Synthesis, structure, and antiviral properties of novel 2-adamantyl-5-aryl-2H-tetrazoles

Article abstract of DOI:10.1007/s10593-021-02931-5

[Figure not available: see fulltext.] The reaction of 5-aryl-NH-tetrazoles with adamantan-1-ol in concentrated sulfuric acid proceeds regioselectively with the formation of the corresponding 2-adamantyl-5-aryl-2H-tetrazoles. Nitration of these compounds l

Full text of DOI:10.1007/s10593-021-02931-5

DOI 10.1007/s10593-021-02931-5
Chemistry of Heterocyclic Compounds 2021, 57(4), 442–447
Synthesis, structure, and antiviral properties
of novel 2-adamantyl-5-aryl-2H-tetrazoles
Olga V. Mikolaichuk1, Vladimir V. Zarubaev2, Anna А. Muryleva2,
Yana L. Esaulkova2, Daria V. Spasibenko3, Alina А. Batyrenko3,
Ilya V. Kornyakov1,4, Rostislav Е. Trifonov3*
1 Saint Petersburg State University,
7/9 University Embankment, Saint Petersburg 199034, Russia; e-mail: st801293@spbu.ru
2 Saint Petersburg Pasteur Research Institute of Epidemiology and Microbiology,
14 Mira St., Saint Petersburg 197101, Russia; e-mail: zarubaev@gmail.com
3 Saint Petersburg State Institute of Technology (Technical University),
26 Moskovsky Ave., Saint Petersburg 190013, Russia; e-mail: rost_trifonov@mail.ru
4 Kola Science Center, Russian Academy of Sciences,
14 Fersmana St., Apatity 184209, Murmansk Oblast, Russia; e-mail: i.kornyakov@spbu.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2021, 57(4), 442–447
Submitted December 7, 2020
Accepted February 25, 2021
The reaction of 5-aryl-NH-tetrazoles with adamantan-1-ol in concentrated sulfuric acid proceeds regioselectively with the formation of
the corresponding 2-adamantyl-5-aryl-2H-tetrazoles. Nitration of these compounds leads to 2-(adamantan-1-yl)-5-(3-nitroaryl)-2H-
1
tetrazoles. The structures and composition of the obtained novel 2-adamantyl-5-aryltetrazoles were proven by IR spectroscopy, H and
13C NMR spectroscopy, high-resolution mass spectrometry, and also by X-ray structural analysis. According to the simultaneous thermal
analysis data, the obtained compounds are thermally stable up to a temperature of about 150°C. In vitro studies have shown that some of
the 2-adamantyl-5-aryltetrazoles exhibit moderate inhibitory activity against influenza A (H1N1) virus. The antiviral selectivity index
(SI) of 2-[2-(adamantan-1-yl)-2H-tetrazol-5-yl]-6-bromo-4-nitroaniline is significantly higher (SI 11) than that of the reference drug
rimantadine (SI 5).
Keywords: 2-(adamantan-1-yl)-5-aryl-2H-tetrazoles, adamantylation, anti-influenza activity, nitration, X-ray structural analysis.
It is known that a number of adamantane derivatives and
other cage hydrocarbons exhibit high antiviral activity.1
Some of these compounds are known drugs against
influenza virus (amantadine, rimantadine).4 (Adamantan-2-yl)-
1-(2-oxoindolin-3-ylidene)thiosemicarbazide A (Fig. 1) reduces
the reproducibility of vaccinia virus, and also exhibits
activity in vitro against some Gram-positive and Gram-
negative bacteria and fungi.2,3 Substituted aminoacetyl-
adamantylamines B exhibit inhibitory activity against vaccinia
virus (Fig. 1).3 1-Adamantanecarboxylic acid amide containing
the (–)-10-amino-2-pinene fragment (structure C)4 and N-(1-
adamantyl)-2,2-diphenylacetamide D proved to be effective
inhibitors of smallpox virus.5 In addition, compounds
containing the adamantyl fragment such as memantine E
(Fig. 1) are also capable of inhibiting the N-methyl-D-aspartate
receptor, which allows them to be considered as potential
agents for the treatment of moderate and severe Alzheimer's
disease.6 Adamantane derivatives have shown in vitro
activity against various coronaviruses.7,8 For instance, amanta-
dine analogs are moderately active against human corona-
virus 229E.7 Moderate antiviral activity has also been found
for amantadine, rimantadine, memantine in bovine models.8
0009-3122/21/57(4)-0442©2021 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2021, 57(4), 442–447
Scheme 1
NH
H
H
NH
N
N
N
O
HN
O
S
A
B
NH2
H
O
N
Me
Me
H
N
Me
O
Me
C
D
E
Figure 1. Adamantane-based biologically active compounds.
One of the promising design options for new highly
effective anti-influenza drugs is the replacement of the
amino group with polynitrogen heterocyclic fragments.9–11
This fragment can be the tetrazole ring, a well-known
pharmacophore9–11 due to its high stability in metabolic
processes and low toxicity. Tetrazole derivatives containing
the adamantyl moiety showed significant activity against
influenza A virus, including rimantadine-resistant influenza
virus strain A/Puerto Rico/8/34 (Fig. 2).12,13
In this work, we obtained a series of NH-unsubstituted
5-aryltetrazoles 2a–h by azidation of aromatic nitriles 1a–h
via the 1,3-dipolar cycloaddition reaction (Scheme 1).
Azidation was carried out in DMF according to a known
method at 115°С.11–14 The reaction of 5-aryl-NH-tetrazoles
2a–h with adamantan-1-ol in concentrated H2SO4 gave a
series of novel 2-adamantyl-5-aryl-2Н-tetrazoles 3a–h. The
adamantylation of NH-tetrazoles 2a–h in H2SO4 proceeds
exclusively at the N-2 nitrogen atom of the tetrazole ring
with the formation of 2-(adamantan-1-yl)-5-aryl-2Н-
tetrazoles 3a–h in high (81–92%) yields. Compounds 3c,d
were nitrated with a sulfuric-nitric acid mixture at 8–10°С
according to the previously described method15 to give
2-(adamantan-1-yl)-5-(nitroaryl)-2Н-tetrazoles 3j,k. Com-
pound 3i was obtained by reduction of nitro compound 3g
with metallic zinc.
spectra of 2-(adamantan-1-yl)-5-aryl-2Н-tetrazoles 3a–k,
the adamantyl moiety appears as broadened singlets at 1.76–
1.87 (compounds 3a–g,i–k), 2.16 (compound 3h), and 2.22–
2.36 ppm and in the form of broadened singlets or
multiplets in the 2.29–2.43 ppm range. In the 13C NMR
spectra of compounds 3a–k, the signals of the endocyclic
carbon atom of the tetrazole fragment were observed at
161.1–164.9 ppm which reliably confirms the preparation
of 2H-regioisomers.14
The IR spectra of compounds 3a,b,e,h contain the
characteristic absorption bands of the cage hydrocarbon
group in the range of 3346–2850 cm–1 which is consistent
with previously published data.16
The data of X-ray structural analysis of compounds
3b,e–g also unambiguously confirm the structure of the
obtained compounds (Fig. 3). According to these data, the
2H-tetrazole ring is a planar highly aromatic system. The
dihedral angle between the planes of the benzene and
tetrazole rings in compounds 3b,e–g is small, which may
indicate π–π conjugation between unsaturated fragments. In
all of the studied compounds, the tetrazole ring appears to
be partially sterically blocked by a cage hydrocarbon
fragment.
It is known that some 2H-tetrazoles, especially those
containing electron-withdrawing substituents, can relatively
easily undergo thermal decomposition with the dissociation
of the N–N bonds and release of molecular nitrogen.11,14
The thermal stability of compound 3g was studied by the
method of simultaneous thermal analysis (Fig. S54,
Supplementary information file). This compound contains
an electron-withdrawing nitro group in the aryl moiety and
is a good model for assessing the stability of compounds of
this series. According to the loss of weight, in the case of
compound 3g molecular nitrogen is released at 156.2°С.
This process is accompanied by a strong exothermic effect.
The complete decomposition of adamantyltetrazole 3g
occurs starting with 250°С with a loss of 33.6% of its mass.
In this work, we studied the antiviral activity of
adamantyltetrazole derivatives 3а,b,d,e,h,i against influenza
The structure, composition, and thermal stability of the
1
obtained compounds were studied by IR spectroscopy, H,
13C NMR spectroscopy, high-resolution mass spectrometry,
X-ray structural analysis, and simultaneous thermal
analysis. The 1H and 13C NMR spectra confirm the
1
structures of all the obtained compounds. In the Н NMR
Figure 2. Adamantyltetrazoles showing high inhibitory activity
against influenza virus.
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Chemistry of Heterocyclic Compounds 2021, 57(4), 442–447
Table 1. Cytotoxic (CC50), antiviral (IC50) activity, selectivity
index (SI) of adamantyltetrazole derivatives 3а,b,d,e,h,i
against the H1N1 influenza A virus strain
Compound
CС50, μg/ml
46 ± 3
>300
IC50, μg/ml
31 ± 4
>300
SI
1
3a
1
3b
4 ± 0.5
<3
2 ± 0.3
<3
2
3d
–
3e
>167
15 ± 3
15 ± 2
12 ± 2
11
2
3h
3i
36 ± 2
60 ± 4
Rimantadine
5
moderate activity against the virus (IC50 15 μg/ml), which
is expressed by the relatively high value of the selectivity
index of SI 11 exceeding the SI value of the reference drug
rimantadine.
The influenza virus used in the study shows resistance to
rimantadine due to the S31N mutation in the viral protein
M2. The activity of compound 3h demonstrated against
this virus may indicate both that it is a specific inhibitor of
such a mutant ion channel and that the target of its action is
another viral protein and the mechanism of action of
compounds of this class is not related to blocking the M2
proton channel.
To conclude, employing the regioselective alkylation of
5-aryl-NH-tetrazoles with adamantan-1-ol in sulfuric acid,
a series of new 2-adamantyl-5-aryl-2H-tetrazoles were
synthesized. The structure of the obtained compounds was
proved by spectral methods and by the X-ray structural
analysis technique. Some of the 2-adamantyl-5-aryl-
tetrazoles exhibit moderate inhibitory activity against
influenza A (H1N1) virus and good selectivity. 2-Adamantyl-
5-aryl-2H-tetrazoles are promising compounds which can
display high anti-influenza activity.
Experimental
IR spectra were registered on an IRPrestige-21
1
Fourier transform spectrometer in KBr pellets. H and 13C
NMR spectra were acquired on a Bruker Avance III 400
spectrometer (400 and 100 MHz, respectively) at 25°C.
High-resolution mass spectrometry was performed on a
Bruker MicroTOF spectrometer (electrospray ionization).
Melting points were determined on a PTP apparatus using
1°С/min heating rate in the melting range. Simultaneous
thermal analysis was performed on a Netzsch STA 449F1
apparatus under a flow of argon (100 ml/min–1) with a
heating rate of 10°С/min in aluminum crucibles. TLC was
performed on Merck KGaA 60 F254 plates, eluent CHCl3–
MeOH, 19:1.
Synthesis of 5-aryl-NH-tetrazoles 2a–h (General
method). The corresponding nitrile 1a–h (10 mmol) was
added to a solution of NaN3 (11.4 mmol) and Me2NH·HCl
(11.2 mmol) in DMF (40 ml). The resulting suspension was
heated at 105–115°C for 10 h. Then, the reaction mixture
was cooled, the precipitate was filtered off and additionally
Figure 3. Molecular structure of compounds 3b,e,f,g with atoms
represented as thermal vibration ellipsoids of 50% probability.
A/Puerto Rico/8/34 (H1N1) virus (Table 1). Analysis of the
obtained data shows that compounds 3а,d,e containing a
halogen atom as a substituent mainly showed moderate
inhibitory activity against the virus (IC50 31–2 μg/ml) and
rather high toxicity against cells (CC50 46–4 μg/ml), which
is expressed by the low values of the selectivity index (SI).
At the same time, tetrazole derivative 3h containing an
amino group and a bromine atom turned out to be the least
toxic to cells (CC50 167 μg/ml) in combination with
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Chemistry of Heterocyclic Compounds 2021, 57(4), 442–447
washed with DMF (2×5 ml). Then cold Н2О (50 ml) was
(3H, br. s, H Ad); 2.33 (6H, d, J = 2.8, H Ad); 2.55 (3H, s,
CH3); 7.33–7.43 (3H, m, Н Ar); 7.90 (1H, d, J = 7.6, Н Ar).
13C NMR spectrum (DMSO-d6), δ, ppm: 21.5 (СH3); 29.3,
35.6, 42.1, 64.0 (С Ad); 126.6, 126.9, 129.4, 130.4, 131.9,
137.1 (С Ar); 164.2 (C tetrazole). Found, m/z: 295.1923
[M+Н]+. C18H23N4. Calculated, m/z: 295.1917.
added to the filtrate and acidified with a solution of 10%
HCl to pH 2–3. The resulting suspension was filtered, and
the precipitate was washed with cold H2O. The product was
air-dried. The physical and spectral characteristics of the
obtained and previously described compounds 2a–d,h
correspond to the literature.13,15,17
2-(Adamantan-1-yl)-5-(3-nitrophenyl)-2H-tetrazole
(3c). Yield 2.52 g (86%), light-yellow crystals, mp 192–
193°C (mp 192–193°C15). 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 1.87 (6H, br. s, H Ad); 2.35 (3H, br. s,
H Ad); 2.43 (6H, br. s, H Ad); 7.70 (1H, t, J = 8.0, Н Ar);
8.31–8.35 (1Н, m, Н Ar); 8.37 (1Н, s, Н Ar); 8.52–8.55
(1H, m, Н Ar). 13C NMR spectrum (CDCl3), δ, ppm: 29.4;
35.8; 42.3; 64.5 (С Ad); 121.8, 124.1, 124.5, 127.6, 129.9,
132.4 (С Ar); 162.4 (C tetrazole). Found, m/z: 348.0814
[M+Na]+. C17H19N5NaO2. Calculated, m/z: 348.1431.
2-(Adamantan-1-yl)-5-(4-chlorophenyl)-2H-tetrazole
(3d). Yield 2.38 g (84%), white crystals, mp 134–136°C
2-Chloro-4-(1H-tetrazol-5-yl)aniline (2e). Yield 1.76 g
1
(90%), white crystals, mp 169–170°C. H NMR spectrum
(DMSO-d6), δ, ppm (J , Hz): 6.05 (2H, s, NH2); 6.94 (1H,
d, J = 8.5, H Ar); 7.71 (1H, dd, J = 8.5, J = 2.0, Н Ar); 7.88
(1H, d, J = 2.0, Н Ar). 13C NMR spectrum (DMSO-d6),
δ, ppm: 112.2, 115.8, 117.4, 127.3, 128.3, 147.9 (С Ar);
156.1 (C tetrazole). Found, m/z: 196.0379 [M+Н]+.
C7H7ClN5. Calculated, m/z: 196.0385.
5-[2-Chloro-4-(trifluoromethyl)phenyl]-1H-tetrazole (2f).
Yield 2.29 g (92%), beige crystals, mp 179–181°C.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.72 (1H,
dd, J = 8.2, J = 1.8, H Ar); 7.86 (1H, s, H Ar); 8.07 (1H, d,
J = 8.2, H Ar). 13C NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 122.6 (d, J = 270.4, CF3); 124.0, 125.4, 127.4,
132.1 (2C), 136.4 (C Ar); 158.8 (C tetrazole). Found, m/z:
270.9969 [M+Na]+. C8H4ClF3N4Na. Calculated, m/z:
270.9969.
2-Nitro-4-(1H-tetrazol-5-yl)phenol (2g). Yield 1.88 g
(91%), yellow crystals, mp 179–181°C. 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 7.34 (1H, d, J = 8.7, H Ar);
8.18 (1H, dd, J = 8.7, J = 2.3, H Ar); 8.55 (1H, d, J = 2.2,
H Ar); 11.84 (1H, br. s, OH). 13C NMR spectrum (DMSO-d6),
δ, ppm: 120.8, 124.6, 133.7, 137.6, 138.3, 154.6 (C Ar);
155.8 (C tetrazole). Found, m/z: 206.0318 [M–Н]–.
C7H4N5O3. Calculated, m/z: 206.0309.
Synthesis of 2-(adamantan-1-yl)-5-aryl-2H-tetrazoles
3a–h (General method). Adamantan-1-ol (1.37 g, 9 mmol)
was added to a solution of 5-arylterazole 2a–h (9 mmol) in
94% H2SO4 (25 ml). The reaction mixture was kept at
room temperature for 60 min and poured into H2O/ice
(60 ml). The product was extracted with CHCl3, the
organic phase was washed with 5% aqueous NaHCO3
(2×25 ml) followed by H2O. It was then dried over
anhydrous MgSO4 and evaporated under reduced pressure.
The physical and spectral characteristics of the obtained
and previously described compounds 3b–d correspond to
the literature.13,15
1
(mp 131–133°C13). H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 1.85 (6H, t, J = 3.2, H Ad); 2.33 (3H, br. s, H Ad);
2.41 (6H, d, J = 2.8, H Ad); 7.47 (2H, d, J = 8.8, Н Ar);
8.12 (2H, d, J = 8.8, Н Ar). 13C NMR spectrum (CDCl3),
δ, ppm: 29.4, 35.9, 42.3, 64.1 (С Ad); 126.5, 128.1 (2C),
129.0, 129.1, 135.9 (С Ar); 163.3 (C tetrazole). Found, m/z:
315.1375 [M+Н]+. C17H20ClN4. Calculated, m/z: 315.1371.
4-[2-(Adamantan-1-yl)-2H-tetrazol-5-yl]-2-chloro-
aniline (3e). Yield 2.47 g (83%), light-yellow crystals,
mp 190–192°C. IR spectrum, ν, cm–1: 3202, 2941, 2916,
1
1635, 1606, 1466, 1420. H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 1.77 (6H, br. s, H Ad); 2.24 (3H, br. s,
H Ad); 2.29 (6H, br. s, H Ad); 5.87 (2H, br. s, NH2), 6.91
(1H, d, J = 8.4, Н Ar); 7.70 (1H, d, J = 8.4, Н Ar); 7.82 (1H,
d, J = 1.6, Н Ar). 13C NMR spectrum (DMSO-d6), δ, ppm:
29.3, 35.7, 42.1, 63.8 (С Ad); 115.9, 117.4, 126.5, 127.4,
131.0, 147.1 (С Ar); 163.5 (C tetrazole). Found, m/z:
330.1496 [M+Н]+. C17H21ClN5. Calculated, m/z: 330.1480.
2-(Adamantan-1-yl)-5-[2-chloro-4-(trifluoromethyl)-
phenyl]-2H-tetrazole (3f). Yield 2.79 g (81%), white
1
crystals, mp 126–128°C. H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 1.76 (6H, br. s, H Ad); 2.24 (3H, br. s,
H Ad); 2.33 (6H, d, J = 2.8, H Ad); 7.89–7.92 (1H, m,
Н Ar); 8.08 (1H, s, Н Ar); 8.15 (1H, d, J = 8.0, H Ar).
13C NMR spectrum (DMSO-d6), δ, ppm: 29.3, 35.5, 42.1,
64.8 (С Ad); 125.0 (в, J = 270.4, CF3); 125.8, 128.1, 130.6,
132.8 (2С), 133.2 (С Ar); 161.1 (C tetrazole). Found, m/z:
383.1252 [M+Н]+. C18H19ClF3N4. Calculated, m/z:
383.1245.
4-[(2-Adamantan-1-yl)-2H-tetrazol-5-yl]-2-nitrophenol
(3g). Yield 2.64 g (86%), light-orange crystals, mp 256–
258°C. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 1.79
(6H, br. s, H Ad); 2.26 (3H, br. s, H Ad); 2.33 (6H, d,
J = 2.4, H Ad); 7.33 (1H, d, J = 8.4, Н Ar); 8.19 (1H, dd,
J = 8.8, J = 2.0, Н Ar); 8.48 (1H, d, J = 2.0, Н Ar); 11.63
(1H, s, OH). 13C NMR spectrum (DMSO-d6), δ, ppm: 29.3,
35.6, 42.1, 64.4 (С Ad); 105.0, 120.3, 123.6, 133.1, 139.6,
154.0 (С Ar); 164.9 (C tetrazole). Found, m/z: 340.1400
[M–Н]–. C17H18N5O3. Calculated, m/z: 340.1415.
2-(Adamantan-1-yl)-5-(4-iodophenyl)-2H-tetrazole (3a).
Yield 3.22 g (88%), light-orange crystals, mp 118–120°C.
IR spectrum, ν, cm–1: 3295, 2917, 2850, 1697, 1449, 1353,
1302, 1116, 1088, 927. 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 1.85 (6H, br. s, H Ad); 2.33 (3H, br. s, H Ad); 2.41
(6H, br. s, H Ad); 7.47 (2H, d, J = 8.4, H Ar); 8.12 (2H, d,
J = 8.8, H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 29.7,
36.1, 42.3, 64.9 (C Ad); 127.5, 128.4, 137.6, 138.0 (C Ar);
163.5 (C tetrazole). Found, m/z: 429.0545 [M+Na]+.
C17H19IN4Na. Calculated, m/z: 429.0547.
2-(Adamantan-1-yl)-5-(о-tolyl)-2H-tetrazole (3b). Yield
2.44 g (92%), light-beige crystals, mp 85–87°C (mp 84–
86°C13). IR spectrum, ν, cm–1: 3292, 2924, 2911, 2856,
1
1476, 1453, 1356, 1316, 1021, 746. H NMR spectrum
2-[2-(Adamantan-1-yl)-2H-tetrazol-5-yl]-6-bromo-
4-nitroaniline (3h). Yield 3.13 g (83%), light-yellow
(DMSO-d6), δ, ppm (J, Hz): 1.77 (6H, br. s, H Ad); 2.24
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Chemistry of Heterocyclic Compounds 2021, 57(4), 442–447
crystals, mp 172–174°C. IR spectrum, ν, cm–1: 3346, 2908,
1611, 1594, 1495, 1323, 1303, 1273, 1142, 1020. H NMR
assessed using the methyl tetrazolium (MTT) assay. A
1
series of threefold dilutions (300–3.7 μg/ml) were prepared
from the studied compounds, after which they were
introduced into the wells of plates with a monolayer of
MDCK cells. The plates were incubated at 36°C for 72 h.
Thereafter, MTT solution was added to the wells which by
the action of mitochondrial enzymes transformed into an
insoluble violet formazan derivative.18 Plates with cells
were kept for 2 h. The sediment in each well was dissolved
in DMSO (0.1 ml). The optical density in the wells was
measured using a Thermo Multiskan FC plate photometer
(Thermo Fisher Scientific, USA) with a wavelength of
540 nm. Based on the obtained data, the CC50 value was
calculated as the concentration of the compound resulting
in a decrease in optical density by half compared to the
wells without addition of compounds.
The study of the antiviral activity of compounds
3а,b,d,e,h,i was carried by determining the reduction of the
degree of cytopathic effect. The experiments used the
influenza A/Puerto Rico/8/34 (H1N1) virus. The studied
compounds in various concentrations were added to
the cells in the wells of the plate, incubated for 1 h, then
the cells were infected with the virus at a dose of
0.01 TCID50 per cell. The cells were incubated for 72 h,
after which the cell viability was determined by the MTT
assay as described above. Based on the obtained data for
each compound, 50% inhibitory concentration (IC50) was
calculated as the concentration of the compound that
reduces the degree of viral cell destruction by 50%, and the
selectivity index (SI) as the ratio of CC50 to IC50.
spectrum (CDCl3), δ, ppm (J, Hz): 2.16 (6H, br. s, H Ad);
2.36 (3H, br. s, H Ad); 2.43 (6H, br. s, H Ad); 8.47 (1H, d,
J = 2.4, Н Ar); 9.07 (1H, d, J = 2.8, H Ar). 13C NMR spect-
rum (CDCl3), δ, ppm: 29.4, 36.1, 42.3, 64.9 (С Ad); 109.0,
109.9, 124.3, 124.5, 129.4, 148.2 (С Ar); 162.1 (C tetrazole).
Found, m/z: 417.0677 [M–Н]–. C17H18BrN6O2. Calculated,
m/z: 417.0680.
4-[2-(Adamantan-1-yl)-2H-tetrazol-5-yl]-2-aminophenol
(3i). HCl and metallic Zn powder in small portions were
successively added to a suspension of 4-[(2-adamantan-
1-yl)-2H-tetrazol-5-yl]-2-nitrophenol (3g) (2 mmol) in a
mixture of i-PrOH (30 ml) and H2O (50 ml). The reaction
mixture was heated to 50°C and maintained until the
disappearance of the starting compound (TLC control,
eluent CHCl3–MeOH, 19:1). The reaction mixture was then
evaporated under reduced pressure. The residue was
neutralized with an aqueous NaOAc to pH 4–5. The formed
precipitate was filtered off, air-dried, and recrystallized
from MeOH. Yield 2.30 g (82%), light-brown crystals,
1
mp 157–159°C. H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 1.78 (6H, br. s, H Ad); 2.25 (3H, br. s, H Ad); 2.30–
2.34 (6H, m, H Ad); 4.77 (2H, br. s, NH2); 6.76 (1H, d,
J = 8.4, Н Ar); 7.15 (1H, dd, J = 6.0, J = 2.0, Н Ar); 7.34
(1H, d, J = 2.0, H Ar). 13C NMR spectrum (DMSO-d6),
δ, ppm: 29.3, 35.6, 42.1, 64.4 (С Ad); 107.5, 123.7, 128.1,
133.1, 137.5, 150.8 (С Ar); 162.5 (C tetrazole). Found,
m/z: 312.1814 [M+Н]+. C17H22N5O. Calculated, m/z:
312.1819.
Nitration of 5-aryltetrazole adamantyl derivatives
(General method). A mixture of concentrated HNO3 (7 ml)
and concentrated H2SO4 (5 ml) was added to a cooled (5°C)
solution of adamantyl derivative of tetrazole 3с,d (6 mmol)
in 75% H2SO4 (7 ml). The reaction mixture was stirred at
8–10°С for 3 h, then the pH of the reaction mixture was
adjusted to 7 by adding an aqueous NaOH. The precipitated
product was filtered off and dried.
X-ray structural analysis of compounds 3b,e–g.
Crystals suitable for X-ray structural analysis were
obtained by slow evaporation of solutions of compounds
3b,e–g in CHCl3–MeOH, 1: 2 mixture at low temperature.
X-ray structural analysis of compounds 3b,e–g was
done on a Rigaku Oxford Diffraction XtaLAB SuperNova
diffractometer with
a
HyPix3000 CCD detector
(compounds 3b,e,f) and on an Agilent Technologies
Xcalibur diffractometer with an Atlas CCD detector
(compound 3g) at 100K using monochromatic focused
CuKα radiation. The obtained data were integrated in the
CrysAlis software package.19 Absorption was corrected
semiempirically. The signs of disordering of the
adamantane group are removed from Figure 3 (compound
3e) for the sake of clarity. The unit cell parameters were
specified by the least-squares method. The structures were
solved and refined using the SHELX software package20
included in the OLEX221 interface. Crystallographic data
of compounds 3b,e–g were deposited at the Cambridge
Crystallographic Data Center (deposits CCDC 1984233
(compound 3b), CCDC 1984234 (compound 3e), CCDC
1984236 (compound 3f), CCDC 1984237 (compound 3g)).
2-(Adamantan-1-yl)-5-(3,5-dinitrophenyl)-2H-tetrazole
(3j). Yield 1.84 g (85%), white crystals, mp 276–277°C
1
(mp 276–277°C15). H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 1.75–1.85 (6H, m, H Ad); 2.29 (3H, br. s, H Ad);
2.39 (6H, br. s, H Ad); 8.96 (1H, t, J = 2.1, Н Ar); 9.07
(2H, d, J = 2.1, Н Ar). 13C NMR spectrum (CDCl3),
δ, ppm: 29.3, 35.5, 45.7, 65.2 (С Ad); 120.3, 126.5, 130.3,
149.3 (С Ar); 161.1 (C tetrazole). Found, m/z: 393.1250
[M+Na]+. C17H17N6NaO4. Calculated, m/z: 393.1282.
2-(Adamantan-1-yl)-5-(4-chloro-3-nitrophenyl)-2H-
tetrazole (3k). Yield 1.95 g (88%), white crystals, mp 149–
1
151°C. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
1.52–1.80 (6H, m, H Ad); 2.18–2.45 (3H, m, H Ad); 2.33
(6H, br. s, H Ad); 7.97 (1H, d, J = 8.4, Н Ar); 8.33 (1H, dd,
J = 8.4, J = 2.0, Н Ar); 8.63 (1H, d, J = 2.0, Н Ar).
13C NMR spectrum (DMSO-d6), δ, ppm: 29.3, 35.6, 42.1,
64.9 (С Ad); 105.0, 114.8, 123.6, 131.7, 133.4, 148.5
(С Ar); 162.9 (C tetrazole). Found, m/z: 360.1225 [M+Н]+.
C17H19ClN5O2. Calculated, m/z: 360.1222.
Supplementary information file containing the IR,
1H and 13С NMR, and mass spectra of all the synthesized
compounds, simultaneous thermal analysis data for
compound 3g, as well as X-ray structural analysis data for
compounds 3b,e–g is available at the journal website at
http://link.springer.com/journal/10593.
The study of the biological activity of compounds
3а,b,d,e,h,i. The cytotoxic properties of compounds were
446

Chemistry of Heterocyclic Compounds 2021, 57(4), 442–447
11. Ostrovskii, V. A.; Popova, E. A.; Trifonov, R. E. Adv.
This work was financially supported by the Russian
Foundation for Basic Research (project 20-53-00039-
Bel_a).
The work was carried out using the equipment of the
resource centers of Saint Petersburg State University
''Magnetic Resonance Research Center'', ''Chemical
Analysis and Materials Research Center'', ''Chemistry
Educational Center''.
Heterocycl. Chem. 2017, 123, 1.
12. Zarubaev, V. V.; Golod, E. L.; Anfimov, P. M.; Shtro, A. A.;
Saraev, V. V.; Gavrilov, A. S.; Logvinov, A. V.; Kiselev, O. I.
Bioorg. Med. Chem. 2010, 18, 839.
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Khim. 2018, 54, 630.]
14. Ostrovskii, V. A.; Koldobskii, G. I.; Trifonov, R. E. In
Сomprehensive Heterocyclic Chemistry III; Zhdankin, V. V.,
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