Synthesis and transformations of 4-phenylethynyl- and 4-styrylpyrazolo[5,1-c][1,2,4]triazines

Article abstract of DOI:10.1007/s10593-021-02964-w

[Figure not available: see fulltext.] Rearrangements of 3-tert-butyl-8-methyl-4-phenylethynyl-1,4-dihydropyrazolo[5,1-c][1,2,4]triazine derivatives by the action of bases led to the formation of aromatic (E)- or (Z)-4-styryl-functionalized compounds. At t

Full text of DOI:10.1007/s10593-021-02964-w

DOI 10.1007/s10593-021-02964-w
Chemistry of Heterocyclic Compounds 2021, 57(6), 656–665
Synthesis and transformations of 4-phenylethynyl-
and 4-styrylpyrazolo[5,1-c][1,2,4]triazines
Sergey M. Ivanov1*, Denis S. Koltun1
1 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky Ave., Moscow 119991, Russia; e-mail: sergey13iv1@mail.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2021, 57(6), 656–665
Submitted November 26, 2020
Accepted December 23, 2020
Rearrangements of 3-tert-butyl-8-methyl-4-phenylethynyl-1,4-dihydropyrazolo[5,1-c][1,2,4]triazine derivatives by the action of bases
led to the formation of aromatic (E)- or (Z)-4-styryl-functionalized compounds. At the same time, 4-styryl-1,4-dihydropyrazolotriazines
did not rearrange to form the expected 4-phenylethylpyrazolo[5,1-c][1,2,4]triazine. The latter was obtained via an alternative route by the
addition reaction of phenylethynylmagnesium bromide to 3-tert-butyl-8-methylpyrazolo[5,1-c][1,2,4]triazine, as well as by reduction of
double bonds in the ring and side chain of the 4-styryl derivative with subsequent selective oxidation by N-bromosuccinimide. The
spectral and X-ray structural data as well as the antimicrobial properties of the synthesized compounds are discussed.
Keywords: 1,2,4-triazine, bromination, hydride shift, oxidation, rearrangement, reduction.
Today, the task of finding ways to synthesize
functionalized heterocycles that can be used to create new
medications remains urgent. 1,2,4-Triazines are known to
exhibit a wide spectrum of biological activity.1–5 In
particular, various derivatives of azolo[1,2,4]triazines are
used as effective antifungal,6 antiviral, and antitumor
drugs.7,8 Methods for the synthesis of such systems have
been systematized in a recent review.9
Earlier, we obtained a number of azolo[1,2,4]triazines
with certain characteristics important for practical
applications. In particular, 4-substituted fluoro(pyrazolo-
[5,1-c][1,2,4]triazin-1(4H)-yl)ethanones exhibit moderate
antimicrobial activity and have been proposed as a novel
type of acidity photogenerators.10 3-tert-Butyl-8-chalco-
genylpyrazolo[5,1-c][1,2,4]triazines were synthesized by a
metal–halogen exchange reaction followed by the action of
elemental sulfur, selenium, or tellurium, and the obtained
compounds were characterized.11,12 Rearrangement of
pyrazolotriazines into functionalized pyrrolotriazines was
observed in reactions with alkyllithium reagents.13 It is
expected that further investigation of their chemical
properties may lead to new potentially biologically active
derivatives.
Earlier, the preparation of monocyclic 5,6-arylacetylenyl-
1,2,4-triazines in moderate yields via the reactions of
aromatic 1,2,4-triazines with lithium phenylacetylenides
was described.14,15 The corresponding 3,5,6-arylethynyl
derivatives were obtained by adding an oxidizing agent
such as DDQ to the reaction mixture.15 In this case,
σН-adducts were detected as unstable intermediates. In this
study, the chemical properties of 4-phenylacetylenide- and
stilbenyl-substituted pyrazolo[5,1-c][1,2,4]triazines were
studied for the first time, a number of previously unknown
saturated and aromatic derivatives were obtained on their
0009-3122/21/57(6)-0656©2021 Springer Science+Business Media, LLC
656

Chemistry of Heterocyclic Compounds 2021, 57(6), 656–665
Scheme 1
basis, and the transformations, structure, and antimicrobial
activity of the synthesized compounds were examined.
3-tert-Butyl-8-methylpyrazolo[5,1-c][1,2,4]triazines 3a,b
were synthesized by reduction of 4-oxo derivatives 1a,b
with borane followed by the action of t-BuONO in
accordance with the literature data.16–18 The aromatization
of oxidative nitration products 2a,b occurs upon treatment
with weak bases (Scheme 1).19 Previously, it was
established on the basis of spectral data that the obtained
triazines 3a,b enter into the reactions of selective addition
of Grignard reagents at position C-4.19 In particular, it was
shown that treatment of triazine 3b with phenyl-
ethynylmagnesium bromide leads to the formation of
compound 4b (Scheme 1). In this work, we have
synthesized for the first time 3-tert-butyl-8-methyl-
4-phenylethynyl-1,4-dihydropyrazolo[5,1-c][1,2,4]triazine
(4a), the structure of which was reliably confirmed using
X-ray structural analysis (Fig. 1).
We found that the treatment of stable azolo[1,2,4]-
triazines 4а,b containing the phenylethynyl moiety with a
catalytic amount of sodium n-butylate with slight heating
in THF produces (E)-3-tert-butyl-8-methyl-4-styrylpyrazolo-
[5,1-c][1,2,4]triazines 5а,b along with a small amount of
oxidative degradation products, compounds 6а,b (Scheme 2).
1
The H NMR spectra of compounds 5а,b contained the
expected doublets of the styryl functionality in the
downfield region of 7.29–8.98 ppm with a coupling
constant of 16.1–16.2 Hz. The corresponding signals of
carbon atoms in the 13C NMR spectra (APT, attached
proton test) appeared in the 115.4–115.9 and 144.2–
145.1 ppm ranges. The configuration of alkene 5b was
unambiguously established by single crystal X-ray
structural analysis (Fig. 2). The spectral characteristics of
oxotriazines 6а,b coincided with those previously
described.16,18,19
On the other hand, the use of a weak base such as
triethylamine in reaction with acetylene 4b led to another
geometric isomer of the exocyclic double bond, (Z)-4-
styrylpyrazolo[5,1-c][1,2,4]triazine 7 (Scheme 2). In this
case, the formation of trace amounts of (E)-alkene 5b was
also detected (by TLC). The structure of compound 7 is
convincingly confirmed by its chemical properties and
Figure 1. The molecular structure of compounds 4а and 8 with
atoms represented as thermal vibration ellipsoids of 50% probability.
Hydrogen atoms of methyl and phenyl groups are not shown.
657

Chemistry of Heterocyclic Compounds 2021, 57(6), 656–665
Scheme 2
spectral data. Thus, the high-resolution mass spectrum of
product 7 is practically identical to the spectrum of alkene
5b: m/z 371.0867 [M+H]+. At the same time, the 13C NMR
spectrum (APT) of compound 7 showed signals of the
Ph–CH=CH group at 115.9 and 138.7 ppm. (Z)-Alkene 7 is
unstable; it can be isolated individually using flash
chromatography, and at room temperature in the absence of
a catalyst it slowly transforms into (E)-isomer 5b. Similar
isomerization reactions are known for substituted
stilbenes.20 Quantitative (96%) formation of (E)-alkene 5b
from (Z)-alkene 7 was observed upon addition of n-BuONa
(Scheme 2).
The oxidation of the triazine ring of 4-phenylethynyl-
1,4-dihydro derivative 4b without affecting the triple bond
was carried out using N-bromosuccinimide and K2CO3 in
EtOAc. 7-Bromo-3-tert-butyl-8-methyl-4-(phenylethynyl)-
pyrazolo[5,1-c][1,2,4]triazine (8) was isolated in good
yield (78%). According to X-ray structural analysis data
(Fig. 1), the Ph–C≡C–C(4) group in compound 8 lies in the
plane of the heterocycle (the largest deviation was less than
4°), whereas in the partially hydrogenated analog 4а the
acetylenyl substituent is practically orthogonal to the azolo-
triazine fragment. Despite the increased steric hindrance,
aromatization led to a decrease in the PhCC–C(4) bond
length (by about 0.06 Å).
To investigate the possibility of synthesizing 4-phenyl-
ethylpyrazolotriazine 10, we performed selective reduction
of the triazine ring in alkenes 5а,b using LiBH4 with
the isolation of 1,4-dihydro derivatives 9а,b (Scheme 3).
The reactions were carried out in an EtOAc–MeOH
mixture in the presence of a phase-transfer catalyst. The
IR spectrum of compounds 9а,b shows characteristic
absorption bands of the N–H groups at 3190 (compound
9а) and 3051 cm–1 (compound 9b). The H NMR spectra
1
Figure 2. The molecular structure of compounds 5b and 9b with
atoms represented as thermal vibration ellipsoids of 50%
probability.
showed the expected 4-СH and N–H signals at 5.65, 9.52
(compound 9а) and 5.58, 9.89 ppm (compound 9b),
respectively, while the coupling constants of the protons at
the double bond of the alkene fragment were 15.9–16.0 Hz.
The peaks of С-4 atoms in the 13С NMR spectra are
localized at 54.12 (compound 9а) and 54.11 ppm
(compound 9b). The spatial structure of compound 9b was
also confirmed by X-ray structural analysis (Fig. 2).
Compound 9b has the expected E-configuration at the
double bond; in this case, the planar 1,2,4-triazine ring
upon reduction transforms into the half-chair configuration,
similar to acetylene 4а.
It was experimentally found that derivatives 9а,b are
stable to the action of various bases and are not isomerized
to the expected aromatic triazine 10 even under severe
conditions: when compounds 9а,b are treated with n-BuLi
in THF at room temperature or with butyl anions in PhMe
658

Chemistry of Heterocyclic Compounds 2021, 57(6), 656–665
Scheme 3
under reflux, only the starting compounds were isolated
from the reaction mixture after acidification.
In the spectra of compound 10, a downfield shift of the
signals of the PhCH2CH2 group by 1.3 ppm (in the
1H NMR spectrum) and by 4.2 ppm (in the 13C NMR
spectrum) in comparison with the signals of the starting
hydrogenated triazine 11 was observed, which confirms the
formation of an aromatic system. The 1H NMR spectrum of
the substituted benzyl bromide 12 showed a new triplet at
5.86 ppm, assigned to the Ph–CHBr–CH2 proton. The
spectrum of derivative 13 contained signals of the CHBr–
CHBr fragment in the form of two doublets at 6.35 and
7.08 ppm with a coupling constant of 11.1 Hz. High-
resolution mass spectra data for compounds 10, 12, and 13
were as expected.
An alternative synthesis of compound 10 can be carried
out by a simpler route from compound 3а and phenyl-
ethylmagnesium bromide with further oxidation of the
intermediate addition product 11. We have established
experimentally that the reaction of compound 3а with
PhCH2CH2MgBr (obtained from phenylethyl bromide and
magnesium in diethyl ether under reflux26) followed by
hydrolysis of the reaction mixture and oxidation with
N-bromosuccinimide leads to 3-tert-butyl-8-methyl-4-phenyl-
pyrazolo[5,1-c][1,2,4]triazine (14) as the main reaction
product (Scheme 4). The expected triazine 10 (9%) and
1,4-diphenylbutane (15) (30%) were also isolated in low
yields (the latter was characterized by X-ray structural
analysis (Fig. 3)).
Compound 10 was obtained by a counter synthesis in
two steps from alkene 5а. The action of diborane generated
in situ from LiBH4 and BF3·Et2O on triazine 5а at low
temperature led to the reduction of double bonds of the
heterocycle and the side chain (Scheme 3). The 13C NMR
spectrum of reaction product 11 does not contain signals of
the alkene fragment, while new peaks of the carbon atoms
of the PhCH2CH2 fragment are observed in the aliphatic
region at 34.5, 39.9 ppm. The high-resolution mass
spectrum confirms the structure of compound 11 by
recording the molecular ion peak with m/z 297.2078
[M+H]+. An attempt to synthesize compound 11 by
reduction of acetylene 4а was unsuccessful. Treatment
of pyrazolotriazine 11 with N-bromosuccinimide under
slight heating led to the isolation of a mixture of the
expected aromatization product 10 and bromo derivative 12
(Scheme 3). The formation of the latter can be explained by
the simultaneous reaction of free radical bromination at the
benzyl position.21 At the same time, we obtained a
diastereomerically pure product 13 by electrophilic bromi-
nation22,23 of stilbene 5а by the action of Br2 (Scheme 3).
Compounds 12 and 13 turned out to be unstable at room
temperature, apparently due to intra- or intermolecular
quaternization reactions previously described for 1,2,4-tri-
azines.24,25
Scheme 4
659

Chemistry of Heterocyclic Compounds 2021, 57(6), 656–665
Figure 3. The molecular structure of compound 15 with atoms
represented as thermal vibration ellipsoids of 50% probability.
In the spectra of phenyl-substituted triazine 14, there
were no signals in the aliphatic region except for the
singlets of the C(8)–Me and t-Bu groups at 2.64 and
1.40 ppm, respectively. The structure of product 14 was
unambiguously confirmed by X-ray structural analysis
(Fig. 4). The phenyl ring is practically in antiperiplanar
conformation with respect to the triazine ring, which
indicates the absence of mutual π-conjugation. Apparently,
the release of the ethylene molecule27 occurs at the stage of
the reaction of the starting triazine 3а with the in situ
generated Grignard reagent, since we did not observe the
formation of product 14 in the reactions of triazine 11 with
N-bromosuccinimide.
Compounds 3b, 4a, 5a, 8, 9a were investigated for the
presence of antibacterial activity against resistant
opportunistic
strains
of
Gram-negative
bacteria
Enterobacter cloacae sp. (clinical strain, multidrug
resistance) and Escherichia coli (DH52 REF Amp100,
recombinant ampicillin-resistant strain) (Table 1).
Compound 8 exhibited bacteriostatic activity against the
Escherichia coli strain at a concentration of 128 μg/ml. The
rest of the compounds did not possess noticeable
antibacterial properties against the studied strains in the
concentration range of 128–256 μg/ml. The value of the
minimum inhibitory concentration of compound 8 will be
clarified in subsequent experiments with lower
concentrations of the substance. The experiments will
continue on strains of Gram-positive bacteria
(Staphylococcus aureus) and yeast-like fungi (Candida
albicans).
Figure 4. Molecular structure of compound 14 and its packing in
the solid state with atoms represented by thermal vibration
ellipsoids of 50% probability. The hydrogen atoms of the methyl
and phenyl groups in the latter case are not shown.
Table 1. Antibacterial activity of compounds 3b, 4a, 5a, 8, 9a
To conclude, as a result of this work the directions of
rearrangements of 3-tert-butyl-8-methyl-4-phenylethynyl-
1,4-dihydropyrazolo[5,1-c][1,2,4]triazines were established
for the first time. It was demonstrated that 4-styryl-1,4-
dihydropyrazolotriazines do not enter this reaction with the
formation of the expected 4-phenylethylpyrazolo[5,1-c]-
[1,2,4]triazine. The latter was obtained by an counter
synthesis, by the reduction of double bonds in the ring and
the side chain of a 4-styryl derivative followed by oxidative
bromination. The chemical properties, spectral, and X-ray
structural characteristics of the isolated compounds were
investigated. The aromatic 4-phenylethynyl derivative
exhibited weak bacteriostatic activity.
Minimum inhibitory
concentration, μg/ml
Compound
Solvent
Escherichia coli
(DH52 REF
Amp100)*
Enterobacter
cloacae sp.
0.5% DMSO/Н2О (40°С)
0.5% DMSO/Н2О (40°С)
0.5% DMSO/Н2О (40°С)
0.5% DMSO/Н2О (40°С)
0.5% DMSO/Н2О (40°С)
–
>256
>256
>256
128
>256
>256
>256
>256
>256
<0.5
3b
4a
5a
8
9a
>256
<0.5
Pefloxacin
* Recombinant ampicillin-resistant strain.
660

Chemistry of Heterocyclic Compounds 2021, 57(6), 656–665
Experimental
added in one portion. The reaction mixture was heated to
50°C and stirred for 1 h at this temperature. After cooling
to room temperature, saturated aqueous KH2PO4 (10 ml)
was added dropwise and the mixture was stirred for
15 min. Then, n-heptane (30 ml) was added, and the
resulting solution was dried over anhydrous MgSO4. The
organic phase was decanted and evaporated under reduced
pressure at 50°C. The residue was washed with a heated
(55°C) MeOH–H2O, 1:1 mixture (3×10 ml), filtered, and
air-dried to obtain compound 5a or 5b. The filtrate was
evaporated under reduced pressure, the residue was
purified by column chromatography on silica gel (eluent
EtOAc–hexane, 1:40–1:2) to give compound 6a or 6b.
Spectral characteristics and mp for compounds 6a,b (yield
of compound 6a was 100–150 mg (5–7%), compound 6b –
40–80 mg (3–5%)) correspond to the literature.18,19
IR spectra were registered on an Agilent Cary 660 FTIR
1
Fourier transform spectrometer in KBr pellets. H and 13C
NMR spectra (APT, attached proton test) were acquired on
Bruker AM-300 (300 and 75 MHz, respectively) and
Bruker DRX-500 (500 and 126 MHz, respectively)
spectrometers in DMSO-d6 1or CDCl3. The residual signals of
DMSO-d6 (2.50 ppm for Н nuclei and 39.5 ppm for 13С
1
nuclei) and CDCl3 (7.26 ppm for Н nuclei and 77.2 ppm
for 13С nuclei) served as internal standards. High-resolution
mass spectra were recorded on a Bruker micrOTOF II mass
spectrometer (electrospray ionization, solvent MeOH or
MeCN) in the positive ion registration mode (capillary
voltage 4500 V). Melting points were determined on a
STUART SMP30 apparatus. Monitoring of the reaction
progress was done by TLC. Merck Silica gel, 60–200 µm
was used for column chromatography. All reactions were
carried out in an argon atmosphere (99.9990% purity).
THF and Et2O were purified by distillation over K/Na in
an argon atmosphere. Compounds 3a,b, and 4b were
Method II. Compound 5b was obtained according to
method I from compound 7 (0.5 g, 1.35 mmol).
3-tert-Butyl-8-methyl-4-((E)-styryl)pyrazolo[5,1-c]-
[1,2,4]triazine (5a). Yield 2.1 g (70%, method I), yellow
powder, mp 152–154°C (decomp.). IR spectrum, ν, cm–1:
3065, 3027, 2991, 2965, 2920, 2871 (СН), 1610, 1576,
1496, 1476, 1455, 1384, 1368, 1318, 1293, 1248, 1216,
1192, 1152, 1114, 1033, 997, 978, 965, 926, 897, 773, 741,
synthesized according to
a
previously described
procedures.16–19
3-tert-Butyl-8-methyl-4-phenylethynyl-1,4-dihydropyra-
zolo[5,1-c][1,2,4]triazine (4a). n-BuMgBr–Et2O solution
(27 ml, 32 mmol) was added dropwise with continuous
stirring over 10 min at room temperature to a solution of
phenylacetylene (3.5 ml, 32 mmol) in THF (100 ml). After
the addition was complete, the mixture was stirred for
another 20 min, and compound 3a (3.0 g, 15.8 mmol) was
added to the obtained phenylethynylmagnesium bromide.
The reaction mixture was heated under reflux for 1 h; after
cooling to room temperature, H2O (200 ml) and
concentrated HCl (20 ml) were successively added drop-
wise. The mixture was kept at room temperature for 24 h.
After evaporation of THF, the formed precipitate was
filtered and sequentially washed on filter with H2O and
EtOAc–hexane, 1:20 mixture, then air-dried. Yield 2.25 g
(75%), white powder, mp 205–215°C (subl.). IR spectrum,
ν, cm–1: 3270, 3193, 3100 (NH), 3080, 3051, 2971, 2935,
2903, 2869 (CH), 1631, 1593, 1543, 1513, 1490, 1469,
1464, 1443, 1403, 1365, 1344, 1325, 1281, 1259, 1240,
1221, 1157, 1124, 1096, 1070, 1036, 994, 977, 906, 849,
1
717, 681, 633, 617, 593, 531, 486, 472. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.65 (9H, s, 3CH3); 2.54 (3H, s,
8-CH3); 7.29–7.40, 7.54–7.60 (6H, m, H Ph, СHСHPh);
3
8.00 (1H, s, 7-СH); 8.92 (1H, d, JHH = 16.1, СHСHPh).
13C NMR spectrum (CDCl3), δ, ppm: 7.6 (8-СH3); 31.8
(С(CH3)3); 37.4 (C(CH3)3); 107.7 (C-8); 115.9 (СHСHPh);
127.6 (3,5-CH Ph); 128.1 (С-4); 129.1 (2,6-CH Ph); 129.9
(4-CH Ph); 136.6 (C-1 Ph); 144.0 (C-7); 144.2 (СHСHPh);
148.7 (C-8a(3)); 149.2 (C-3(8a)). Found, m/z: 293.1752
[M+H]+. C18H21N4. Calculated, m/z: 293.1761.
7-Bromo-3-tert-butyl-8-methyl-4-((E)-styryl)pyrazolo-
[5,1-c][1,2,4]triazine (5b). Yield 1.48 g (74%, method I),
0.48 g (96%, method II), bright-yellow crystals, mp 181–
183°C (decomp.). IR spectrum, ν, cm–1: 2980, 2918 (СН),
1612, 1576, 1566, 1496, 1476, 1460, 1380, 1368, 1321,
1275, 1242, 1194, 1145, 1118, 1061, 971, 772, 757, 744,
686. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.74 (9H,
s, 3CH3); 2.57 (3H, s, 8-CH3); 7.43–7.50 (3H, m, Н-3–5
3
Ph); 7.61 (H, d, JHH = 16.2, СHСHPh); 7.69 (2Н, d,
1
3
814, 793, 757, 691, 657, 603, 534, 426. H NMR spectrum
3JHH = 6.9, Н-2,6 Ph); 8.98 (H, d, JHH = 16.2, СHСHPh).
(DMSO-d6), δ, ppm: 1.29 (9H, s, 3CH3); 2.50 (3H, s,
8-CH3); 6.29 (1H, s, 4-CH); 7.21 (1H, s, 7-CH); 7.32–7.37
(5H, m, H Ph); 10.49 (1H, br. s, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 7.5 (СH3); 28.9 (C(CH3)3); 37.5
(C(CH3)3); 44.3 (С-4); 84.2 (С(4)ССPh); 85.8
(С(4)ССPh); 93.5 (C-8); 121.7 (C-8a); 129.2 (3,5-CH Ph);
129.5 (4-CH Ph); 131.7 (2,6-CH Ph); 136.8 (C-1 Ph);
140.9 (C-7); 145.4 (C-3). Found, m/z: 293.1761 [M+H]+.
C18H21N4. Calculated, m/z: 293.1761.
Synthesis of compounds 5а,b and 6a,b (General
procedure). Method I. Compound 4a (3.0 g, 10.3 mmol) or
compound 4b (2.0 g, 5.39 mmol) (for the synthesis of
compounds 5а or 5b, respectively) was dissolved in a
mixture of THF (100 ml) and n-BuOH (10 ml), and NaH
(60% dispersion in mineral oil; 0.5 g, 12.5 mmol) was
13C NMR spectrum (CDCl3), δ, ppm: 8.0 (8-СH3); 31.7
(C(CH3)3); 37.7 (C(CH3)3); 107.9 (C-8); 115.4 (СHСHPh);
127.6 (C-4); 127.9 (3,5-CH Ph); 129.2 (2,6-CH Ph); 130.2
(4-CH Ph); 136.2 (C-1 Ph); 136.6 (C-7); 145.1 (СHСHPh);
148.5 (C-8a(3)); 150.0 (C-3(8a)). Found, m/z: 371.0858
[M+H]+. C18H20BrN4. Calculated, m/z: 371.0866.
7-Bromo-3-tert-butyl-8-methyl-4-((Z)-styryl)pyrazolo-
[5,1-c][1,2,4]triazine (7). NEt3 (3 ml, 21.5 mmol) was
added to a solution of compound 4b (1.0 g, 2.7 mmol) in
THF (10 ml), and the resulting mixture was heated under
reflux for 24 h (TLC control for the disappearance of
compound 4b). The solvents were evaporated under
reduced pressure, and H2O (50 ml) and EtOAc (50 ml)
were added. The organic phase was washed with 5%
aqueous HCl (2×50 ml) followed by H2O (100 ml), and
661

Chemistry of Heterocyclic Compounds 2021, 57(6), 656–665
dried over anhydrous MgSO4. The mixture was filtered, the
dropwise addition of 85% aqueous H3PO4 (7 ml, 0.1 mol)
with vigorous stirring. The organic phase was separated,
washed successively with 5% aqueous H3PO4 (3×50 ml),
H2O (100 ml), dried over anhydrous MgSO4, and filtered.
The filtrate was evaporated under reduced pressure at 50°C.
The compounds were isolated by column chromatography
on silica gel (eluent EtOAc–hexane, 1:10–1:7)
filtrate was evaporated under reduced pressure at 55°C.
Compound 7 was isolated by column chromatography on
silica gel (eluent EtOAc–hexane, 1:20–1:10). Yield 0.6 g
(60%), yellow powder, mp 88–90°C (decomp.). IR spectrum,
ν, cm–1: 3051, 2979, 2970, 2918, 2868 (CH), 1659, 1653,
1637, 1612, 1575, 1545, 1497, 1461, 1443, 1400, 1381,
1367, 1320, 1267, 1242, 1218, 1191, 1175, 1144, 1122,
3-tert-Butyl-8-methyl-4-((E)-styryl)-1,4-dihydropyra-
zolo[5,1-c][1,2,4]triazine (9a). Yield 0.78 g (78%), mp 200–
210°C (subl.). IR spectrum, ν, cm–1: 3263, 3190 (NH),
3097, 3078, 2971, 2934, 2902, 2870 (CH), 1687, 1658,
1652, 1627, 1591, 1565, 1560, 1544, 1510, 1497, 1472,
1463, 1454, 1405, 1364, 1341, 1261, 1215, 1079, 1028,
987, 975, 927, 872, 852, 785, 744, 691. 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 1.18 (9H, s, 3CH3); 1.91 (3H,
1
1048, 970, 952, 786, 743, 690, 668, 651, 548, 521. H NMR
spectrum (CDCl3), δ, ppm: 1.52 (9H, s, 3CH3); 2.53 (3H, s,
8-CH3); 6.74–6.78 (3H, m, H Ph, СHСHPh); 7.08–7.21
(4H, m, H Ph, СHСHPh). 13C NMR spectrum (CDCl3),
δ, ppm: 8.0 (8-СH3); 30.5 (C(CH3)3); 37.6 (C(CH3)3); 108.4
(C-8); 115.9 (СHСHPh); 127.8 (3,5-CH Ph); 128.6
(2,6-CH Ph); 129.0 (4-CH Ph); 135.6 (C-1 Ph); 136.3
(C-7); 138.7 (СHСHPh); 147.0 (C-8a(3)); 149.9(C-3(8a)).
Found, m/z: 371.0867 [M+H]+. C18H20BrN4. Calculated, m/z:
371.0866.
3
s, 8-CH3); 5.65 (1Н, d, JHH = 7.2, 4-CН); 6.03 (1Н, dd,
3
3JHH = 16.0, JHH = 7.2, PhCHCH); 6.33 (1Н, d,
3JHH = 16.0, PhCHCH); 7.04–7.22 (5H, m, Н Ph); 7.09
(1H, s, 7-CН); 9.52 (1Н, s, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 6.7 (8-СH3); 28.4 (C(CH3)3); 36.6
(C(CH3)3); 54.1 (С-4); 126.0 (3,5-CH Ph); 127.5 (4-CH
Ph); 128.1 (2,6-CH Ph) (signals of some carbon atoms are
not observed due to the low solubility of the sample).
Found, m/z: 295.1925 [M+H]+. C18H23N4. Calculated, m/z:
295.1917.
7-Bromo-3-tert-butyl-8-methyl-4-(phenylethynyl)pyra-
zolo[5,1-c][1,2,4]triazine (8). Ground K2CO3 (5.0 g,
36.2 mmol) followed by N-bromosuccinimide (0.23 g,
1.3 mmol) was added to the colorless solution of
compound 4b (0.5 g, 1.3 mmol) in EtOAc (50 ml); a
change in the color of the solution to dark-orange was
observed. The reaction mixture was heated to 50°C and
stirred vigorously for 30 min. Upon completion of the
reaction, the reaction mixture was cooled to room
temperature, H2O (100 ml) and Na2SO3 (2.0 g, 15.9 mmol)
were added, and the mixture was stirred for 15 min. Then,
the organic phase was separated, and the aqueous solution
was extracted with EtOAc (3×20 ml). The combined
organic phases were dried over anhydrous MgSO4, the
drying agent filtered off, and the filtrate was evaporated
under reduced pressure. Compound 5 was isolated by column
chromatography on silica gel (eluent EtOAc–hexane, 1:50–
1:30). Yield 0.39 g (78%), yellow crystals, mp 141–142°C.
IR spectrum, ν, cm–1: 3060, 2970, 2956, 2925, 2902, 2866
(СН), 2207, 1998 (С≡С), 1686, 1658, 1653, 1607, 1622,
1571, 1528, 1502, 1472, 1458, 1444, 1422, 1363, 1383,
1336, 1313, 1250, 1268, 1208, 1160, 1178, 1142, 1115,
1050, 1067, 1022, 994, 952, 924, 840, 762, 691, 675, 649,
7-Bromo-3-tert-butyl-8-methyl-4-((E)-styryl)-1,4-di-
hydropyrazolo[5,1-c][1,2,4]triazine (9b). Yield 0.43 g
(72%), light-yellow powder, mp 221–222°C. IR spectrum,
ν, cm–1: 3463, 3434, 3398, 3341, 3307, 3293, 3247, 3175,
3076, 3051 (NH), 2969, 2931, 2867, 2750 (CH), 1685,
1652, 1621, 1583, 1538, 1492, 1472, 1452, 1395, 1378,
1352, 1316, 1276, 1249, 1200, 1128, 1099, 1055, 1009,
974, 923, 905, 873, 789, 812, 753, 731, 695, 635, 608, 538,
1
507, 432. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
1.17 (9H, s, 3CH3); 1.86 (3H, s, 8-CH3); 5.58 (1Н, d,
3
3
3JHH = 7.6, 4-CН); 6.00 (1Н, dd, JHH = 15.9, JHH = 7.6,
3
PhCHCH); 6.38 (1Н, d, JHH = 15.9, PhCHCH); 7.04–7.22
(5H, m, Н Ph); 9.89 (1Н, s, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 6.8 (8-СH3); 28.3 (C(CH3)3); 36.7
(C(CH3)3); 54.1 (С-4); 93.6 (C-8); 122.0 (СHСHPh); 126.0
(3,5-CH Ph); 127.5 (4-CH Ph); 127.9 (2,6-CH Ph); 128.0
(C-1 Ph); 132.9 (СHСHPh); 135.0, 148.7, 149.9 (C-3,7,8a).
Found, m/z: 373.1008 [M+H]+. C18H22BrN4. Calculated, m/z:
373.1022.
1
613, 553, 572, 525. H NMR spectrum (CDCl3), δ, ppm:
1.76 (9H, s, 3CH3); 2.57 (3H, s, 8-CH3); 7.46–7.56 (3H, m,
H-3–5 Ph); 7.74–7.79 (2H, m, H-2,6 Ph). 13C NMR spect-
rum (CDCl3), δ, ppm: 8.1 (8-СH3); 30.0 (C(CH3)3); 37.5
(C(CH3)3); 78.8 (C-1 Ph); 109.6 (C-8); 112.4 (С≡С–Ph);
116.0 (С≡С–Ph); 120.9 (С-4); 128.9 (3,5-CH Ph); 131.0
(4-CH Ph); 132.2 (2,6-CH Ph); 136.7, 147.17, 153.30
(С-3,7,8а). Found, m/z: 369.0708 [M+H]+. C18H18BrN4.
Calculated, m/z: 369.0709.
Synthesis of compounds 9а,b (General method).
Compound 5a (1.0 g, 3.4 mmol) or compound 5b (0.6 g,
1.6 mmol) was dissolved in a mixture of EtOAc (30 ml)
and MeOH (5 ml), and the resulting solution was cooled to
0°C in an ice bath. LiBH4 (0.8 g, 36.7 mmol) was added to
the cooled solution in small portions over 10 min. Then,
NBu4Br (0.5 g, 1.5 mmol) was added, and the resulting
mixture was stirred for 5 h at room temperature. Next,
cooled (0°С) H2O (100 ml) was added, followed by a
3-tert-Butyl-8-methyl-4-(2-phenylethyl)-1,4-dihydro-
pyrazolo[5,1-c][1,2,4]triazine (11). Compound 5a (0.5 g,
1.7 mmol) was dissolved in Et2O (40 ml), and the resulting
solution was cooled to 0°C in an ice bath. BF3·Et2O (5 ml,
40.5 mmol) was added in one portion to the cooled
solution, then LiBH4 (1.1 g, 50.5 mmol) was added with
vigorous stirring in small portions over 30 min. The
mixture was then stirred for another hour at the same
temperature. Next, cooled (0°C) H2O (10 ml) was added
dropwise over 10 min and with vigorous stirring. Then, the
reaction mixture was carefully poured into Н2О (300 ml)
and EtOAc (50 ml), and KOH (20 g, 0.36 mol) was added
to the resulting two-phase mixture in small portions with
stirring over 20 min. Then, NBu4Br (0.5 g, 1.5 mmol) was
added, the mixture was stirred for 1 h and kept at room
662

Chemistry of Heterocyclic Compounds 2021, 57(6), 656–665
temperature for 24 h. The precipitate formed upon
stirred at 50–60°C for 30 min. It was then cooled to room
temperature, and H2O (100 ml) and Na2SO3 (2 g, 15.9 mmol)
were added. The organic phase was separated, the aqueous
solution was extracted with EtOAc (2×50 ml). The
combined organic phases were successively washed with
1% aqueous K2CO3 (50 ml) and H2O (100 ml), dried over
anhydrous MgSO4, filtered, and the filtrate was evaporated
under reduced pressure. The residue was purified by
column chromatography on silica gel (eluent EtOAc–
heptane, 1:100–1:20). Spectral and X-ray structural
parameters of 1,4-diphenylbutane 15 (yield 0.25 g (30%),
colorless needles, mp 50–51°C) correspond to the literature
data.28,29
evaporation of the solvents was filtered and dissolved in a
CHCl3–heptane, 5:1 mixture. Compound 11 was isolated
by column chromatography on silica gel (eluent CHCl3–
heptane, 1:10). After evaporation of the solvents, the
residue was washed with cooled (0°С) EtOAc–heptane,
1:10 mixture (3×5 ml). Yield 0.37 g (74%) white powder,
mp 190–200°C (subl.). IR spectrum, ν, cm–1: 3467, 3435,
3305, 3272 (NH), 3082, 2975 (CH), 1625, 1560, 1544,
1508, 1459, 1399, 1370, 1036, 984, 923, 670, 567, 481,
1
424. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 1.13
3
(9H, s, 3CH3); 1.86 (2H, t, JHH = 7.0, PhCH2CH2); 1.93
(3H, s, 8-CH3); 2.35–2.45 (2Н, m, partially overlaps with
the solvent signal, PhCH2CH2); 4.99–5.03 (1Н, m, 4-CН);
7.08–7.21 (6Н, m, Н Ph, 7-CН); 9.92 (1Н, s, NH).
13C NMR spectrum (DMSO-d6), δ, ppm: 10.4 (8-СH3); 32.1
(C(CH3)3); 37.9 (C(CH3)3); 34.5, 39.9 (PhCH2CH2); 55.7
(C-4); 96.3 (C-8); 129.0 (4-CH Ph); 131.4 (3,5-CH Ph);
131.5 (2,6-CH Ph); 140.9, 142.5, 144.2, 153.1 (С-1 Ph,
C-3,7,8a). Found, m/z: 297.2078 [M+H]+. C18H25N4.
Calculated, m/z: 297.2074.
Synthesis of compounds 10 and 12 by oxidation of
dihydro derivative 11. Method III. Compound 11 (0.5 g,
1.7 mmol) was dissolved in EtOAc (40 ml). Crystalline
K2CO3 (5.0 g, 36.2 mmol) was added to the resulting
solution. N-Bromosuccinimide (0.3 g, 1.7 mmol) was
added in one portion with vigorous stirring; the solution
turned bright-yellow. The mixture was stirred at 50–60°C
for 20 min. Then, the reaction mixture was cooled to room
temperature and H2O (100 ml) and Na2SO3 (2.0 g,
15.9 mmol) were added. The organic phase was separated,
the aqueous solution was extracted with EtOAc (2×50 ml),
the combined organic phases were successively washed
with 1% aqueous K2CO3 (50 ml) and H2O (100 ml), dried
over anhydrous MgSO4, filtered, and the filtrate was
evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel (eluent
EtOAc–heptane, 1:20–1:10)
Synthesis of compounds 10, 14, and 15 from
2-phenylethyl bromide and triazine 3a. Method IV.
2-Phenylethyl bromide (0.1 ml, 0.73 mmol) was added in
one portion to a mixture of Mg turnings (0.2 g, 8.23 mmol),
Et2O (30 ml), and a few crystals of I2. The mixture was
heated under reflux until initiation of the reaction
(3–5 min). 2-Phenylethyl bromide (1 ml, 7.32 mmol) was
then added dropwise with vigorous stirring over 1 h. Then
the mixture was heated under reflux for a further 1 h,
cooled to room temperature, and filtered. The filtrate was
added dropwise with stirring to a solution of compound 3a
(1 g, 5.26 mmol) in THF (20 ml). The resulting mixture
was heated under reflux for 30 min, cooled to room
temperature, and poured into cooled (0°C) 5% aqueous
HCl (100 ml). After stirring for 5 min, the mixture was
extracted with EtOAc (4×30 ml). The combined organic
phases were washed with H2O (100 ml), dried over
MgSO4, filtered, and crystalline K2CO3 (10 g, 72.4 mmol)
was added to the filtrate. Then, N-Bromosuccinimide (3 g,
16.9 mmol) was added in one portion with vigorous
stirring; the solution turned bright-yellow. The mixture was
3-tert-Butyl-8-methyl-4-(2-phenylethyl)pyrazolo[5,1-c]-
[1,2,4]triazine (10). Yield 0.31 g (62%, method III),
0.14 g (9%, method IV), yellow powder, mp 90–91°C.
IR spectrum, ν, cm–1: 3079, 3024, 2969, 2921, 2872 (СН),
1603, 1585, 1515, 1493, 1478, 1457, 1367, 1332, 1285,
1272, 1254, 1215, 1203, 1165, 1146, 1126, 1030, 1005,
1
990, 897, 780, 761, 713, 700, 639, 556, 522. H NMR
spectrum (CDCl3), δ, ppm: 1.71 (9H, s, 3CH3); 2.68 (3H, s,
8-СH3); 3.17–3.23 (2Н, m, CH2CH2Ph); 3.71–3.76 (2H, m,
CH2CH2Ph); 7.31–7.43 (5H, m, H Ph); 8.11 (1H, s, 7-CH).
13C NMR spectrum (CDCl3), δ, ppm: 7.6 (8-СH3); 30.3;
31.3 (CH2CH2Ph); 31.4 (C(CH3)3); 37.2 (C(CH3)3); 107.9
(C-8); 126.6 (4-CH Ph); 128.4; 128.8 (2,3,5,6-CH Ph);
134.0 (C-1 Ph); 144.2 (C-7); 140.6, 147.6, 148.8
(C-3,4,8a). Found, m/z: 295.1920 [M+H]+. C18H23N4.
Calculated, m/z: 295.1917.
4-(2-Bromo-2-phenylethyl)-3-tert-butyl-8-methylpyra-
zolo[5,1-c][1,2,4]triazine (12). Yield 75 mg (15%, method
IV), yellow liquid. IR spectrum, ν, cm–1: 3083, 3051, 2987,
2967, 2923, 2853 (CH), 1685, 1670, 1653, 1637, 1623,
1582, 1561, 1545, 1527, 1508, 1497, 1474, 1458, 1384,
1370, 1327, 1315, 1269, 1202, 1170, 1151, 1109, 1077,
1045, 1028, 995, 963, 899, 827, 756, 714, 699, 683, 658,
1
637, 592, 541, 516, 497, 440, 422. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.48 (9H, s, 3CH3); 2.65 (3H, s,
8-СH3); 4.00–4.04 (1Н, m, CH2CHBrPh); 4.30–4.34 (1Н,
3
m, CH2CHBrPh); 5.86 (1Н, t, JHH = 7.8, CH2CHBrPh);
6.88–6.90 (2Н, m, Н Ph); 7.16–7.20 (3Н, m, Н Ph); 8.20
(1H, s, 7-CH). 13C NMR spectrum (CDCl3), δ, ppm: 7.7
(8-СH3); 31.2 (C(CH3)3); 37.2 (CH2CHBrPh); 39.3
(C(CH3)3); 44.3 (CH2CHBrPh); 108.8 (C-8); 127.5 (4-CH
Ph); 128.8; 129.0 (2,3,5,6-CH Ph); 130.6 (C-1 Ph); 144.2
(C-7); 137.1, 147.5, 148.8 (C-3,4,8a). Found, m/z:
373.1017 [M+H]+. C18H21BrN4. Calculated, m/z: 373.1022.
3-tert-Butyl-8-methyl-4-phenylpyrazolo[5,1-c][1,2,4]-
triazine (14). Yield 0.52 g (37%, method IV), yellow
powder, mp 137–138°C. IR spectrum, ν, cm–1: 3435, 3399,
3368, 3341, 3307, 3294, 3272, 3248, 3234, 3153, 3117,
3083, 3066 (NH), 3037, 3015, 2996, 2978, 2963, 2948,
2914, 2873, 2838 (CH), 1686, 1671, 1654, 1638, 1624,
1577, 1561, 1545, 1525, 1510, 1493, 1476, 1461, 1443,
1422, 1396, 1372, 1330, 1228, 1200, 967, 869, 778, 757,
703, 673, 658, 639, 622, 583, 528, 503, 480, 427. 1H NMR
spectrum (CDCl3), δ, ppm: 1.40 (9H, s, 3CH3); 2.64 (3H, s,
8-CH3); 7.39–7.42 (2H, m, H-2,6 Ph); 7.59–7.61 (3H, m,
H-3–5 Ph); 7.93 (1Н, s, 7-СH). 13C NMR spectrum
663

Chemistry of Heterocyclic Compounds 2021, 57(6), 656–665
(CDCl3), δ, ppm: 7.6 (8-СH3); 32.0 (C(CH3)3); 37.7
The biological studies of compounds 3b, 4a, 5a, 8,
and 9a were conducted at the Yaroslavl State Pedagogical
University named after K. D. Ushinsky by the method of
double serial dilutions using turbidimetric control of the
growth of microorganisms in triplicate in accordance with
the requirements of the guidelines MUK 4.2.1890-04
(''Opredelenie chuvstvitelnosti microorganismov k antibak-
terialnym preparatam'') ("Determination of the sensitivity
of microorganisms to antibacterial drugs") and the
international standard CLSI-M07-A9-2012. Under the
experimental conditions, due to the low solubility in
aqueous solutions (DMSO concentration 0.5%), the
compounds were studied in the form of suspensions in the
concentration range of 128–256 μg/ml.
(C(CH3)3); 108.5 (C-8); 128.9 (3,5-CH Ph); 129.7 (2,6-CH
Ph); 130.3 (4-CH Ph); 130.3 (C-1 Ph); 144.7 (C-7); 149.5,
150.8, 154.7 (C-3,4,8а). Found, m/z: 267.1604 [M+H]+.
C16H19N4. Calculated, m/z: 267.1604.
(±)-4-((1R,2S)-1,2-Dibromo-2-phenylethyl)-3-tert-butyl-
8-methylpyrazolo[5,1-c][1,2,4]triazine (13). Br2 (0.1 ml,
1.95 mmol) was added in one portion with vigorous stirring
in the dark to a solution of compound 5a (0.2 g,
0.68 mmol) in CHCl3 (5 ml). The reaction mixture was
stirred for 5 min at room temperature, then the solvent was
removed under reduced pressure. The residue was purified
by column chromatography on silica gel (eluent EtOAc–
heptane, 1:100–1:50). Yield 0.22 g (71%), orange liquid.
IR spectrum, ν, cm–1: 2976, 2916, 2872 (СН), 1652, 1623,
1474, 1460, 1370, 1331, 1297, 1242, 1193, 1104, 1049,
981, 956, 882, 837, 770, 695, 636, 612, 591, 550.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.84 (9H, s,
Supplementary information file containing IR spectra,
1H and 13C NMR and high-resolution mass spectra of the
synthesized compounds as well as X-ray structural analysis
data for compounds 4а, 5b, 8, 14 is available at the journal
website at http://link.springer.com/journal/10593.
3
3CH3); 2.67 (3H, s, 8-СH3); 6.35 (1Н, d, JHH = 11.1,
CHBrCHBrPh,); 7.08 (1Н, d, 3JHH = 11.1, CHBrCHBrPh,);
7.40–7.54 (3Н, m, Н Ph); 7.60–7.68 (2Н, m, Н Ph); 8.18
(1H, s, 7-CH). 13C NMR spectrum (CDCl3), δ, ppm: 7.7
(8-СH3); 32.0 (C(CH3)3); 37.8 (C(CH3)3); 47.2; 50.2
(CHBrCHBrPh); 109.0 (C-8); 128.4; 129.2 (2,3,5,6-CH
Ph); 129.52 (4-CH Ph); 129.8 (C-1 Ph); 144.4 (C-7); 138.9,
147.9, 148.8 (C-3,4,8a). Found, m/z: 453.0108 [M+H]+.
C18H20Br2N4. Calculated, m/z: 453.0108.
X-ray structural analysis was carried out at the
Department of Structural Research of the N. D. Zelinsky
Institute of Organic Chemistry, Russian Academy of Sciences.
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664

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