric and theoretical studies of the
protonation of Allura red AC and Ponceau 4R. J. Mol. Struct.
2ꢈ17, 1144, 216–224.
[
[
2ꢌ] Fizer, M.; Sidey, V.; Tupys, A.; Ostapiuk, Yu.; Tymoshuk, O.;
Bazel, Ya. On the structure of transition metals complexes
with the new tridentate dye of thiazole series: Theoretical and
experimental studies. J. Mol. Struct. 2ꢈ17, 1149, 66ꢋ–682.
28] Slivka, M.; Korol, N.; Pantyo, V.; Baumer, V.; Lendel, V. Regio-
and stereoselective synthesis of [1,3]thiazolo[3,2-b][1,2,4]
triazol-ꢌ-ium salts via electrophilic heterocyclization of 3-S-pro-
pargylthio-4H-1,2,4-triazoles and their antimicrobial activity.
Heterocycl. Commun. 2ꢈ17, 23, 10ꢋ–113.
[43] Laikov, D. N. Fast evaluation of density functional exchange-
correlation terms using the expansion of the electron density
in auxiliary basis sets. Chem. Phys. Lett. 1ꢉꢉ7, 281, 151–156.
[44] Chen, T.; Lu, F. Multiwfn: a multifunctional wavefunction ana-
lyzer. J. Comput. Chem. 2ꢈ12, 33, 580–5ꢋ2.
[
[
2ꢋ] Fizer, M.; Slivka, M.; Rusanov, E.; Turov, A.; Lendel, V. [1,3]
Thiazolo[2′,3′:3,4][1,2,4]triazolo[1,5-a]pyrimidines – a new het-
erocyclic system accessed via bromocyclization. J. Heterocycl.
Chem. 2ꢈ1ꢆ, 52, ꢋ4ꢋ–ꢋ52.
[45] Nikolaienko, T. Y.; Bulavin, L. A.; Hovorun, D. M. JANPA: an open
source crossplatform implementation of the natural popula-
tion analysis on the java platform. Comput. Theor. Chem. 2ꢈ14,
1050, 15–22.
[46] Hanwell, M. D.; Curtis, D. E.; Lonie, D. C.; Vandermeersch, T.;
Zurek, E.; Hutchison, G. R. Avogadro: an advanced semantic
chemical editor, visualization, and analysis platform. J. Chem-
informatics. 2ꢈ12, 4, 1–1ꢌ.
30] Fizer, M.; Slivka, M.; Mariychuk, R.; Baumer, V.; Lendel, V.
3
-Methylthio-4-phenyl-5-phenylamino-1,2,4-triazole hexa-
bromotellurate: X-ray and computational study. J. Mol. Struct.
ꢈ1ꢊ, 1161, 226–236.
2
[
[
31] Fizer, M.; Slivka, M.; Baumer, V.; Lendel, V. Synthesis of 3-alkyl- [4ꢌ] Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual molecular
5
-allylamino-2-benzoylimino-1,3,4-thiadiazoles via Dimroth
dynamics. J. Mol. Graph. 1ꢉꢉꢇ, 14, 33–38.
rearrangement. Heterocycl. Commun. 2ꢈ1ꢇ, 22, ꢌꢋ–83.
32] Ayers, P. W.; Parr, R. G. Variational principles for describing
chemical reactions: the Fukui function and chemical hardness
revisited. J. Am. Chem. Soc. 2ꢈꢈꢈ, 122, 2010–2018.
Supplementary Material: The online version of this article offers
supplementary material (https://doi.org/10.1515/hc-2018-0048).
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