Aminonitrones as highly reactive bifunctional synthons. An expedient one-pot route to 5-amino-1,2,4-triazoles and 5-amino-1,2,4-oxadiazoles-potential antimicrobials targeting multi-drug resistant bacteria

Article abstract of DOI:10.1039/c9nj04529e

The developed one-pot protocol to 5-amino-1,2,4-triazoles or 5-amino-1,2,4-oxadiazoles includes an interplay between aminonitrones R¹C(NH₂)N⁺(Me)O^- (R¹ = Alk, Ar, Het), isocyanides R²NC (R² = Alk, Ar), Br₂, and hydrazines (for the triazoles) or hydroxylamine (for the oxadiazoles). This formally four-component reaction, involving aminonitrones, isocyanides, bromine, and N-nucleophiles, proceeds very rapidly under mild conditions (10 min, 20-25 °C), and is insensitive to moisture and air (in undried CHCl₃-MeOH, in air) and it gives the heterocyclic systems in good yields (up to 86%; 26 examples). The reaction scope includes aromatic-, heteroaromatic-, and aliphatic aminonitrones and also aliphatic- and aromatic isocyanides. Results of DFT calculations (M06-2X/6-311+G(d,p) level of theory) indicate that the O-nucleophilic center of bifunctional aminonitrones is more reactive than the N center; it first reacts with in situ generated R²NCBr₂ to grant 2-methyl-1,2,4-oxadiazolium salts, which are then converted to the target heterocyclic systems upon treatment with hydrazines or hydroxylamine. The nature and strength of the intramolecular hydrogen bonds N-H?N and O-H?N, which significantly contribute to the total energies of different transition states and products of the nucleophilic substitution, were studied theoretically using the topological analysis of the electron density distribution within the framework of Bader's theory (QTAIM method). Several new 5-amino-3-aryl-1,2,4-triazoles and -1,2,4-oxadiazoles exhibit high antibacterial activity against multidrug-resistant bacteria strains such as Staphylococcus aureus and Klebsiella pneumoniae (MIC = 8 mg L^-1).

Full text of DOI:10.1039/c9nj04529e

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PAPER
Aminonitrones as highly reactive bifunctional
synthons. An expedient one-pot route to 5-amino-
1,2,4-triazoles and 5-amino-1,2,4-oxadiazoles –
potential antimicrobials targeting multi-drug
resistant bacteria†
Cite this: New J. Chem., 2019,
43, 17358
a
a
a
Mikhail V. Il’in,
Alexandra A. Sysoeva,
Dmitrii S. Bolotin,
*
a
b
Alexander S. Novikov,
Vitalii V. Suslonov,
Elizaveta V. Rogacheva,c
Liudmila A. Kraeva*cd and Vadim Yu. Kukushkin
*
a
The developed one-pot protocol to 5-amino-1,2,4-triazoles or 5-amino-1,2,4-oxadiazoles includes an
interplay between aminonitrones R1C(NH2)QN+(Me)OÀ (R1 = Alk, Ar, Het), isocyanides R2NC (R2 = Alk, Ar), Br2,
and hydrazines (for the triazoles) or hydroxylamine (for the oxadiazoles). This formally four-component
reaction, involving aminonitrones, isocyanides, bromine, and N-nucleophiles, proceeds very rapidly under mild
conditions (10 min, 20–25 1C), and is insensitive to moisture and air (in undried CHCl3–MeOH, in air) and it
gives the heterocyclic systems in good yields (up to 86%; 26 examples). The reaction scope includes
aromatic-, heteroaromatic-, and aliphatic aminonitrones and also aliphatic- and aromatic isocyanides. Results
of DFT calculations (M06-2X/6-311+G(d,p) level of theory) indicate that the O-nucleophilic center of
bifunctional aminonitrones is more reactive than the N center; it first reacts with in situ generated R2NCBr2 to
grant 2-methyl-1,2,4-oxadiazolium salts, which are then converted to the target heterocyclic systems upon
treatment with hydrazines or hydroxylamine. The nature and strength of the intramolecular hydrogen bonds
N–HÁÁÁN and O–HÁÁÁN, which significantly contribute to the total energies of different transition states
and products of the nucleophilic substitution, were studied theoretically using the topological analysis of the
electron density distribution within the framework of Bader’s theory (QTAIM method). Several new 5-amino-
3-aryl-1,2,4-triazoles and -1,2,4-oxadiazoles exhibit high antibacterial activity against multidrug-resistant
bacteria strains such as Staphylococcus aureus and Klebsiella pneumoniae (MIC = 8 mg LÀ1).
Received 2nd September 2019,
Accepted 16th October 2019
DOI: 10.1039/c9nj04529e
rsc.li/njc
references therein). Our recent experimental and theoretical
studies, which appeared concurrently with relevant works by
Introduction
Oximes and, in particular, amidoximes are widely utilized precursors Xu,2 Merino3 and coworkers, indicate that O-functionalization of
in organic and organometallic syntheses (see our reviews1 and (amid)oxime species via their nucleophilic addition to unsaturated
species, which very often comprises the first step of their synthetic
transformations, proceeds via initial tautomerization of (amid)-
oxime to (amino)nitrones,2–4 and the latter tautomeric form acts
as an active nucleophile in these O-functionalizations (Scheme 1).5
This finding prompted us to study the reactivity of such amidoxime
congeners as aminonitrones to explore their potential as
bifunctional nucleophilic organic synthons, particularly for
the preparation of heterocyclic compounds.
Although aminonitrone species, which represent the nitrone
tautomer ‘‘frozen’’ by N-alkylation (Scheme 1, right), can be
easily obtained by the reaction of nitriles and N-substituted
hydroxylamine (MeOH, 3 h, reflux; see the ESI†), their chemistry has
received undeservedly little attention. Indeed, while the chemistry of
amidoxime species is well developed, almost nothing is known
a Institute of Chemistry, Saint Petersburg State University,
Universitetskaya Nab., 7/9, Saint Petersburg, Russian Federation.
E-mail: d.s.bolotin@spbu.ru, v.kukushkin@spbu.ru
b Center for X-ray Diffraction Studies, Saint Petersburg State University,
Universitetskii Pr., 26, Saint Petersburg, Russian Federation
c Saint Petersburg Pasteur Institute, Mira Str., 14, Saint Petersburg,
Russian Federation. E-mail: lykraeva@yandex.ru
d S. M. Kirov Military Medical Academy, Lebedeva Str., 6, Saint Petersburg,
Russian Federation
† Electronic supplementary information (ESI) available: Analytical and spectro-
scopy data for aminonitrones, syntheses and characterization of aminonitrones,
syntheses and characterization of 1–26, crystal data for 13 and 14, the HRESI+-MS,
IR, 1H and 13C{1H} NMR spectra of the aminonitrones and also 1–26, and details
of DFT calculations. CCDC 1901802 and 1901803. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c9nj04529e
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Scheme 2, a),12 carbodiimides (110 1C; 5–36 h; dry solvents; b),13 or
highly toxic cyanogen bromide (30 1C, overnight; c).14 In addition,
chlorooximes were introduced in the two-step 36 h-long procedure
including isocyanides and hydroxylamine to yield 5-amino-1,2,4-
oxadiazoles15 (d).
Our aminonitrone-based approach has significant advantages
over the known oxime-based synthetic procedures to yield 5-amino-
1,2,4-oxadiazoles,12–15 which also allows the synthesis of 5-amino-
1,2,4-triazoles under the same mild conditions (e). Our interest in
Scheme 1 Amidoxime–aminonitrone tautomerism.
about the reactions of structurally relevant aminonitrones. useful properties of novel systems, as well as the availability of
Aminonitrones can be oxidized to imino-nitroxides6 and azo facilities to assay their biological effects, led us to study the
compounds,7 or reduced to amidines.7,8 These species can also be antibiotic properties of the obtained 5-amino-1,2,4-triazoles and
involved in heterocyclization to form imidazolones,9 imidazoles,9 5-amino-1,2,4-oxadiazoles. Antibacterial activity has previously been
1,2,4-oxadiazolines,9,10 1,2,5-oxadiazin-4-ones,8 and diazepines8b and studied for a wide range of 1,2,4-triazoles16 and 1,2,4-oxadiazoles,17
they are useful reactants to achieve 2-substituted 1,2,4-oxadiazolium but it has never been verified for their 5-amino-derivatives; the
salts.11 It is noteworthy in the context of this work that multi- latter heterocyclic systems were previously considered only from the
component reactions based on aminonitrones are unknown.
We now report an expedient aminonitrone-based one-pot route to
5-amino-1,2,4-oxadiazoles and 5-amino-1,2,4-triazoles that can also
be treated as a formally multicomponent reaction. A general overview
of synthetic strategies leading to these 5-amino-substituted hetero-
cyclic systems indicates a number of procedures, among which the
viewpoint of their application in materials chemistry.14b,18
Results and discussion
Aminonitrone-based synthesis of 5-amino-1,2,4-triazoles and
5-amino-1,2,4-oxadiazoles
most useful processes employ amidoxime or hydrazone species, Consequent addition of dibromine, the aminonitrone R1C(NH2)Q
respectively, and cyanamides (catalyzed by ZnCl2; 80 1C, 26–54 h; N+(Me)OÀ, and any of the bifunctional nucleophiles H2NXH
Scheme 2 Reported amidoxime-based and novel aminonitrone-based approaches to 5-aminoheterocycles.
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(hydroxylamine; hydrazine, phenyl- and benzylhydrazines were characterized by HRESI+-MS, IR, and 1H- and 13C{1H} NMR
taken as model mono-substituted hydrazines) to a solution spectroscopies. Compounds 1,11 15,11 18,19 and 2315 were previously
of R2NC in CHCl3 at RT for 10 min resulted in the generation reported and they were identified by comparison of their NMR
of 5-R(H)N-1,2,4-oxadiazoles (15–26) or 5-R(H)N-1,2,4-triazoles spectra with the reported spectral data and also by measuring
(1–14), which, after work-up, were isolated in up to 86% yields their HRESI+-mass spectra. 1-Substituted triazoles 13 and 14 were
(Scheme 3). Heterocycles 2–14, 16–17, and 19–22 were additionally characterized by single-crystal XRD (see the ESI†).
For the aromatic aminonitrones the reaction typically proceeded
in higher yields than that for aliphatic substrates [R2 = Cy; 61–86%
(R1 = Ar; 1–8 and 15–22) vs. 48 and 52% (R1 = Me; 12 and 26)].
Sterically hindered R2 significantly reduced the yield of heterocycles
and, thus, isocyanides XylNC and tBuNC gave 9, 11, 23, and 25 in
29–57% yields. The nature of the bifunctional nucleophile had
almost no effect on the yield of heterocycles and 1, 13, 14, and 15
(R1 = Ph; R2 = Cy; X = NH, NPh, NBn, and O, respectively) were
isolated in similar yields (79–85%). Electronic effects of substitu-
ents in aromatic aminonitrones also had no significant effect on
the yield of heterocycles. It is important to note that traces of water
and dioxygen did not affect the yields of 1–26; employment of dry
solvents and/or an inert atmosphere (under Ar) did not improve the
yields.
For the first step of the reactions (generation of 1,2,4-
oxadiazolium salts; see below), weak donor solvents should
be used. We found no significant effect on the yields of 1–26
upon the utilization of CHCl3, CH2Cl2, and ClCH2CH2Cl,
whereas in more donating Me2CO, Me2SO, and DMF, the yields,
in general, were by 15–30% lower. When the first step of the
reaction was conducted in MeOH or EtOH, the treatment led to
a spectrum of by-products and finally gave 1–26 in 1H NMR
yields less than 35%. Utilization of MeOH or EtOH is possible
on the second step of the reaction, when the formed 1,2,4-
oxadiazolium salt reacts with H2NX. Increasing the molar ratio
between RNC and Br2 relative to the aminonitrone to
(1.5) : (1.5) : 1 did not lead to an appropriate increase in the
yields of 1–26, whereas the decrease to 1 : 1 : 1 resulted in yield
reduction by 10–15%, compared to the reactions performed
with the (1.2) : (1.2) : 1 molar ratio. Increasing the ratio of
Et3N : aminonitrone from 1 : 1 to (1.5) : 1 and then to 2 : 1 led
to a gradual decrease of the yields of 1–26 by ca. 5–10%,
whereas the decrease of the ratio resulted in substantial yield
reduction.
Regioselectivity of the reactions with unsymmetric
nucleophiles
When the unsymmetric bifunctional nucleophiles (H2NX;
X = NHPh, NHBn, OH) were applied, in each case, generation
of a mixture of regioisomers was observed (Fig. 1).
The reactions including phenyl- and benzylhydrazines
(for 13 and 14, respectively) proceed to give mixtures of the
5-amino-1,2,4-triazole (major) and 3-amino-1,2,4-triazole (minor)
forms in 95 : 5 and 90: 10 molar ratios, correspondingly (based
on 1H NMR and GC-MS monitoring). Similarly, when H2NOH
was employed for the preparation of 15–26, in each case a
Scheme 3 Preparation of 5-amino-1,2,4-triazoles and 5-amino-1,2,4-
oxadiazoles. Reagent ratios: aminonitrone (1 equiv.), isocyanide (1.2 equiv.),
regioisomeric mixture of 5-amino-1,2,4-oxadiazole (major) and
3-amino-1,2,4-oxadiazole (minor) is generated in an approxi-
H2NX (1.5 equiv.), Br2 (1.2 equiv.), and Et3N (1 equiv.). * Combined yields for
mately 95: 5 molar ratio (except 19, where this molar ratio was
87: 13). In all cases (except 19 and 24), the major 5-amino isomer
obtained mixtures of 5-amino and 3-amino regioisomers are represented
(19: B10 : 1; 24: B20 : 1, respectively).
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1,2,4-triazole or 1,2,4-oxadiazole systems (1–26) via the ANRORC
route (c).
In order to extend the existing knowledge on the reactivity of
aminonitrone species, we focused our attention on the first step
(a) and conducted an additional computational study. As can
be inferred from our previous work,25 aminonitrone species
exist in two tautomeric forms, viz. the major aminonitrone
form featuring the O-nucleophilic site (Scheme 5, A) and the
minor iminohydroxamic acid form featuring the N-nucleophilic
site (B). The aminonitrone species A can form O-iminoacyl
aminonitrones D, whereas the iminohydroxamic species B
can form N-iminoacylated intermediates E. Both D and E may
further undergo heterocyclization in a basic medium leading
to the same product (F). Thus, which site of the starting
bifunctional nucleophile reacts first in the sequence of the
two nucleophilic substitutions was an open question.
Fig. 1 Two regioisomers of 13–26.
was isolated from the reaction mixture as a pure compound by
column chromatography. In the cases of 19 and 24, the major
5-amino isomer was contaminated with traces of the minor
3-amino isomer; close retention times on silica gel—that
remained almost the same even upon substantial variation of
eluent systems—did not lead to complete separation. Lower
selectivity of the reaction in the case of 19 could be explained
in terms of the +M effect of the NMe2 group leading to decreased
electrophilicity of the C-3 atom. Variation in solvents (for 13 and
14; CHCl3, CH2Cl2, and ClCH2CH2Cl) or solvent mixtures (for 19;
CHCl3, CH2Cl2, ClCH2CH2Cl and MeOH, or EtOH) did not affect
significantly the molar ratios of the regioisomers.
Results of DFT calculations (M06-2X/6-311+G(d,p) level of
theory, for details see the ESI†) performed for exact pairs of the
reactants (R1 = Ph; R2 = Cy) reveal that (i) isomer A is thermo-
dynamically more favorable than B (by 0.9 kcal molÀ1 in terms
Insights into the reactivity of aminonitrones: a plausible
mechanism of the reaction
The overall reaction route includes three principal steps. The
first step is the initial generation of carbonimidic dibromides
Br2CQNR2 from isocyanides and dibromine (Scheme 4, a).20
Isocyanide dihalides are known to react with a series of nucleo-
philes,20a,21 including bifunctional nucleophiles22 to give hetero-
cyclic systems. Accordingly, in the next step, Br2CQNR2 reacts
with aminonitrone to give electrophilically activated 5-amino-
2-methyl-1,2,4-oxadiazolium salt via two consequent nucleophilic
substitutions (b).11 Although uncharged 1,2,4-oxadiazoles are
typically inactive toward nucleophilic attack, these heterocyclic
systems bearing strong electron-withdrawing perfluoroalkyl groups
undergo ANRORC rearrangements,23 which usually proceed for
electron-deficient aromatic systems.24 Positive charge on the
aromatic system of a generated 2-methyl-1,2,4-oxadiazolium
salt facilitates the nucleophilic attack by H2NX to grant the
Scheme 5 Plausible routes for the nucleophilic substitutions at an iso-
Scheme 4 A plausible mechanism of the reaction.
cyanide dibromide by an aminonitrone.
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Scheme 6 Energy profiles for plausible routes of the nucleophilic substitution.
of Gibbs free energies; Scheme 6), (ii) the reaction pathway properties of O–HÁÁÁN contact in E (viz. relatively large magnitude
A + C - D is more kinetically favorable than the reaction pathway of the electron density and negative energy density in appropriate
B + C - E (by 12.2 kcal molÀ1 in terms of Gibbs free energies of BCP, G(r) { |V(r)|, a large value of Wiberg bond index) suggests
activation), and (iii) the formation of E is more thermodynamically that this hydrogen bond has a large degree of covalent compo-
profitable than the formation of D (by 8.8 kcal molÀ1 in terms of nents and it is relatively strong (Table 5S, ESI†). Thus, higher
Gibbs free energies of reaction). Based on the theoretical calcula- thermodynamic stability of this isomer compared with D may
tions and experimental observations it can be concluded that the be accounted for by the presence of the strong intramolecular
aminonitrone species are first acylated via the O atom. Because of O–HÁ Á ÁN hydrogen bond in E.
the relatively high activation energy, alternative N-acylation at room
temperature is hardly possible.
Antibacterial activity of 5-amino-1,2,4-triazoles and
5-amino-1,2,4-oxadiazoles
Because the suggested transition states and the iminoacylated
intermediates feature intramolecular hydrogen bonds, which may We studied antibacterial activity of aminoheterocycles 1–26, as
significantly contribute to their total energy, we have estimated well as the activity of all starting aminonitrones, against
the strength of the intramolecular hydrogen bonds N–HÁÁÁN and bacterial species from the ESKAPE group. It is important to
O–HÁÁÁN in optimized equilibrium model structures of transition note that the widespread use of antibiotics led to a significant
states and products of nucleophilic substitution using the increase of the resistance of bacteria that circulate not only in
topological analysis of the electron density distribution within the the hospital environment, but also in outpatient settings.31 The
framework of Bader’s theory (QTAIM method).26 This approach has greatest danger is posed by bacterial species from the ESKAPE
already been successfully used by us upon studies of different group (i.e. Enterococcus faecium, Staphylococcus aureus, Klebsiella
hydrogen bonds in various organic,27 organometallic,28 and pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and
coordination compounds,29 as well as for the investigation of Enterobacter species). They are often multi-resistant to antibiotics;
properties of transition states in cycloaddition reactions.30 The according to ref. 32, the proportion of resistant strains can even
results are summarized in Table 5S (ESI†).
reach 95%. The greatest resistance to antibiotics is noted in strains
The QTAIM analysis performed for the optimized equilibrium S. aureus and K. pneumonia; the former uses a wide range of
model structures of transition states and products of nucleophilic resistance mechanisms. Therefore, new small molecules that affect
substitution demonstrates the presence of appropriate bond critical cell viability have recently been developed.33
points (3, À1) (BCPs; Fig. 141S and 142S, ESI†) for intramolecular
In our antibacterial experiments, initially, compounds 1–26
hydrogen bonding N–HÁÁÁN and O–HÁÁÁN in all cases (Table 5S, were tested by the disk diffusion method to choose the most
ESI†). The low magnitude of the electron density (0.017–0.019 a.u.), active species. Starting aminonitrones generally exhibited no
positive values of the Laplacian (0.064–0.067 a.u.), and very close to significant activity toward the studied bacterial strains, whereas
zero positive energy density in BCPs for N–HÁÁÁN contacts in TS1 selected heterocyclic compounds were then studied by the
and D and O–HÁÁÁN contact in TS2 as well as negligible Wiberg minimum inhibitory concentration (MIC) method according
bond indices (0.01–0.02) for these interactions are typical for purely to the international standard EUCAST 2018 (Version 8.1)
noncovalent weak hydrogen bonds, whereas analysis of the (Table 1).
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Table 1 Minimum inhibitory concentrations (mg LÀ1) of the selected 1,2,4-oxadiazoles and 1,2,4-triazoles toward ESKAPE bacterial pathogens
NJC
Enterococcus
faecalis
Staphylococcus
aureus
Klebsiella
pneumoniae
Acinetobacter
baumannii
Pseudomonas
aeruginosa
Enterobacter
cloacae
No.
2
3
5
6
8
10
12
16
4300
75
4300
8
8
75
4300
150
0.3
8
8
8
8
75
8
8
150
75
8
8
8
75
75
8
150
75
8
75
8
1.25
300
300
300
300
150
300
75
4300
32
4300
32
300
300
300
300
0.6
8
4300
8
8
0.6
150
1.25
Ciprofloxacin
2.5
As it can be inferred from the obtained experimental data, the generation of not only 1-H-, but also 1-alkyl- and 1-aryl-
the selected compounds have encouraging activity against 1,2,4-triazoles.
S. aureus and K. pneumoniae. Some of our compounds also
Second, based on our experimental data and theoretical
exhibit activity against E. faecalis (6 and 8) and A. baumannii calculations one can suggest that although aminonitrones
(5, 10, 16), whereas no significant activity was observed against possess two nucleophilic sites featured by the aminonitrone
P. aeruginosa and E. cloacae.
and iminohydroxamic acid tautomers, the most reactive is the
On the one hand, 2, 3, 5, 6, 10, and 16 demonstrated MIC O-nucleophilic aminonitrone form. This observation shed light
8 mg LÀ1 toward S. aureus, which is similar to the MIC values on the reactivity patterns of aminonitrone species and this adds
for Chloramphenicol and Amikacin and it is only twice higher than to the existing knowledge on the reactivity of aminonitrones.
that of such very strong antibiotics as Linezolid and Vancomicin. Our studies also provide additional information on the reactivity of
The activity of the aminoheterocycles toward S. aureus is in the relevant amidoximes, whose reactions are generally determined by
range between the activity of 1-H-5-alkylthio-1,2,4-triazoles34 and the reactivity of their minor tautomeric aminonitrone forms.3,4
5-alkylthio-1,2,4-triazoles bearing ciprofloxacin moieties35 and Results of DFT calculations and topological analysis of the electron
lies in the same activity interval as 3,5-diaryl-1,2,4-oxadiazoles.36 density distribution within the framework of Bader’s theory (QTAIM
On the other hand, compounds 2, 3, 8, 10, 12, and 16 exhibited method) reveal that intramolecular hydrogen bonds N–HÁÁÁN and
MIC 8 mg LÀ1 against K. pneumoniae, which is similar to the O–HÁÁÁN may significantly affect the thermodynamic stability of the
activity of Cefuroxime, Chloramphenicol, and Amikacin. This formed iminoacylated intermediates.
activity is comparable with the activity of 5-alkyl-3-aryl-1,2,4-
oxadiazoles,37 but lower than that of ciprofloxacin-derived against S. aureus and K. pneumoniae in our experiments (MIC =
5-alkylthio-1,2,4-triazoles.35a 8 mg LÀ1) is comparable with that of the known antibiotics,
Third, while the efficacy of compounds 2, 3, 8, 10, 12, and 16
Currently no solid ‘‘structure–activity’’ correlations for the they represent a novel type of antimicrobials, to which bacterial
tested compounds were observed. It is noteworthy, however, populations have not yet evolved resistance. In light of the
that the antibacterially active compounds are almost exclusively worldwide crisis of antimicrobial drug resistance, the clinical
represented by the 1,2,4-triazoles and only one example of a efficacy of our heterocycles may prove to be much higher than
1,2,4-oxadiazole (16) manifests this type of activity. Furthermore, that of long-used antibiotics. These considerations stimulate
antibacterial studies could also be focused on the ortho-substituted our interest in the antibacterial properties of 5-amino-
3-phenyl-1,2,4-oxadiazoles and -triazoles, wherein both (16 and aminoheterocyclic systems, and further investigations are in
2, respectively) displayed high activities against S. aureus and progress in our group.
K. pneumoniae.
Experimental
Materials and instrumentation
Concluding remarks
The results of this work can be considered from at least three Solvents, nitriles, N-methylhydroxylamine hydrochloride, iso-
perspectives. First, we found an efficient synthetic utilization of cyanides, bromine, triethylamine, hydroxylamine hydrochloride,
aminonitrones, whose synthetic potential is practically uncovered. hydrazine hydrate, and phenyl- and benzylhydrazine were
The developed one-pot reaction that can be treated as a formally obtained from commercial sources and used as received. All
four-component reaction comprises a facile and convenient one- syntheses were conducted in air. Chromatographic separation
pot route to 5-amino-1,2,4-triazoles and 5-amino-1,2,4-oxadiazoles; was carried out on Macherey-Nagel silica gel 60 M (0.063–
this synthesis is based on commercially available and/or easily 0.2 mm). Analytical TLC was performed on unmodified Merck
accessible precursors. The reaction proceeds very rapidly under ready-to-use plates (TLC silica gel 60 F254) with UV detection.
mild conditions (at RT for only 10 min) in undried solvents Melting points were measured on a Stuart SMP30 apparatus
in air. The suggested method is applicable for the preparation in capillaries and are not corrected. Electrospray ionization
of both the 3-alkyl- or 3-aryl heterocycles, as well as for mass-spectra were obtained on a Bruker maXis spectrometer
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equipped with an electrospray ionization (ESI) source. The (for 1–12; 1.5 mmol) or hydroxylamine (for 15–26; 1.5 mmol) in
instrument was operated in positive ion mode using an m/z range MeOH (3 mL) was added. For 13 and 14 liquid phenyl- or
50–1200. The nebulizer gas flow was 1.0 bar and the drying gas flow benzylhydrazine, respectively, was added without additional
4.0 L minÀ1. For HRESI+, the studied compounds were dissolved in dissolution in MeOH. The reaction mixture was left for an
MeOH. Infrared spectra (4000–400 cmÀ1) were recorded on a additional 4 min at RT and then the solvent was evaporated
Shimadzu IR Prestige-21 instrument in KBr pellets. 1H, 13C{1H} in vacuo at 40 1C. Final substrates 1–26 were isolated via column
NMR spectra were measured on a Bruker Avance 400 spectrometer chromatography (for each product, the eluent is specified in
in CDCl3, (CD3)2SO, and CD3OD at ambient temperature; the characterization).
residual solvent signal was used as the internal standard.
Analytical and spectroscopy data for 1–26
X-ray structure determinations
Compounds 1–26 were characterized by HRESI+-MS, IR, and
1H- and 13C{1H} NMR spectroscopies. In addition, 13 and 14
Single-crystal X-ray diffraction experiments were carried out using
Agilent Technologies ‘‘SuperNova’’ and ‘‘Xcalibur’’ diffractometers
with monochromated CuKa (14) and MoKa (13) radiation, respec-
tively. The crystals were kept at 130(2) and 100(2) K during all data
collection. The structures were solved by the Superflip38 (13) and
ShelXT39 (14) structure solution programs using Charge Flipping
and Intrinsic Phasing methods, respectively, and refined by means
of the ShelXL40 program, incorporated in the OLEX241 program
package. CCDC numbers 1901802 and 1901803 contain the sup-
plementary crystallographic data for this paper.
were studied by single-crystal X-ray diffraction.
The HRESI+ mass-spectra of 1–26 exhibit peaks corresponding
to the quasi-ions [M + H]+, [M + Na]+, [2M + H]+, and [2M + Na]+.
The IR spectra of 1–26 display one to three weak-to-medium bands
in the range of 3438–3058 cmÀ1, which were attributed to the N–H
stretches. Weak-to-strong bands at 3098–2726 cmÀ1 were assigned
to the n(C–H). The IR spectra of 1–26 display one or two medium-to-
very-strong bands in the range of 1676–1530 cmÀ1, which were
attributed to the CQN stretches.
1
The H NMR spectra of 1–12 expectedly display two sets of
Details of DFT calculations
signals from 1H- and 2H-1,2,4-triazole tautomers, which are
commonly observed for 5-amino-1,2,4-triazole derivatives.12a,48
Thus, 1–7 and 9–12 display a broad signal of N–NH in the
region of d 13.61–11.76 (no signal of the NH was observed for 8,
which could be explained in terms of fast exchange with water).
The full geometry optimization of all model structures has been
carried out at the DFT level of theory using the M06-2X
functional with 54% Hartree–Fock exchange42 with the help of
the Gaussian-0943 program package. The standard 6-311+G(d,p)
basis sets were used for all atoms. No symmetry restrictions have
been applied during the geometry optimization procedure. The
solvent effects were taken into account using the SMD conti-
nuum solvation model by Truhlar and coworkers44 with chloro-
form as a solvent. The Hessian matrices were calculated
analytically for all optimized model structures to prove the
location of correct minima or saddle points (transition state)
on the potential energy surface (no imaginary frequencies or
only one imaginary frequency, respectively) and to estimate the
thermodynamic parameters, the latter being calculated at 25 1C
(Tables 1S–2S, ESI†). The nature of the transition states was
studied by the analysis of vectors associated with the imaginary
frequency and by the calculation of intrinsic reaction coordi-
nates (IRC) using the Gonzalez–Schlegel method.45 The topolo-
gical analysis of the electron density distribution with the help of
the atoms in molecules (QTAIM) method developed by Bader26
has been performed by using the Multiwfn program.46 The
Wiberg bond indices were computed by using the Natural Bond
Orbital (NBO) partitioning scheme.47 The Cartesian atomic
coordinates for all optimized equilibrium model structures are
presented in Table 3S (ESI†).
1
The H NMR spectra of 2, 5, 6, and 9–11 recorded in (CD3)2SO
reveal two signal sets of N–NH in the triazole ring and NH in the
1
amino-group. The H NMR spectra of 23, 25 and 26 measured
in CDCl3 display one set of signals (d 1.45–1.35) of the methyl
moiety, whereas the spectrum of 19 and 24 displays two signals
of the CH3 moiety at d 3.04, 3.07 and 3.76, 3.73 respectively,
which indicates the availability of two isomeric forms of these
compounds around the N–O bond in the 1,2,4-oxadiazolium
ring (similarly there is two sets of signals in other areas). In the
1H NMR spectrum of 3, 4, 6, and 12, the CHNH signals overlap
with the residual signals of water. The 13C{1H} NMR spectra of
13–18, 20–23, 25, and 26 recorded in CDCl3 exhibit one set of
signals of the C atoms of the 1,2,4-oxadiazolium ring in the
region of d 171.22–152.95, whereas the spectra of 19 and 24
1
display two sets of signals. This is coherent with the H NMR
data indicating the availability of the two isomeric forms.
Conflicts of interest
There are no conflicts to declare.
Syntheses of 1–26
Acknowledgements
A solution of Br2 (1.2 mmol) in CHCl3 (1 mL) was dropwise
added (1 min) to a stirred solution of isocyanide (1.2 mmol) in This work is a combination of two projects of the Russian
CHCl3 (1 mL) placed in a 10 mL round-bottomed flask. The Foundation for Basic Research: the synthetic part and the study
mixture was kept under stirring for 2 min at RT in air and then of antibacterial activity were supported by grant 18-33-20012,
an aminonitrone (1.0 mmol) and Et3N (1.0 mmol) were added whereas quantum chemical calculations by grant 19-03-00044.
to the reaction mixture. After 3 min a solution of hydrazine Physicochemical studies were performed at the Center for
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NJC
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