Synthesis of Novel Azides and Triazoles on the Basis of 1н-Pyrazole-3(5)-Carboxylic Acids

Article abstract of DOI:10.1007/s10593-020-02643-2

[Figure not available: see fulltext.] The goal of this work was to obtain novel ligands basedis on 1H-pyrazole-3(5)-carboxylic acids containing the triazole moiety at positions 3(6) or 4. Another goal was to study the possibility of joining pyrazole carbo

Full text of DOI:10.1007/s10593-020-02643-2

DOI 10.1007/s10593-020-02643-2
DOI 10.1007/s10593-020-02643-2
Chemistry of Heterocyclic Compounds 2020, 56(2), 180–191
Synthesis of novel azides and triazoles
on the basis of 1Н-pyrazole-3(5)-carboxylic acids
Aleksander I. Dalinger1, Alexey V. Medved'ko1, Alexandra I. Balalaeva1,
Irina А. Vatsadze2, Igor L. Dalinger2, Sergey Z. Vatsadze1*
1 Lomonosov Moscow State University
1, Build. 3, Leninskie Gory, Moscow 119992, Russia
2 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky Ave., Moscow 119991, Russia; e-mail: szv@org.chem.msu.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(2), 180–191
Submitted December 6, 2019
Accepted December 9, 2019
The goal of this work was to obtain novel ligands based on 1H-pyrazole-3(5)-carboxylic acids containing the triazole moiety at positions
3(5) or 4. Another goal was to study the possibility of joining pyrazole carboxylic acid fragments with various framework structures to
create polychelated ligands that can be used in medicinal chemistry and metal complex catalysis. Methods have been developed for the
synthesis of previously unknown N-unsubstituted 5- and 4-azido-1H-pyrazole-3-carboxylic acids from the corresponding available amino
derivatives in high yields. For the first time, the joining of bispidines to azoles was carried out using the copper-catalyzed [3+2]
cycloaddition reaction.
Keywords: azides, bispidines, pyrazole, catalysis, click chemistry, complexes, CuAAC reaction, [3+2] cycloaddition, ligands.
1H-Pyrazole-3(5)-carboxylic acids, in particular 5-aryl-
1H-pyrazole-3-carboxylic acids, exhibit a wide spectrum of
biological activity.1 They are partial agonists of nicotinic
acid receptors,2 inhibitors of protein-protein interactions of
replication protein A,3 play the role of frameworks of
protein tyrosine phosphatase 1B inhibitors,4 are inhibitors
of tissue-nonspecific alkaline phosphatase.5 5-Hetaryl-1H-
pyrazole-3-carboxylic acids are known inhibitors of human
carbonic anhydrases I, II, IX, and XII.6
Earlier, we demonstrated the possibility of using
isomeric N-substituted 5(3)-aryl(hetaryl)-1H-pyrazole-3(5)-
carboxylic acids as ligands in lanthanide luminescent
complexes.7,8 Of principal importance was not only the
presence of the carboxyl group, which allows such
structures to form stable chelate complexes, but also the
presence in the adjacent position of a nitrogen atom of the
pyridine type capable of interacting with metal ions. At
the same time, such structures should be of considerable
interest as ligands for use in metal complex catalysis.
As part of the project to create novel catalytic systems
being developed for use in metal complex catalysis, the
design of organic molecules that would combine not one
but two pyrazolecarboxylates in their structure so that they
could force both chelating systems for coordination to one
metal moiety was carried out (Fig. 1). Such a structure may
have a higher binding constant with metals, which will
increase the stability of the catalyst, and additional spatial
limitations will lead to an increase in selectivity.
To study the possibility of joining a conformationally
rigid bicyclic core of a potential catalyst (in this case, bis-
pidine) to the coordinating moiety (pyrazole fragments), it was
decided to use the 1,2,3-triazole ring as a linker, the formation
of which easily occurs as a result of the copper-catalyzed
[3+2] cycloaddition reaction of azides with alkynes.
0009-3122/20/56(2)-0180©2020 Springer Science+Business Media, LLC
180

Chemistry of Heterocyclic Compounds 2020, 56(2), 180–191
In the synthesis of triazoles, 3-azido- and 4-azido-1H-
Core
Core =
pyrazole-5-carboxylic acids, which were obtained by us for
the first time, were used as the 1,3-dipoles. Phenyl-
acetylene, propargyl alcohol, methyl propiolate, and
cyclopentylacetylene were selected as acetylene
derivatives. This choice can be explained by the need to
test acetylenes with different electronic and steric
properties in reactions with new substrates.
N
H
N
H
Linker
Linker
N
N
Linker =
NH
N
HN
N
N
For the synthesis of 5- and 4-azido-1H-pyrazole-
3-carboxylic acids 5, 6, 5- and 4-amino-1H-pyrazole-
3-carboxylic acids 2, 4 were employed as the precursors.
Amino acids 2, 4 were obtained in 70–80% yields via
reduction of the nitro group of the corresponding nitro
acids 1, 3 by heating under reflux with hydrazine hydrate in
the presence of catalytic amounts of FeCl3·6H2O and
activated carbon in H2O according to the literature
procedure21 (Scheme 1). The corresponding nitro acids 1, 3
were synthesized from 3(5)-methyl-1H-pyrazole according
to the published procedures.22–24 5-Azido- and 4-azido-1H-
pyrazole-3-carboxylic acids 5, 6 were obtained by
diazotization of the corresponding amino acids 2, 4 with
NaNO2 in 2 M aqueous HCl at 0–5°С. The diazonium salt
formed in this case was without isolation subjected to a
reaction with an aqueous solution of NaN3. The presence of
the azido group in compounds 5, 6 was determined by the
appearance of characteristic absorption bands in the IR
spectrum at 2125 and 2150 cm–1. An additional
confirmation of the presence of the azido group in
compound 6 is the signal at –138.07 ppm in the 14N NMR
spectrum.
Attempts to directly access 5-(4-phenyl-1H-1,2,3-triazol-
1-yl)-1H-pyrazole-3-carboxylic acid by cycloaddition
of phenylacetylene to azido acid 5 were unsuccessful
(Scheme 1). The reactions of equimolar amounts of azide 5
and phenylacetylene were carried out in the presence of
CuSO4·5H2O (1–10 mol %) and Na ascorbate (5–30 mol %)
in t-BuOH–H2O, 1:1 or MeOH–H2O, 1:1 at 20–60°С in an
inert atmosphere for 1–5 days. In no case was triazole
formation observed; only the starting reagents were
isolated. The reason for this is probably the coordination of
Cu(I) ions with azido acid 5 and their removal from the
reaction. The coordination of Cu(I) ions prevents the
formation of copper acetylenides, which is a prerequisite in
the mechanism of copper-catalyzed azide-alkyne cyclo-
addition (CuAAC) (Scheme 1). Another reason for the
unsuccessful reaction may be the high value of the stability
constant of the pyrazolecarboxylic acid complex with the
Cu(II) ion, which also removes the catalytically active
M
O
O
O
O
Figure 1. Design of bispyrazolecarboxylates. The core is
bispidine derivatives, the linker is triazole.
A review of the literature showed that 1-(1H-pyrazol-
5-yl)-1H-1,2,3-triazoles have been little studied: there are
only a few examples of the synthesis of 1-(1H-pyrazol-5-yl)-
1H-1,2,3-triazoles;9–15 derivatives of 1-(1H-pyrazol-4-yl)-
1H-1,2,3-triazoles have not been studied at all. Moreover,
derivatives of 1-(1H-pyrazol-5-yl)-1H-1,2,3-triazoles con-
taining the MeSO2 pharmacophore group have proven them-
selves as potential selective inhibitors of human cyclo-
oxygenase-2 (COX-2) with excellent anti-inflammatory
activity at the level of clinically used anti-inflammatory drugs.9
The goal of this work was to obtain novel ligands based
on N-unsubstituted 1H-pyrazole-3(5)-carboxylic acids
containing the triazole fragment at position 3(5) or 4, as
well as to study the possibility of joining pyrazole-
carboxylic acids with 3,7-diazabicyclo[3.3.1]nonane-type
framework structures to create polychelating ligands. The
presence of an unsubstituted nitrogen atom in the pyrazole
ring of the target compounds is important because it creates
additional opportunities for functionalization.16,17
It should be noted that 5-(1H-1,2,3-triazol-1-yl)-1H-
pyrazole-3-carboxylic acids and 4-(1H-1,2,3-triazol-1-yl)-
1H-pyrazole-3-carboxylic acids, as well as the correspond-
ing carboxylates are not described in the literature.
In our opinion, the optimal approach for the synthesis of
triazolylpyrazoles is based on the use of the corresponding
azidopyrazoles, since the introduction of a triple bond into
N-unsubstituted pyrazolecarboxylates is synthetically more
complicated than the introduction of the azido group.18,19
Despite the fact that N-unsubstituted azidopyrazoles are
well studied,10,20 azidopyrazolecarboxylic acids and their
derivatives are not described. Therefore, the first objective
of this work was the development of methods for
introducing the azido group into N-unsubstituted pyrazole-
carboxylic acids.
Scheme 1
181

Chemistry of Heterocyclic Compounds 2020, 56(2), 180–191
metal from the reaction. To prevent coordination of Cu
2120 cm–1, indicative of the absence of an azido group in
this structure. The presence in the mass spectrum of
compound 8 of [M]+ signals with m/z 189 and 191 with an
intensity ratio of 3:1 confirms the presence of a chlorine
atom.
No examples of such transformations have been found
in the literature for pyrazoles. Some studies have shown a
possible mechanism for a similar acid-catalyzed conversion
of aryl azides to amines.28–30 It should be noted that this
transformation is observed only during the esterification of
azido acid 6 with an azido group in position 4 of the
pyrazole ring and is not observed in the case of the
presence of an azido group in position 5 (for azido acid 5)
A study of the limits of applicability of the new reaction to
other pyrazole systems will be the subject of a separate
publication.
ions, it was decided to esterify the carboxyl group of azido
acids 5, 6. Ethyl 5-azido-1H-pyrazole-3-carboxylate (7)
was obtained in 84% yield by heating the corresponding
azido acid 5 in unhydrous EtOH under reflux in the
presence of 2 equiv of SOCl2 for 4 h (Scheme 2). The
isolated product did not require additional purification. An
attempt to obtain ethyl 4-azido-1H-pyrazole-3-carboxylate
(10) from the corresponding azido acid 6 by a similar
method led to an unexpected result. Instead of the expected
ethyl azidocarboxylate 10, heating azido acid 6 in unhydrous
EtOH in the presence of 2 equiv SOCl2 afforded amino
chloro derivative 8 with a yield of 86% as the sole product.
Scheme 2
N3
N3
SOCl2
CO2Et
CO2Et
CO2H
CO2H
In order to avoid such reactions, the synthesis strategy of
ethyl azidocarboxylate 10 was changed. It was decided first
to esterify the corresponding amino acid 4 with the
formation of ethyl 4-amino-1H-pyrazole-3-carboxylate (9)
and its subsequent conversion to azidocarboxylate 10
(Scheme 2). Ethyl 4-amino-1H-pyrazole-3-carboxylate (9)
was obtained in the form of hydrochloride with a
quantitative yield by heating amino acid 4 in the presence
of an equivalent amount of SOCl2 in absolute EtOH for
12 h. The structure of the product was confirmed by
1H and 13C NMR spectroscopy. Ethyl 4-azido-1H-pyrazole-
3-carboxylate (10) was obtained by diazotization of the
corresponding aminocarboxylate 9 with NaNO2 in 2 M
aqueous HCl at 0–5°С. The diazonium salt formed in this
case, without isolation, was subjected to a reaction with
NaN3 in the form of an aqueous solution. The product was
isolated in 65% yield and did not require further
purification. The substance was fully characterized using
1H, 13C NMR, IR spectroscopy, high-resolution mass
spectrometry, and elemental analysis. The formation of the
azido group was determined by the appearance of the
absorption band in the IR spectrum (2101 cm–1)
corresponding to the azido group.
NH
NH
EtOH, , 4 h
84%
N
N
7
5
N3
H2N
SOCl2
Cl
EtOH, , 4 h
86%
N
N
N
HN
HN
6
8
–Cl+H3N
H2N
CO2H
SOCl2
CO2Et
EtOH, , 12 h
99%
HN
4
N
HN
9
1. 2 M HCl, NaNO2
0–5°C, 30 min
N3
CO2Et
2. NaN3, H2O, 3–4 h
65%
HN
10
N
The proposition of the formation of an amino chloro
derivative with structure 8 was made on the basis of the
obtained 1H, 13C NMR, IR spectroscopy, and mass spectro-
1
1
metry data. The H NMR spectrum of compound 8 shows
In the H and 13C NMR spectra of 4-azido-substituted
signals at 4.28 ppm (2H, q, J = 7.1 Hz) and 1.28 ppm (3H,
t, J = 7.1 Hz) indicating the formation of an OCH2CH3
fragment, an NH2 group signal at 4.84 ppm (2H, br. s), and
a singlet at 13.19 ppm with an intensity of 1H,
corresponding to the proton at the nitrogen atom of the
pyrazole ring. In this case, there is no signal of a proton at
the carbon atom in the pyrazole ring in the aromatic region,
which indicates its possible substitution. The 13C NMR
spectrum shows a signal at 159.3 ppm corresponding to the
carboxylate carbon atom COOСН2СН3, signals of three
carbon atoms of the pyrazole ring at 131.9, 126.5, and
117.3 ppm, as well as signals of the СН2СН3 fragment at
60.2 and 14.3 ppm. The arrangement of the substituents in
the ring is confirmed by comparing the obtained signals of
the carbon atoms of the pyrazole ring with those described
in the literature for similar amino chloro derivatives.25–27 In
the IR spectra of the starting azido acid 6 and the obtained
amino chloro derivative 8, absorption bands of the carbonyl
group are observed at 1710 cm–1. However, in comparison
with the IR spectrum of compound 6, the IR spectrum of
compound 8 does not have an absorption band at 2160–
pyrazolecarboxylic acids and their esters, strongly
broadened signals were observed due to slow (in the NMR
time scale) dynamic processes, which did not allow reliable
determination of the structure of these compounds. To
establish the reason for the existence of the dynamic
phenomena in the NMR spectra, as well as an
unambiguous correlation between the signals of protons
and carbon atoms in the 1H and 13C NMR spectra of
1
1
compounds 6, 7, and 10, Н–13С HSQC, H–13C HMBC,
1H–15N HMBC experiments were performed, which
completely confirmed the structure of the obtained
compounds.
Our approach to use esters of the azido acids, not acids
themselves in the cycloaddition reactions turned out to be
successful.
The addition of phenylacetylene to ethyl azidocarb-
oxylate 7 in the presence of CuSO4·5H2O (5 mol %) and
Na ascorbate (10 mol %) was carried out in t-BuOH–H2O,
1:1 system under an inert atmosphere. At room
temperature, the addition proceeds very slowly, so it was
decided to increase the temperature of the reaction mixture
182

Chemistry of Heterocyclic Compounds 2020, 56(2), 180–191
(60°C). Under such conditions, the reaction was complete
isomeric triazolylcarboxylates 11a–d. Due to poor
solubility of ethyl azidocarboxylate 10 in t-BuOH, all
acetylene addition reactions were carried out in MeOH–
H2O, 1:1 system under an inert atmosphere (Scheme 4).
The addition of phenylacetylene to azidocarboxylate 10
in the presence of CuSO4·5H2O (5 mol %) and Na ascorbate
(10 mol %) requires more drastic conditions than in the
case of azidocarboxylate 7. The reaction proceeds with
complete conversion of azide 10 at 60°C in 48 h. Product
13a was isolated in 66% yield. The addition of ethyl azido-
carboxylate 10 to an equimolar amount of propargyl
alcohol both at room temperature and when heated to 60°C
occurred with incomplete conversion of azide 10, as in the
case of azide 7. Therefore, a fourfold excess of propargyl
alcohol was employed, in which case the reaction took
place at 60°С in 16–17 h with complete conversion of the
azide producing triazole 13b in 31% yield. The low yield
of the product is probably due to its good solubility in H2O,
which makes it difficult to isolate. In the 1H NMR
spectrum, individual broadened signals are observed in the
region of NH protons and pyrazole protons with the ratio of
intensities of 0.2 to 0.8 with the total intensity of one
proton each. The explanation for this observation may be
the presence of two NH tautomers. The remaining signals
of both tautomers coincide. Triazole 13c was obtained by
addition of an equimolar amount of methyl propiolate to
azide 10. The reaction readily proceeds at 25°C with
complete conversion in 16 h. The yield of the cor-
responding triazole 13c was 82%. The addition of cyclo-
pentylacetylene to azide 7 was only possible upon heating.
The reaction proceeds completely in 72 h at 60°C. The
corresponding triazole 13d was isolated in 22% yield.
in 10–12 h. Triazole 11a was isolated in 57% yield.
Triazoles 11b–c were obtained similarly (Scheme 3). The
addition of ethyl azidocarboxylate 7 to an equimolar
amount of propargyl alcohol both at room temperature and
at 60°C resulted in an incomplete conversion of azide 7.
Therefore, we took a fourfold excess of propargyl alcohol;
in this case, the reaction took place at 60°C in 10–12 h with
a complete conversion of azide and with an 86% yield of
triazole 11b. Triazole 11c was obtained by addition of an
equimolar amount of methyl propiolate to azide 7. The
reaction readily proceeds with complete conversion at 25°C
in 12 h. The yield of the corresponding triazole 11c was
also 86%. The addition of cyclopentylacetylene to azide 7
at room temperature is slow. Even after a week, complete
conversion of the azide was not observed. It was decided to
carry out the reaction by heating. Indeed, when heated to
60°С, the reaction proceeds completely in 10–12 h. The
corresponding triazole 11d was isolated in 91% yield. In all
cases, compounds 11a–d formed as the only products and
did not require additional purification.
The products were identified by the appearance of
triazole proton signals in the 9.28–8.40 ppm range and
signals of the R substituents of the triazole fragment in the
1H NMR spectrum, as well as the disappearance of the
absorption band of the azido group in the IR spectrum at
2160–2120 cm–1. In the 13C NMR spectrum, the signals of
the carbon atoms of the pyrazole and triazole rings are
observed in the 152.0–99.4 ppm range. In addition, the
structure of the obtained compounds was confirmed by
high-resolution mass spectrometry and elemental analysis.
Compounds 12a–d were obtained by alkaline hydrolysis
of the corresponding triazolylcarboxylates 11a–d by
treatment with aqueous KOH (3 equiv) at 60°С for 12 h,
followed by acidification with 2 M aqueous HCl to pH 1.
The formed precipitate was filtered off. The corresponding
5-(1H-1,2,3-triazol-1-yl)-1H-pyrazole-3-carboxylic acids
12a–d were isolated in 56–80% yields (Scheme 3). The
Scheme 4
1
structure of compounds 12a–d was determined by H, 13C
NMR, IR spectroscopy and confirmed by high-resolution
mass spectrometry, and, for compounds 12a,c, also by
elemental analysis.
4-(1H-1,2,3-Triazol-1-yl)-1H-pyrazole-3-carboxylates
13a–d were obtained analogously to the preparation of the
Scheme 3
The products were identified by the appearance of
1
triazole proton signals in the H NMR spectrum in the
9.15–8.18 ppm range and signals of the R substituents of
the triazole fragment, as well as the disappearance of the
absorption band of the azide group in the IR spectrum at
2160–2120 cm–1. It should be noted that, in contrast to the
1H and 13C NMR spectra of the isomeric triazolyl-
1
carboxylates 11a–d, the H NMR spectra of compounds
13a–d show a strongly broadened signal of the pyrazole
proton in the range of 8.55–8.28 ppm, while the 13C NMR
183

Chemistry of Heterocyclic Compounds 2020, 56(2), 180–191
spectra exhibit strongly broadened signals of carbon atoms
introduction into the subsequent hydrolysis reaction, bis-
triazolylpyrazolecarboxylates 17 and 19 must be
thoroughly purified of traces of Cu(II) either by washing
with a large amount of H2O or by passing through a short
column with silica gel using CHCl3–MeOH, 1:5 as an
eluent.
of the triazole and pyrazole rings in the 150.8–120.3 ppm
range. The signal broadening is probably related either to
the existence of products in two tautomeric forms, which
correlates with 1H and 13C NMR spectra of the correspond-
ing azidocarboxylates 6 and 10 or to intramolecular
dynamic processes due to steric constraints.
Bistriazolylpyrazolecarboxylic acid 18 was obtained by
alkaline hydrolysis of carboxylate 17 at 70°C for 1 day,
followed by acidification with 2 M aqueous HCl. It turned
out that in order to achieve a good result, it is very
important to carefully acidify to at least pH 3–4, since it is
in this case that a precipitate forms, which is then filtered.
In a more acidic environment, the product turns into a
water-soluble protonated form, which greatly complicates
the isolation of the product which is free of inorganic salts.
Target compound 18 was isolated in 68% yield. The
Compounds 14a–d were obtained via alkaline hydro-
lysis of the corresponding triazolylcarboxylates 13a–d by
treatment with an aqueous KOH solution (3 equiv) at 70°С
for 12 h, followed by acidification with 2 M aqueous HCl
solution to pH 1. The formed precipitate was filtered off. The
corresponding 4-(1H-1,2,3-triazol-1-yl)-1H-pyrazole-3-carb-
oxylic acids 14a–d were isolated in 55–79% yields. The
1
structure of compounds 14a–d was determined by H, 13C
NMR, IR spectroscopy and confirmed by high-resolution
mass spectrometry.
1
structure of the product was established by IR, H, 13C
To synthesize bispyrazolecarboxylic acids 18 and 20
based on 3,7-diazabicyclo[3.3.1]nonanes, we used the
method that we developed earlier by introducing
azidopyrazolecarboxylates into the [3+2] cycloaddition
reaction, namely, joining of the bispidine framework with
pyrazole moieties via triazole linkers. In order to achieve
this, a method was developed for introducing acetylene
fragments into bispidine by bis-N-alkylation with propargyl
bromide. 1,5-Dimethylbispidin-9-one (15) was taken as the
starting framework (Scheme 4), which we already obtained
previously according to a published procedure.31 Bispropar-
gylation of bispidine 15 was carried out by heating in
MeCN under reflux in the presence of 2 equiv of propargyl
bromide and 2 equiv DIPEA for 10 h. Purification of the
isolated bispropargylbispidine 16 was carried out using
column chromatography. The yield of pure product was
73% (Scheme 5). Bistriazolylpyrazole carboxylate 17 was
obtained by addition of 2 equiv of azidopyrazole carb-
oxylate 7 to bispropargylbispidine in an inert atmosphere in
the t-BuOH–H2O, 1:1 system in the presence of
CuSO4·5H2O (5 mol %) and Na ascorbate (10 mol %).
The reaction proceeds at room temperature for 48 h with a
good yield (88%). Compound 17 is formed as the only
product. Bistriazolylpyrazolecarboxylate 19 was obtained
by addition of 2 equiv of azidopyrazolecarboxylate 10 to
bispropargylbispidine 16 in an inert atmosphere in the
MeOH–H2O, 1:1 system in the presence of CuSO4·5H2O
(5 mol %) and Na ascorbate (10 mol %). The reaction
proceeds at room temperature for 12 h also with a good
yield (78%). Compound 19 formed as the only product.
The products were identified by the appearance of
triazole proton signals in the 1H NMR spectrum at 8.51 ppm
for compound 17 and at 8.32 ppm for compound 19, the
appearance of signals of pyrazole fragments and the
disappearance of the signal of acetylene protons, as well as
the disappearance of the absorption band of the azide group
NMR spectroscopy and confirmed by high-resolution mass
spectrometry. The results of elemental analysis suggest that
the compound crystallizes in the form of hydrate 18·4H2O.
During the synthesis of bistriazolylpyrazolecarboxylic
acid 20 by alkaline hydrolysis of the corresponding
carboxylate 19 by a similar method, great difficulties arose
at the product isolation step. When acidified with 2 M
aqueous HCl, it was not possible to select a suitable pH
value of the medium at which an unprotonated form exists.
At pH 5–6, a precipitate formed, which contained a
partially protonated form of the product. At lower pH
values, the product was completely converted to a
protonated water-soluble form. In order to exclude the
formation of inorganic salts and facilitate the isolation of
the product, it was decided to obtain the target bis-
triazolylpyrazolecarboxylic acid 20 by hydrolysis of
carboxylate 19 in an acidic medium. Compound 20 was
obtained by heating carboxylate 19 under reflux for 4 h in
concentrated HCl with addition of glacial AcOH (1:1) to
ensure good solubility (Scheme 5). The structure of the
product was established by IR, 1H, 13C NMR spectroscopy,
and confirmed by high-resolution mass spectrometry. In the
1H NMR spectrum, there is a signal of the methyl group of
AcOH at 1.90 ppm in a 1:1 ratio in respect to the signals of
compound 20, which does not change even after prolonged
drying of the product under reduced pressure at 80°C. The
results of elemental analysis allow us to propose the
following composition of the product: 20·3HCl·AcOH.
Probably, three HCl molecules protonate the three main
centers of the molecule, and AcOH is located in the cavity
of the molecule, which thus acts as a receptor.
An unexpected additional confirmation of certain
receptor properties of compounds 18 and 20 was found
when studying their solubility in DMF, which was carried
out in order to obtain single crystals suitable for X-ray
structural analysis. Upon evaporation of the solution of
acid 18 and subsequent drying under reduced pressure of
the obtained solid sample it was found (by NMR
spectroscopy) that the resulting dry product contained a
complex of composition 18·DFM. If similar manipulations
are carried out with a product of the composition
20·3HCl·AcOH, then the replacement of the AcOH
molecule with the DMF molecule is clearly seen from the
NMR spectrum.
1
in the IR spectrum at 2160–2120 cm–1. In the H NMR
spectrum of compound 19, a strongly broadened signal of
the pyrazole proton is observed at 8.36 ppm, which is super-
imposed on the signal of the triazole proton at 8.32 ppm.
The structure of the obtained compounds was also
established using 13C NMR spectroscopy and confirmed by
high-resolution mass spectrometry, and for compound 17,
by elemental analysis. It is worth noting that before
184

Chemistry of Heterocyclic Compounds 2020, 56(2), 180–191
CO2Et
N
Scheme 5
Br
7
N
N
N
H
HC
DIPEA
CH
CH
CuSO4·5H2O
Na ascorbate
Me
Me
Me
Me
Me
NH
NH
N
N
N
N
N
O
O
O
t-BuOH–H2O, 1:1
MeCN, , 10 h
73%
N
N
N
Me
48 h
88%
H
N
15
16
17
N
10, CuSO4·5H2O
Na ascorbate
MeOH–H2O, 1:1
12 h
1. KOH, H2O
70°C, 24 h
2. 2 M HCl
68%
CO2Et
CO2H
H
N
N
78%
N
N
CO2Et
N
Me
O
N
N
N
N
N
N
H
Me
O
N
N
N
N
Me
N
N
CO2Et
N
N
19
N
N
Me
H
N
18
concd HCl
AcOH
, 4 h
N
N
H
H
CO2H
N
84%
N
N
N
CO2H
Me
O
N
N
N
N
Me
N
N
CO2H
N
20
N
H
1
To conclude, we have developed methods for the
synthesis of previously unknown N-unsubstituted 5- and
4-azido-1H-pyrazole-3-carboxylic acids from the cor-
responding available amino derivatives. The possibility of
catalytic cycloaddition of alkynes with substituents of
various nature with the formation of the corresponding
triazoles was studied. For the first time, joining of
bispidines with azoles was carried out using the copper-
catalyzed [3+2] cycloaddition reaction. Along with the
successful synthesis of the target compounds, we
established fundamental spectral differences as well as
differences in the reactivity of 5- and 4-azido-1H-pyrazole-
3-carboxylates. For the first time, additional two-
dimensional NMR experiments were carried out for these
compounds, which made it possible to unequivocally
establish their structures.
spectrometer in DMSO-d6. For Н and 13С nuclei, TMS
was used as internal standard, for 14N nuclei, nitromethane
was used. Mass spectra were recorded on a Finnigan MAT
INCOS-50 (direct injection, EI ionization, 70 eV) mass
spectrometer. High-resolution mass spectra were recorded
on a Bruker MicroOTOFII mass spectrometer with
electrospray ionization. Elemental analysis was performed
on a PerkinElmer Series II 2400 CHNS/O analyzer.
Melting points were determined by the capillary method on
Stuart SMP20 and Electrothermal IA9000 apparatuses.
Monitoring of the reaction progress and assessment of the
purity of synthesized compounds were done by TLC on
Merck TLC Silica gel 60G F254 plates. Carl Roth Silica
gel 60, 0.04–0.063 mm was used for column chromato-
graphy.
All reagents and solvents used in the work (purity 90.0–
99.9+ %) were supplied by commercial sources (Sigma-
Aldrich, abcr, IREA 2000), and, if necessary, subjected to
further purification by standard routines immediately
before use to achieve analytical purity.
Experimental
IR spectra were registered on a Thermo Scientific
Nicolet iS5 FTIR spectrometer with iD1 Transmission and
1
iD7 ATR (diamond) accessories. H and 13C NMR spectra
5-Nitro-1Н-pyrazole-3-carboxylic acid (1) was
obtained from 3(5)-methyl-1Н-pyrazole (41 g) according to
published methods.22,23 Yield of the oxidation step 33 g
(85%), mp 175–176°С (mp 174–175°С23). 1H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 15.02 (2H, br. s,
NH, COOH); 7.41 (1H, s, Н-4 pyrazole).
were acquired on Bruker Avance 400 (400 and 101 MHz,
respectively), Bruker DRX-500 (500 and 126 MHz,
respectively), Bruker AM-300 (300 and 75 MHz,
respectively), and Bruker Avance IIIHD 500 (500 and
126 MHz, respectively) spectrometers at 298 К (unless
other temperature is indicated). 14N NMR spectrum of
compound 6 was registered on a Bruker DRX-500 (36 MHz)
4-Nitro-1Н-pyrazole-3-carboxylic acid (3) was
obtained from 3(5)-methyl-1Н-pyrazole (30 g) according to
185

Chemistry of Heterocyclic Compounds 2020, 56(2), 180–191
a published method.24 Combined yield over nitration and
13.14 (2Н, br. s, NH, COOH); 7.69 (1H, s, Н-5 pyrazole).
13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 161.5;
129.6 (br. s); 124.2. 13C NMR spectrum (126 MHz,
DMSO-d6, 343 K), δ, ppm: 161.4; 130.5; 128.7; 124.2.
14N NMR spectrum, δ, ppm: –138.07 (N3). Found, m/z:
154.0354 [M+H]+. C4H4N5O2. Calculated, m/z: 154.0360.
Found, %: C 31.43; H 1.83; N 45.74. С4H3N5O2.
Calculated, %: C 31.38; H 1.98; N 45.74.
oxidation steps 34 g (59%), colorless solid, mp 208–209°С
(mp 206–208°С24).
Synthesis of 5- and 4-amino-1Н-pyrazole-3-carboxy-
lic acids 2, 4 (General method). Reduction of the nitro
group was carried out according to a published method.21
The corresponding nitro acid 1, 3 (0.032 mol) was
suspended in H2O (30 ml). Activated carbon (0.8 g),
N2H4·H2O (95%, ρ 1.023 g/cm3) (6.55 ml, 6.71 g, 0.134 mol),
and FeCl3·6H2O (64 mg) were added to the suspension with
stirring. The reaction mixture was heated under reflux for
30 h. The hot solution was filtered, the filtrate was
evaporated to dryness under reduced pressure. The
resulting dry residue was dissolved in H2O (20 ml) and
carefully acidified with 2 M aqueous HCl to pH 4–5. The
formed precipitate was filtered off and washed with a small
amount of H2O. The product was dried in a vacuum
desiccator over P2O5 to constant weight.
Ethyl 5-azido-1Н-pyrazole-3-carboxylate (7). 3-Azido-
1Н-pyrazole-5-carboxylic acid (5) (1.5 g, 0.0098 mol) was
dissolved in absolute EtOH (20 ml). SOCl2 (1.45 ml, 2.38 g,
0.020 mol) was added dropwise to the solution, and the
mixture was heated under reflux for 4 h. The solvent was
evaporated under reduced pressure on the rotary
evaporator. H2O was added to the solid residue, and the
mixture was extracted with EtOAc. The organic phase was
separated and dried over anhydrous Na2SO4, then
evaporated under reduced pressure. Yield 1.51 g (84%),
yellow solid, mp 92–93°С. IR spectrum, ν, cm−1: 3261
(NH), 2125 (N3), 1701 (C=O). 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm (J, Hz): 13.92 (1Н, s, NH);
6.55 (1H, s, Н-4 pyrazole); 4.30 (2Н, q, J = 7.1,
OCH2СH3); 1.28 (3H, t, J = 7.2, OCH2СH3). 13C NMR
spectrum (101 MHz, DMSO-d6), δ, ppm: 158.4; 147.5;
135.1; 98.7; 61.2; 14.1. Found, m/z: 182.0671 [M+H]+.
C6H8N5O2. Calculated, m/z: 182.0673. Found, %: C 39.84;
H 3.80; N 38.22. С6H7N5O2. Calculated, %: C 39.78;
H 3.90; N 38.66.
5-Amino-1Н-pyrazole-3-carboxylic acid (2). Yield
1
3.25 g (80%), colorless solid, mp 245–246°С. H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 5.77 (1H, s, Н-4
pyrazole). 13C NMR spectrum (126 MHz, DMSO-d6),
1
δ, ppm: 162.2; 152.8; 138.3; 92.3. H NMR spectrum and
mp of the obtained compound correspond to the published
data.23
4-Amino-1Н-pyrazole-3-carboxylic acid (4). Yield
3.05 g (75%), purple solid, mp 212–213°С. 1H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 7.05 (1Н,
s, Н-5 pyrazole); 5.23 (2H, br. s, NH2). 13C NMR spectrum
(75 MHz, DMSO-d6), δ, ppm: 162.4; 136.2; 125.5; 119.5.
Synthesis of 5- and 4-azido-1Н-pyrazole-3-carboxylic
acids 5, 6 (General method). The corresponding amino acid
2, 4 (0.0173 mol) was dissolved in 2 М aqueous НСl (50 ml),
and the formed solution was cooled to 0°С in an ice bath.
Aqueous NaNO2 (0.019 mol) was dropwise added to the
reaction mixture. The mixture was stirred for 30 min, then
aqueous NaN3 (0.026 mol) was carefully added. The
reaction mixture was stirred for 3–4 h. The formed precipi-
tate was filtered off on a fritted glass filter and washed with
a small amount of H2O, then dried in a vacuum desiccator
over P2O5 to constant weight. The filtrate was extracted
with EtOAc, the organic phase was separated and dried
over anhydrous Na2SO4. The dried organic phase was
evaporated under reduced pressure on the rotary evaporator
to afford a solid. Both solids were combined.
Ethyl
4-amino-5-chloro-1Н-pyrazole-3-carboxylate
(8). 4-Azido-1Н-pyrazole-3-carboxylic acid (6) (1.19 g,
0.0078 mol) was dissolved in absolute EtOH (25 ml). SOCl2
(1.3 ml, 2.14 g, 0.0179 mol) was added dropwise to the
solution, and the mixture was heated under reflux for 4 h.
The reaction mixture was evaporated to dryness on the
rotary evaporator under reduced pressure, washed with a small
amount of H2O, and extracted with EtOAc. The organic
phase was separated and dried over anhydrous Na2SO4.
The dried extract was evaporated to dryness under reduced
pressure. The resulting brown oil was dried to constant
weight in a vacuum desiccator over P2O5. The product
gradually crystallizes upon standing. Yield 1.27 g (86%),
yellow solid, mp 101–102°С. IR spectrum, ν, cm−1: 3407
(NH2), 1710 (C=O). 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 13.19 (1H, br. s, NH); 4.84 (2H, br. s,
NH2); 4.28 (2H, q, J = 7.1, OCH2СH3); 1.28 (3H, t, J = 7.1,
OCH2СH3). 13C NMR spectrum (101 MHz, DMSO-d6),
δ, ppm: 159.3; 131.9; 126.5; 117.3; 60.2; 14.3. Mass
spectrum, m/z (Irel, %): 189 [М]+ (64), 191 [M]+ (21), 161
[M–C2H4]+ (35), 143 [M–EtOH]+ (100). Found, m/z:
212.01967 [M+Na]+. C6H8ClN3NaO2. Calculated, m/z:
212.01972.
5-Azido-1Н-pyrazole-3-carboxylic acid (5). Yield 2.32 g
(87%), yellow solid, mp 164–165°С. IR spectrum, ν, cm−1:
1
3309 (NH), 3101 (OH), 2125 (N3), 1675 (C=O). H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 13.76 (2Н, br. s,
NH, COOH); 6.48 (1H, s, Н-4 pyrazole). 13C NMR
spectrum (101 MHz, DMSO-d6), δ, ppm: 160.3; 147.6;
136.9; 98.9. Found, m/z: 154.0363 [M+H]+. C4H4N5O2.
Calculated, m/z: 154.0360. Found, %: C 31.51; H 1.82;
N 45.37. С4H3N5O2. Calculated, %: C 31.38; H 1.98;
N 45.74.
Ethyl 4-amino-1Н-pyrazole-3-carboxylate hydro-
chloride (9). Amino acid 4 (2 g, 0.0157 mol) was
suspended in absolute EtOH (20 ml). SOCl2 (1.17 ml,
1.92 g, 0.0161 mol) was added dropwise to the suspension.
The mixture was heated under reflux for 12 h until
homogenization. A cherry-colored solution formed. The
solvent was evaporated to dryness under reduced pressure
on the rotary evaporator. The solid residue was dried in a
vacuum desiccator to constant weight. Yield 3.0 g (99%),
4-Azido-1Н-pyrazole-3-carboxylic acid (6). Yield 1.88 g
(71%), brown solid, mp 139–140°С. IR spectrum, ν, cm−1:
3249 (NH), 3145 (COOH), 2150 (N3), 1710 (C=O).
1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm: 13.46
(2Н, br. s, NH, COOH); 7.75 (1H, s, Н-5 pyrazole).
1H NMR spectrum (500 MHz, DMSO-d6, 343 K), δ, ppm:
1
pink solid, mp 114–115°C. H NMR spectrum (400 MHz,
186

Chemistry of Heterocyclic Compounds 2020, 56(2), 180–191
+
DMSO-d6), δ, ppm (J, Hz): 10.22 (4Н, br. s, NH, NH3);
J = 7.3, H Ph); 7.23 (1H, s, Н-4 pyrazole); 4.37 (2Н, q,
J = 7.0, OCH2CH3); 1.34 (3H, t, J = 7.07, OCH2CH3).
13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm: 158.3;
146.9; 146.3; 135.4; 130.0; 129.0; 128.4; 125.5; 119.5; 99.7;
61.5; 14.1. Found, m/z: 284.1140 [M+H]+. C14H14N5O2.
Calculated, m/z: 284.1142. Found, %: C 58.86; H 4.55;
N 24.97. С14H13N5O2. Calculated, %: C 59.36; H 4.63;
N 24.72.
Ethyl 5-[4-(hydroxymethyl)-1Н-1,2,3-triazol-1-yl]-1Н-
pyrazole-3-carboxylate (11b). Yield 347 mg (86%),
yellow solid, mp 223–224°С. IR spectrum, ν, cm−1: 3384
(OH), 3218 (NH), 1701 (C=O). 1H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm (J, Hz): 14.45 (1Н, s, NH); 8.48 (1H, s,
Н-5 triazole); 7.19 (1H, s, Н-4 pyrazole); 5.31 (1H, t,
J = 5.6, СН2OH); 4.60 (2H, d, J = 4.2, СН2OH); 4.36 (2H,
q, J = 6.8, OCH2CH3); 1.33 (3H, t, J = 6.7, OCH2CH3).
13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm: 158.3;
148.7; 146.4; 135.3; 121.0; 99.6; 61.4; 54.8; 14.1. Found,
m/z: 238.0937 [M+H]+. C9H12N5O3. Calculated, m/z:
238.0935.
8.03 (1H, s, Н-3 pyrazole); 4.28 (2Н, q, J = 7.0,
OCH2СH3); 1.30 (3Н, t, J = 7.1, OCH2СH3). 13C NMR
spectrum (101 MHz, DMSO-d6), δ, ppm: 160.5; 133.7;
127.3; 116.6; 60.8; 14.1. Found, m/z: 178.05868 [M+Na]+.
C6H9N3NaO2. Calculated, m/z: 178.05870.
Ethyl
4-azido-1Н-pyrazole-3-carboxylate
(10).
Hydrochloride 9 (3 g, 0.0157 mol) was dissolved in 2 M
aqueous HCl (80 ml), and the solution was cooled to 0°С in
the ice bath. Aqueous NaNO2 (1.38 g, 0.02 mol) was added
dropwise to the solution. The mixture was stirred for 30 min,
then aqueous NaN3 (0.025 mol) was carefully added. The
reaction mixture was stirred for 3–4 h. The formed
precipitate was filtered off and washed with a small amount
of H2O, then dried in a vacuum desiccator over P2O5 to
constant weight. The filtrate was extracted with EtOAc, the
organic phase was separated and dried over anhydrous
Na2SO4. The dried organic phase was evaporated under
reduced pressure on the rotary evaporator to afford a solid.
Both solids were combined. Yield 1.86 g (65%), light-pink
solid, mp 122–123°C. IR spectrum, ν, cm−1: 3210 (NH), 2101
(N3), 1678 (C=O). 1H NMR spectrum (500 MHz, DMSO-d6),
δ, ppm (J, Hz): 13.97 (0.4H, br. s, NH); 13.64 (0.6Н, br. s,
NH); 7.92 (0.7H, br. s, Н-5 pyrazole); 7.68 (0.3H, br. s,
Н-5 pyrazole); 4.29 (2Н, q, J = 7.1, OCH2CH3); 1.29 (3Н,
Methyl 1-[3-(ethoxycarbonyl)-1Н-pyrazol-5-yl]-1Н-
1,2,3-triazole-4-carboxylate (11c). Yield 390 mg (86%),
beige solid, mp 190–191°С. IR spectrum, ν, cm−1: 3196
(NH), 1719 (С=О), 1684 (C=O). 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm (J, Hz): 14.59 (1Н, s, NH);
9.28 (1H, s, Н-5 triazole); 7.29 (1H, s, Н-4 pyrazole); 4.35
1
t, J = 7.0, ОСН2СН3). H NMR spectrum (500 MHz,
CDCl3), δ, ppm (J, Hz): 12.20 (1H, br. s, NH); 7.70 (1H, s,
Н-5 pyrazole); 4.50 (2Н, q, J = 7.1, OCH2CH3); 1.46 (3Н,
t, J = 7.0, ОСН2СН3). 13C NMR spectrum (126 MHz,
DMSO-d6), δ, ppm: 161.5; 158.5; 134.6; 133.8; 123.7;
60.9; 14.6. 13C NMR spectrum (126 MHz, CDCl3), δ, ppm:
160.8; 131.8; 126.6; 124.4; 61.6; 14.4. Found, m/z: 204.0496
[M+Na]+. C6H7N5NaO2. Calculated, m/z: 204.0492.
(2H, q,
t,
= 6.9, OСН2СН3). 13C NMR spectrum (101 MHz,
DMSO- 6), δ, ppm: 160.4; 158.2; 145.4; 139.2; 135.4;
J = 6.9, OCH2CH3); 3.86 (3H, s, OCH3); 1.33 (3H,
J
d
127.4; 100.6; 61.5; 52.1; 14.1. Found, m/z: 266.0886
[M+H]+. C10H12N5O4. Calculated, m/z: 266.0884. Found,
%: C 45.31; H 4.08; N 26.43. С10H11N5O4. Calculated, %:
C 45.29; H 4.18; N 26.41.
Synthesis of 5-(1Н-1,2,3-triazol-1-yl)-1Н-pyrazole-
3-carboxylates 11a–c (General method). Ethyl 5-azido-
1Н-pyrazole-3-carboxylate 7 (1.7 mmol) and the cor-
responding acetylene (phenylacetylene, propargyl alcohol,
methyl propiolate, and cyclopentylacetylene; in the case of
compound 11b, a 4-fold excess of propargyl alcohol was
used) (1.7 mmol) were dissolved in t-BuOH (4 ml). A
solution of Na ascorbate (34 mg, 0.17 mmol, 10 mol %) in
H2O (2 ml) was added with vigorous stirring to the reagent
solution. The flask was evacuated and filled with argon. A
solution of CuSO4·5H2O (21 mg, 0.085 mmol, 5 mol %) in
H2O (2 ml) was then added to the reaction mixture. The
reaction mixture was stirred at 60°С (for compounds
11a,b,d) and at 25°C (for compound 11c) for 12 h, and the
mixture was poured into ice water. The formed precipitate
was filtered off and washed with a small amount of H2O,
then dried in a vacuum desiccator over P2O5. The filtrate
was extracted with EtOAc, the organic phase was separated
and dried over anhydrous Na2SO4. The dried organic
phase was evaporated under reduced pressure on the
rotary evaporator to afford a solid. Both solids were
combined.
Ethyl
5-(4-cyclopentyl-1Н-1,2,3-triazol-1-yl)-1Н-
pyrazole-3-carboxylate (11d). Yield 425 mg (91%), beige
solid, mp 179–180°С. IR spectrum, ν, cm−1: 3246 (NH),
2955 (CH), 1711 (C=O). H NMR spectrum (400 MHz,
1
DMSO-d6), δ, ppm (J, Hz): 14.40 (1Н, s, NH); 8.40 (1H, s,
Н-5 triazole); 7.14 (1H, s, Н-4 pyrazole); 4.34 (2H, q,
J = 7.1, OCH2CH3); 3.16 (1Н, q, J = 7.4, CH cyclopentane);
2.06–1.96 (2H, m, CH2 cyclopentane); 1.74–1.60 (6H, m,
CH2 cyclopentane); 1.32 (3H, t, J = 7.1, ОСН2СН3).
13C NMR spectrum (75 MHz, DMSO-d6), δ, ppm: 158.4;
152.0; 146.8; 135.2; 119.2; 99.4; 61.4; 36.1; 32.7; 24.7;
14.1. Found, m/z: 276.1451 [M+H]+. С13H18N5O2.
Calculated, m/z: 276.1455.
Synthesis of 5-(1Н-1,2,3-triazol-1-yl)-1Н-pyrazole-
3-carboxylic acids 12a–d (General method). The
corresponding carboxylate 11a–d (0.0019 mol) was
dissolved in aqueous KOH (330 mg, 0.0059 mol; 25 ml of
solution). The formed solution was stirred at 60°С for 12 h.
Then, the solution was passed through a thin layer of silica
gel and acidified by 2 M aqueous HCl to рН 1. The formed
precipitate was filtered off and dried in a vacuum
desiccator over P2O5. The filtrate was extracted with
EtOAc, the organic phase was separated and dried over
anhydrous Na2SO4. The dried organic phase was
evaporated under reduced pressure on the rotary evaporator
to afford a solid. Both solids were combined.
Ethyl 5-(4-phenyl-1Н-1,2,3-triazol-1-yl)-1Н-pyrazole-
3-carboxylate (11a). Yield 275 mg (57%), beige solid,
mp 210–211°С. IR spectrum, ν, cm−1: 3203 (NH), 1710
1
(C=O). H NMR spectrum (400 MHz, DMSO-d6), δ, ppm
(J, Hz): 14.53 (1Н, s, NH); 9.19 (1H, s, Н-5 triazole); 7.97
(2Н, d, J = 7.5, H Ph); 7.48 (2H, t, J = 7.6, H Ph); 7.37 (1H, t,
5-(4-Phenyl-1Н-1,2,3-triazol-1-yl)-1Н-pyrazole-3-carb-
oxylic acid (12a). Yield 344 mg (71%), colorless solid,
187

Chemistry of Heterocyclic Compounds 2020, 56(2), 180–191
mp 269–270°С. IR spectrum, ν, cm−1: 3141 (NH), 2985
separated, and then dried over anhydrous Na2SO4 and
evaporated under reduced pressure on the rotary evaporator
to obtain a solid residue.
(OH), 1689 (C=O). 1H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm (J, Hz): 14.38 (1Н, s, NH); 13.88 (1H,
br. s, COOH); 9.18 (1H, s, Н-5 triazole); 7.98 (2Н, d,
J = 7.3, H Ph); 7.48 (2H, t, J = 7.5, H Ph); 7.37 (1H, t,
J = 7.3, H Ph); 7.19 (1H, s, Н-4 pyrazole). 13C NMR
spectrum (101 MHz, DMSO-d6), δ, ppm: 159.8; 146.9;
146.2; 136.5; 130.0; 129.0; 128.4; 125.5; 119.5; 99.6.
Found, m/z: 256.0834 [M+H]+. C12H10N5O2. Calculated, m/z:
256.0829.
Ethyl 4-(4-phenyl-1Н-1,2,3-triazol-1-yl)-1Н-pyrazole-
5-carboxylate (13a). Yield 617 mg (66%), beige solid,
mp 220–221°С. IR spectrum, ν, cm−1: 3240 (NH), 1703
1
(C=O). H NMR spectrum (400 MHz, DMSO-d6), δ, ppm
(J, Hz): 14.15 (1H, br. s, NH); 8.93 (1H, s, Н-5 triazole);
8.54 (1H, br. s, Н-3 pyrazole); 7.91 (2H, d, J = 7.6, H Ph);
7.48 (2H, t, J = 7.6, H Ph); 7.36 (1H, t, J = 7.4, H Ph); 4.20
(2H, q, J = 7.2, OCH2CH3); 1.12 (3H, t, J = 7.1,
OCH2CH3). 13C NMR spectrum (126 MHz, DMSO-d6),
δ, ppm: 160.5; 146.0; 136.0; 130.4; 129.0; 128.1; 125.2;
124.4; 121.1; 60.6; 13.7. Found, m/z: 284.1144 [M+H]+.
C14H14N5O2. Calculated, m/z: 284.1142.
5-[4-(Hydroxymethyl)-1Н-1,2,3-triazol-1-yl]-1Н-pyra-
zole-3-carboxylic acid (12b). Yield 318 mg (80%), orange
solid, mp 264–265°С. IR spectrum, ν, cm−1: 3213 (OH),
2971–2350 (COOH), 1699 (C=O). 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 14.27 (1Н, s, NH); 13.81
(1H, br. s, СООН); 8.45 (1H, s, Н-5 triazole); 7.11 (1H, s,
Н-4 pyrazole); 5.29 (1H, br. s, CH2OH); 4.58 (2H, s,
СН2OH). 13C NMR spectrum (101 MHz, DMSO-d6),
δ, ppm: 160.0; 148.7; 146.2; 136.6; 120.9; 99.4; 54.8.
Found, m/z: 210.0614 [M+H]+. C7H8N5O3. Calculated, m/z:
210.0622.
1-(3-Carboxy-1Н-pyrazol-5-yl)-1Н-1,2,3-triazole-4-carb-
oxylic acid (12c). Yield 340 mg (80%), colorless solid,
mp 190–191°C. IR spectrum, ν, cm−1: 3142 (NH), 3088–
2526 (COOH), 1694 (C=O). 1H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 14.38 (1Н, s, NH); 13.59 (2H, br. s,
СООН); 9.13 (1H, s, Н-5 triazole); 7.20 (1H, s, Н-4
pyrazole). 13C NMR spectrum (101 MHz, DMSO-d6),
δ, ppm: 161.4; 159.7; 145.5; 140.3; 136.6; 127.1; 100.4.
Found, m/z: 224.0414 [M+H]+. C7H6N5O4. Calculated, m/z:
224.0414.
5-(4-Cyclopentyl-1Н-1,2,3-triazol-1-yl)-1Н-pyrazole-
3-carboxylic acid (12d). Yield 263 mg (56%), colorless
solid, mp 244–245°С. IR spectrum, ν, cm−1: 3300 (NH),
3200–2574 (COOH), 2957 (cyclopentyl), 1664 (C=O).
1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz):
14.22 (1H, s, NH); 13.75 (1H, br. s, СООН); 8.38 (1H, s,
Н-5 triazole); 7.08 (1H, s, Н-4 pyrazole); 3.18 (1Н, q,
J = 7.9, CH cyclopentane); 2.06–1.97 (2H, m, CH2 cyclo-
pentane); 1.83–1.55 (6H, m, CH2 cyclopentane). 13C NMR
spectrum (126 MHz, DMSO-d6), δ, ppm: 159.8; 152.0;
146.4; 136.5; 119.2; 99.3; 36.1; 32.8; 24.7. Found, m/z:
248.1144 [M+H]+. С11H14N5O2. Calculated, m/z: 248.1142.
Synthesis of 4-(1Н-1,2,3-triazol-1-yl)-1Н-pyrazole-
3-carboxylate 13a–d (General method). Ethyl 4-azido-1Н-
pyrazole-3-carboxylate (10) (3.3 mmol) and the cor-
responding acetylene (phenylacetylene, propargyl alcohol,
methyl propiolate, and cyclopentylacetylene; in the case of
compound 13b, a 4-fold excess of propargyl alcohol was
used) (3.3 mmol) were dissolved in MeOH (15 ml). A
solution of Na ascorbate (67 mg, 0.33 mmol, 10 mol %) in
H2O (7.5 ml) was added with vigorous stirring to the
reagent solution. The flask was evacuated and filled with
argon. A solution of CuSO4·5H2O (43 mg, 0.17 mmol,
5 mol %) in H2O (7.5 ml) was then added to the reaction
mixture. The reaction mixture was stirred at 25°С for 48 h
(for compound 13a), 16 h (for compounds 13b,c), or at
60°C for 72 h (for compound 13d). The solvent was
removed from the reaction mixture under reduced pressure
on the rotary evaporator. The dry residue was extracted
with EtOAc, the organic layer was washed with H2O and
Ethyl
4-[4-(hydroxymethyl)-1Н-1,2,3-triazol-1-yl]-
1Н-pyrazole-5-carboxylate (13b). Yield 241 mg (31%),
pale-yellow solid, mp 164–165°C. IR spectrum, ν, cm−1:
3371 (ОН), 3247 (NH), 1705 (C=O). H NMR spectrum
1
(400 MHz, DMSO-d6), δ, ppm (J, Hz): 14.49 (0.2H, br. s,
NH); 14.04 (0.8H, br. s, NH); 8.45 (0.8H, br. s, Н-3
pyrazole); 8.12 (0.2Н, br. s, Н-3 pyrazole); 8.31 (1H, s, Н-5
triazole); 5.28 (1H, s, СН2ОН); 4.60 (2H, s, СН2ОН); 4.21
(2H, q, J = 7.1, ОСН2СН3); 1.18 (3H, t, J = 7.1,
ОСН2СН3). 13C NMR spectrum (126 MHz, DMSO-d6),
δ, ppm: 160.6; 147.7; 135.7; 127.9; 125.5; 121.4; 60.6;
54.9; 13.8. Found, m/z: 238.0936 [M+H]+. C9H12N5O3.
Calculated, m/z: 238.0935.
Methyl 1-[5-(ethoxycarbonyl)-1Н-pyrazol-4-yl]-1Н-
1,2,3-triazole-4-carboxylate (13c). Yield 718 mg (82%),
colorless solid, mp 195–196°C. IR spectrum, ν, cm−1: 3150
(NH), 1740 (C=O), 1703 (C=O). 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm (J, Hz): 14.14 (1H, br. s,
NH); 9.15 (1H, s, Н-5 triazole); 8.55 (1H, s, Н-3 pyrazole);
4.16 (2H, q, J = 7.1, OCH2CH3); 3.86 (3H, s, OCH3); 1.12
(3H, t, J = 7.0, OCH2CH3). 13C NMR spectrum (126 MHz,
DMSO-d6), δ, ppm: 160.6; 160.4; 138.3; 136.0; 132.0;
128.4; 120.3; 60.7; 52.0; 13.8. Found, m/z: 266.0890
[M+H]+. C10H12N5O4. Calculated, m/z: 266.0884.
Ethyl 4-(4-cyclopentyl-1Н-1,2,3-triazol-1-yl)-1Н-pyra-
zole-5-carboxylate (13d). Yield 200 mg (22%), brown
solid, mp 149–150°C. IR spectrum, ν, cm−1: 3230 (NH),
2957 (cyclopentyl), 1700 (С=О). 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm (J, Hz): 14.12 (1H, br. s,
NH); 8.34 (1H, s, Н-5 triazole); 8.18 (1H, s, Н-3 pyrazole);
4.17 (2H, q, J = 7.1, OCH2CH3); 3.15 (1H, t, J = 7.5, CH
cyclopentane); 2.02 (2H, d, J = 9.1, CH2 cyclopentane);
1.73–1.60 (6H, m, CH2 cyclopentane); 1.13 (3H, t, J = 7.1,
OCH2CH3). 13C NMR spectrum (126 MHz, DMSO-d6),
δ, ppm: 160.1; 150.8; 135.0; 129.4; 123.8; 121.6; 60.7;
36.1; 32.9; 24.7; 13.8. Found, m/z: 276.1449 [M+H]+.
С13H18N5O2. Calculated, m/z: 276.1455.
Synthesis of (1Н-1,2,3-triazol-1-yl)-1Н-pyrazole-
3-carboxylic acids 14a–d (General method). The
corresponding carboxylate 13a–d (0.0015 mol) was
dissolved in aqueous KOH (295 mg, 0.0053 mol; 30 ml of
solution). The formed solution was stirred at 70°С for 12 h.
Then, the solution was passed through a thin layer of silica
gel and acidified by 2 M aqueous HCl to рН 1. The formed
precipitate was filtered off and dried in a vacuum
desiccator over P2O5. The filtrate was extracted with
188

Chemistry of Heterocyclic Compounds 2020, 56(2), 180–191
EtOAc, the organic phase was separated and dried over
was purified by flash column chromatography on silica gel,
eluent petroleum ether – EtOAc, 1:1. After purification, a
colorless oil formed, which crystallized into colorless solid.
Yield 3.2 g (73%), colorless solid, mp 69–70°С. IR spect-
rum, ν, cm−1: 3299 (СН alkyne), 3268 (СН alkyne), 1729
(C=O). 1H NMR spectrum (400 MHz, CDCl3), δ, ppm
(J, Hz): 3.39 (4H, d, J = 2.5, 2CH2); 3.09 (4H, d,
J = 11.1, 2CH2); 2.60 (4H, d, J = 10.8, 2CH2); 2.24 (2H, t,
J = 2.4, 2CH); 1.03 (6H, s, 2CH3). 13C NMR spectrum
(126 MHz, CDCl3), δ, ppm: 214.6; 78.2; 73.6; 64.3; 46.3;
45.7; 19.9. Found, m/z: 245.16478 [M+H]+. C15H21N2O.
Calculated, m/z: 245.16484. Found, %: C 73.63; H 8.30;
N 11.38. С15H20N2O. Calculated, %: C 73.74; H 8.25;
N 11.47.
anhydrous Na2SO4. The dried organic phase was
evaporated under reduced pressure on the rotary evaporator
to afford a solid. Both solids were combined.
4-(4-Phenyl-1Н-1,2,3-triazol-1-yl)-1Н-pyrazole-5-carb-
oxylic acid (14a). Yield 211 mg (55%), colorless solid,
mp 262–263°C. IR spectrum, ν, cm−1: 3176 (NH), 3095
(OH), 1687 (C=O). 1H NMR spectrum (500 MHz,
DMSO-d6), δ, ppm (J, Hz): 13.88 (2H, br. s, NH, COOH);
8.94 (1H, s, Н-5 triazole); 8.36 (1H, br. s, Н-3 pyrazole);
7.91 (2H, d, J = 7.7, H Ph); 7.48 (2H, t, J = 7.6, H Ph); 7.37
(1H, t, J = 7.4, H Ph). 13C NMR spectrum (126 MHz,
DMSO-d6), δ, ppm: 161.3; 146.0; 136.3; 130.5; 129.0;
128.1; 125.3; 124.3; 121.3. Found, m/z: 256.0828 [M+H]+.
C12H10N5O2. Calculated, m/z: 256.0829.
Diethyl 5,5'-{4,4'-[(1,5-dimethyl-9-oxo-3,7-diazabicyclo-
[3.3.1]nonane-3,7-diyl)bis(methylene)]bis(1Н-1,2,3-tri-
azole-4,1-diyl)}bis(1Н-pyrazole-3-carboxylate) (17). Ethyl
5-azido-1Н-pyrazole-3-carboxylate 7 (593 mg, 3.27 mmol)
and bispropargyl 16 (400 mg, 1.64 mmol) were dissolved
in t-BuOH (10 ml). A solution of Na ascorbate (33 mg,
0.164 mmol, 10 mol %) in H2O (5 ml) was added to the
reagent solution. The flask was evacuated and filled with
argon. A solution of CuSO4·5H2O (20 mg, 0.08 mmol,
5 mol %) in H2O (5 ml) was then added to the reaction
mixture. The reaction mixture was stirred at room
temperature for 2 days. A beige precipitate formed. The
progress of the reaction was monitored by TLC (eluent
petroleum ether – EtOAc, 1:1) by the disappearance of
spots of the reagents (visualization in the iodine chamber).
The formed precipitate was filtered off, washed with H2O,
and dried in a vacuum desiccator over P2O5 to constant
weight. The filtrate was extracted with EtOAc, washed
with H2O, the organic phase was separated and dried over
anhydrous Na2SO4. The dried organic phase was
evaporated under reduced pressure on the rotary evaporator
to afford a solid. The extracted product was purified by
flash chromatography on silica gel, eluent CHCl3–MeOH,
5:1. Both solids were combined. Yield 878 mg (88%),
beige solid, mp 202–203°С. IR spectrum, ν, cm−1: 1730
4-[4-(Hydroxymethyl)-1Н-1,2,3-triazol-1-yl]-1Н-pyra-
zole-5-carboxylic acid (14b). Yield 188 mg (60%), light-
orange solid, mp 212–213°С. IR spectrum, ν, cm−1: 3154
1
(CH2OH), 2925 (COOH), 1716 (C=O). H NMR spectrum
(500 MHz, DMSO-d6), δ, ppm: 8.33 (1H, s, Н-5 triazole);
8.26 (1H, s, Н-3 pyrazole); 4.59 (2H, s, СН2ОН). 13C NMR
spectrum (126 MHz, DMSO-d6), δ, ppm: 161.0; 147.6;
130.9; 130.5 (br. s); 125.3; 121.6; 54.9. Found, m/z:
210.0627 [M+H]+. C7H8N5O3. Calculated, m/z: 210.0622.
1-(5-Carboxy-1Н-pyrazol-4-yl)-1Н-1,2,3-triazole-
4-carboxylic acid (14c). Yield 264 mg (79%), colorless
solid, mp 268–269°С. IR spectrum, ν, cm−1: 3379 (NH),
3344 (COOH), 3304 (COOH), 1715 (C=O). 1H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 13.98 (1H, br. s,
NH); 13.26 (2H, br. s, СООН); 9.02 (1H, s, Н-5 triazole);
8.41 (1H, br. s, Н-3 pyrazole). 13C NMR spectrum (126 MHz,
DMSO-d6), δ, ppm: 161.6; 161.0; 139.4; 136.3; 131.6;
128.3; 120.7. Found, m/z: 224.0423 [M+H]+. C7H6N5O4.
Calculated, m/z: 224.0414.
4-(4-Cyclopentyl-1Н-1,2,3-triazol-1-yl)-1Н-pyrazole-
5-carboxylic acid (14d). Yield 278 mg (75%), brown
solid, mp 239–240°С. IR spectrum, ν, cm−1: 3147 (NH),
2957 (cyclopentane), 2454 (COOH), 1681 (C=O). 1H NMR
spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz): 13.69
(2H, br. s, NH, COOH); 8.25 (1H, br. s, Н-3 pyrazole);
8.21 (1H, s, Н-5 triazole); 3.17 (1H, q, J = 7.6, CH
cyclopentane); 2.02 (2H, d, J = 8.2, CH2 cyclopentane);
1.78–1.57 (6H, m, CH2 cyclopentane). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm: 160.9; 150.8; 135.6; 127.8;
123.6; 121.8; 36.1; 32.8; 24.7. Found, m/z: 248.1152
[M+H]+. С11H14N5O2. Calculated, m/z: 248.1142.
1,5-Dimethyl-3,7-di(prop-2-yn-1-yl)-3,7-diazabicyclo-
[3.3.1]nonan-9-one (16). 1,5-Dimethyl-3,7-diazabicyclo-
[3.3.1]nonan-9-one (15) (3.00 g, 0.018 mol) was dissolved
in MeCN (50 ml). Propargyl bromide (2.71 ml, 4.25 g,
0.036 mol) and DIPA (6.3 ml, 4.65 g, 0.036 mol) were
added to the solution. The reaction mixture was heated
under reflux with stirring for 10 h. The progress of the
reaction was monitored by TLC (visualization in iodine
chamber). The solvent was evaporated to dryness under
reduced pressure on the rotary evaporator. The residue was
dissolved in CH2Cl2 (75 ml) and washed with H2O (2×45 ml).
The organic layer was separated and dried over anhydrous
Na2SO4. The solvent was evaporated to dryness under
reduced pressure on the rotary evaporator. A brown oil
formed, which crystallized upon standing. The brown oil
1
(С=О), 1722 (EtO–C=O). H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm (J, Hz): 14.44 (2Н, br. s, NH); 8.51
(2H, s, Н-5 triazole); 7.20 (2H, s, Н-4 pyrazole); 4.36 (4H,
q, J = 7.1, 2OCH2CH3); 3.74 (4H, s, 2CH2); 3.08 (4Н, d,
J = 10.7, 2CH2); 2.40 (4Н, d, J = 10.7, 2CH2); 1.33 (6H, t,
J = 7.1, 2СН2СН3); 0.86 (6Н, s, 2CH3). 13C NMR spectrum
(101 MHz, DMSO-d6), δ, ppm: 214.3; 158.4; 146.1; 143.8;
135.5; 121.9; 99.5; 64.4; 61.4; 50.8; 46.0; 20.0; 14.1.
Found, m/z: 607.2866 [M+H]+. C27H35N12O5. Calculated,
m/z: 607.2848. Found, %: C 52.83; H 5.44; N 27.75.
С27H34N12O5. Calculated, %: C 53.46; H 5.65; N 27.71.
5,5'-{4,4'-[(1,5-Dimethyl-9-oxo-3,7-diazabicyclo[3.3.1]-
nonane-3,7-diyl)bis(methylene)]bis(1Н-1,2,3-triazole-
4,1-diyl)}bis(1Н-pyrazole-3-carboxylic acid) hydro-
chloride dihydrate (18·HCl·2H2O). Biscarboxylate 17
(1.543 g, 0.0025 mol) was dissolved in aqueous KOH
(0.56 g, 0.01 mol; 25 ml of solution). The formed solution
was stirred at 70°С for 24 h. Then, the solution was passed
through a thin layer of silica gel and acidified by 2 M
aqueous HCl to рН 2–3. The formed beige precipitate was
filtered off, washed with a small amount of cold H2O, and
dried in a vacuum desiccator over P2O5 to constant weight.
189

Chemistry of Heterocyclic Compounds 2020, 56(2), 180–191
Yield 933 mg (68%), light-gray solid, mp 267–268°С.
vacuum desiccator successively over P2O5 and KOH for
1
IR spectrum, ν, cm−1: 3111 (OH), 1713 (C=O). H NMR
2 days. The product was isolated as monoacetate trihydro-
spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 14.28 (2Н,
s, NH); 11.52 (2Н, br. s, СООН); 8.80 (2H, s, Н-5
triazole); 7.11 (2H, s, Н-4 pyrazole); 4.24 (4H, s, 2NСН2);
3.62 (4Н, d, J = 10.6, 2СН2 bispidine); 2.96 (4Н, d,
J = 10.6, 2СН2 bispidine); 0.87 (6Н, s, 2CH3). 13C NMR
spectrum (126 MHz, DMSO-d6), δ, ppm (J, Hz): 208.7;
159.8; 146.0; 139.4; 137.1; 123.7; 99.2; 62.2; 49.6; 45.6;
16.0. Found, m/z: 551.2213 [M+H]+. C23H27N12O5.
Calculated, m/z: 551.2222. Found, %: C 44.40; H 5.50;
N 26.90. С23H31ClN12O7. Calculated, %: C 44.34; H 5.02;
N 26.98.
chloride. Yield 595 mg (84%), yellow solid, mp 244–245°С.
1
IR spectrum, ν, cm−1: 2922 (OH), 1728 (С=O). H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 11.44 (2H,
br. s, NH); 10.29 (2Н, br. s, 2COOH); 8.69 (2H, s, Н-5
triazole); 8.24 (2H, s, Н-5 pyrazole); 4.25 (4H, s, 2NCH2);
3.60 (4H, d, J = 11.3, 2СН2 bispidine); 2.97 (4H, d, J = 11.2,
2СН2 bispidine); 1.90 (3Н, s, СH3COOH); 0.89 (6H, s,
2CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm:
208.6; 172.1 (CH3COOH); 161.0; 138.6; 132.81; 130.45;
128.4; 121.3; 62.3; 49.9; 45.6; 21.2 (CH3COOH); 16.0.
Found, m/z: 551.2231 [M+H]+. C23H27N12O5. Calculated, m/z:
Diethyl 4,4'-{[(1,5-dimethyl-9-oxo-3,7-diazabicyclo-
[3.3.1]nonane-3,7-diyl)bis(methylene)]bis(1Н-1,2,3-tri-
551.2222. Found, %: C 42.07; H 4.89; N 23.37.
С25H33Cl3N12O7. Calculated, %: C 41.71; H 4.62; N 23.35.
azole-4,1-diyl)}bis(1Н-pyrazole-3-carboxylate)
(19).
1
Ethyl 4-azido-1Н-pyrazole-3-carboxylate (10) (2.32 g, 12.8
mmol) and bispropargyl 16 (1.55 g, 6.4 mmol) were
dissolved in MeOH (70 ml). A solution of Na ascorbate
(127 mg, 0.64 mmol, 10 mol %) in H2O (35 ml) was added
to the reagent solution. The flask was evacuated and filled
with argon. A solution of CuSO4·5H2O (80 mg, 0.32 mmol, 5
mol %) in H2O (35 ml) was then added to the reaction
mixture. The reaction mixture was stirred at room
temperature for 12 h. A beige precipitate started to form
immediately. The progress of the reaction was monitored
by TLC (eluent petroleum ether – EtOAc, 1:1) by the
disappearance of spots of the reagents (visualization in the
iodine chamber). The formed precipitate was filtered off
and washed with H2O, and dried in a vacuum desiccator
over P2O5 to constant weight. The filtrate was extracted
with CH2Cl2, washed with H2O, the organic phase was
separated and dried over anhydrous Na2SO4. The dried
organic phase was evaporated under reduced pressure on
the rotary evaporator to afford a solid. The extracted and
filtered products were purified by flash chromatography on
silica gel, eluent CHCl3–MeOH, 5:1. Both solids were then
combined. Yield 3.03 g (78%), beige solid, mp 211–212°С.
IR spectrum, ν, cm−1: 3235 (NH), 2928 (СН2), 1710 (C=O
Supplementary information file, containing Н and13С
1
1
1
NMR, as well as Н–13С HSQC, H–13C HMBC, H–15N
HMBC 2D NMR spectra for compounds 6, 7, 10, is
available at the journal website at http://link.springer.com/
journal/10593.
This work was supported by the Russian Science
Foundation (grant 19-73-20090).
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ester), 1682 (C=O ketone). H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm (J, Hz): 14.12 (2H, br. s, 2NH); 8.36
(2H, br. s, Н-5 pyrazole); 8.32 (2H, s, Н-5 triazole); 4.17
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