Ultrasonic-assisted unusual four-component synthesis of 7-azolylamino-4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines

Article abstract of DOI:10.3762/bjoc.16.27

Four-component reactions of 3-amino-1,2,4-triazole or 5-amino-1H-pyrazole-4-carbonitrile with aromatic aldehydes and pyruvic acid or its esters under ultrasonication were studied. Unusual for such a reaction type, a cascade of elementary stages led to the

Full text of DOI:10.3762/bjoc.16.27

Ultrasonic-assisted unusual four-component synthesis of
7-azolylamino-4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines
Yana I. Sakhno1, Maryna V. Murlykina1,2, Oleksandr I. Zbruyev1, Anton V. Kozyryev1,
Svetlana V. Shishkina1,2, Dmytro Sysoiev3, Vladimir I. Musatov1, Sergey M. Desenko1,2
and Valentyn A. Chebanov*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 281–289.
1Division of Chemistry of Functional Materials, State Scientific
Institution “Institute for Single Crystals” of National Academy of
Sciences of Ukraine, Nauky Av. 60, 61072 Kharkiv, Ukraine, 2Faculty
of Chemistry, V. N. Karazin Kharkiv National University, Svobody Sq.
4, 61077 Kharkiv, Ukraine and 3Institute of Organic Chemistry and
Biochemistry of the Czech Academy of Sciences, Flemingovo
náměstí 542/2, 166 10 Praha 6, Czech Republic
doi:10.3762/bjoc.16.27
Received: 16 December 2019
Accepted: 19 February 2020
Published: 27 February 2020
Associate Editor: I. Baxendale
Email:
© 2020 Sakhno et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Valentyn A. Chebanov* - chebanov@isc.kh.ua
* Corresponding author
Keywords:
5-amino-1H-pyrazole-4-carbonitrile; 3-amino-1,2,4-triazole;
7-azolylaminotetrahydroazolo[1,5-a]pyrimidines; heterocycle;
multicomponent reaction; ultrasonication
Abstract
Four-component reactions of 3-amino-1,2,4-triazole or 5-amino-1H-pyrazole-4-carbonitrile with aromatic aldehydes and pyruvic
acid or its esters under ultrasonication were studied. Unusual for such a reaction type, a cascade of elementary stages led to the for-
mation of 7-azolylaminotetrahydroazolo[1,5-a]pyrimidines.
Introduction
Tetrahydropyrimidines are heterocycles of high pharmacologi- dihydroazolopyrimidines I obtained via well-known reactions
cal importance, and they have attracted the attention of medici- of aminoazoles with α,β-unsaturated ketones [8-11] or via their
nal chemists because of their various biological activities [1]. multicomponent analogues. On the other hand, multicompo-
Furthermore, tetrahydropyrimidines containing fused azole nent reactions (MCRs) directly leading to tetrahydroazolopy-
rings are a privileged class of heterocycles due to their antiviral rimidine heterocyclic systems have also been published [4,5,16-
[2], antitubercular, antitumor [3], antibacterial [4,5], and bone- 24]. In particular, multicomponent approaches were described
anabolic activities [6,7]. Previously, some tetrahydroazolopy- for the synthesis of 7-hydroxytetrahydroazolopyrimidines by
rimidines II (Scheme 1) were synthesized using sequential syn- the reaction of aminoazoles, aromatic aldehydes, and some car-
thetic routes [8-15], in most cases involving the reduction of the bonyl compounds (Scheme 1, IV and Scheme 2, VI and VIII)
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Beilstein J. Org. Chem. 2020, 16, 281–289.
Scheme 1: Synthesis of tetrahydroazolopyrimidine derivatives.
Scheme 2: Various multicomponent reactions involving pyruvic acids (pyruvates) and different α-aminoazoles.
[4,5,16-23]. Oxygen-bridged tetrahydroazolopyrimidines III Thus, using nonclassical activation methods such as ultrasoni-
were also obtained via similar MCRs when using salicylic alde- cation and microwave irradiation enabled us to develop highly
hydes, allowing further intermolecular cyclization [23,24].
selective procedures for obtaining triazolo-, tetrazolo-, and
pyrazolopyrimidines [4,5,16-20,27-29], as well as oxygen-
One of the promising reagents for the synthesis of diverse types bridged tetrahydropyrazolopyrimidines [4,19], furanone
of azoloazines by multicomponent and sequential reactions is [17,30], and pyrrolone derivatives [5,16-18].
pyruvic acid, along with its derivatives (Scheme 2). The selec-
tivity of such interactions can be tuned, for example, by appli- Besides the presence of an OH group in the tetrahydropyrimi-
cation of a condition-based divergence strategy [25], which is dine moiety (e.g., Scheme 2, VI and VIII), the formation of
based on the variation of solvents, catalysts, and activation heterocycles that are amino-substituted in a similar position is
methods [16,26-29].
also possible and has been described [31,32]. In particular, the
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Beilstein J. Org. Chem. 2020, 16, 281–289.
reaction of methyl pyruvate and anilines led to the formation of undescribed 7-azolylamino-substituted tetrahydroazolopyrim-
4-arylamino-substituted tetrahydroquinolines (Scheme 3). To idines, is reported for the first time herein.
the best of our knowledge, an analogous reaction has not been
described for aminoazoles.
Thus, using 2 equivalents of 5-aminopyrazole-4-carbonitrile
1a/b in MCRs with aromatic aldehydes 2a–c and pyruvic acid
We were interested to study reactions similar to the ones shown (3a) in acetic acid at room temperature under ultrasonication for
in Scheme 3, involving aromatic aldehydes and pyruvic acid but 90 min gave 3-cyano-7-((4-cyano-1H-pyrazol-5-yl)amino)-5-
using aminoazoles instead of anilines. Therefore, the present aryl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylic
work is devoted to the study of multicomponent reactions in- acids 4a–c. There is also the possibility of applying ethyl pyru-
volving 3-amino-1,2,4-triazole or 5-aminopyrazoles, aromatic vate (3b) instead of pyruvic acid as a reactant in the reaction
aldehydes, and pyruvic acid or its esters under ultrasonication. with 3-substituted-5-aminopyrazole-4-carbonitriles (R = H,
CH3) 1a/b and aromatic aldehydes 2a–f (ultrasonication in
Results and Discussion
acetic acid at room temperature for 120 min). In this case, the
It was discovered that MCRs involving 3-amino-1,2,4-triazole corresponding ethyl 3-cyano-7-((4-cyano-3-substituted-1H-
or 5-amino-1H-pyrazole-4-carbonitrile with aromatic alde- pyrazol-5-yl)amino)-2-substituted-5-aryl-4,5,6,7-tetrahydropy-
hydes and pyruvic acid or its esters under ultrasonication led to razolo[1,5-a]pyrimidine-7-carboxylates (substituents = H, CH3)
the formation of 4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines 4d–o were isolated in 45–80% yields (Scheme 4, Table 1).
4a–u (Scheme 4) containing an azolylamino substituent in the
7-position via an unusual pseudo four-component reaction, The same products were isolated while carrying out this reac-
rather than two heterocycles of the types V–X (Scheme 2). It tion in acetic acid at room temperature with intensive stirring
should be noted that such a type of MCR, giving previously instead of ultrasonic irradiation. However, the reaction time had
Scheme 3: Synthesis of 4-arylamino-substituted tetrahydroquinolines.
Scheme 4: Ultrasound-assisted multicomponent reactions of 3-amino-1,2,4-triazole or 5-amino-1H-pyrazole-4-carbonitrile, aldehydes, and pyruvic
acid/ethyl pyruvate.
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Beilstein J. Org. Chem. 2020, 16, 281–289.
Table 1: Synthesis of compounds 4a–u.
starting material
US reaction time (min)
90
product
yield (%)
76
1
X
R
R1
2
R2
H
3
4
1a
H
H
2a
3a
4a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
„
„
„
„
„
„
„
„
„
„
„
„
„
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
4-CH3O
4-Cl
4-H
4-CH3O
4-Cl
4-Br
2b
2c
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2e
2f
H
H
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3a
3a
3a
3a
3a
3a
90
90
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
86
75
60
73
55
80
64
53
45
68
55
63
55
47
60
65
70
76
34
49
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
H
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
4-COOCH3
4-CN
H
4-CH3O
4-Cl
4-Br
4-COOCH3
4-CN
4-CH3O
3-CH3O
2-CH3O
4-OH
„
N
N
N
N
N
N
2b
2g
2h
2k
2j
H
H
H
H
4s
4t
4u
3-OH
2-OH
H
2i
H
to be increased to 24 h, and the yields and purity of the com- cycles 4p–u. The condensation of compounds 1c, 2a–f, and 3a
pounds 4 decreased (as seen via TLC and NMR analysis), obvi- in dry DMF under otherwise identical conditions was a way to
ously due to the worse homogenization and mass transfer com- avoid the rapid conversion of triazolyl derivatives 4p–u into
pared to ultrasonication.
7-hydroxytriazolo[1,5-a]pyrimidines 5a–f and to isolate the
heterocycles 4p–u, but in lower yields in comparison to the
Literature data [17,26,27,33-35] indicates that 5-aminopyra- reaction in acetic acid.
zoles bearing an electron-withdrawing substituent in the 4-posi-
tion, such as a carbonitrile group, often behave similar to We consequently screened various condensation conditions,
3-amino-1,2,4-triazole; therefore, we studied the latter under the specifically by applying different temperatures in the range of
same reaction conditions. We showed that the pseudo four-com- 0–110 °C (both with the help of conventional heating and
ponent heterocyclization of two equivalents of 3-amino-1,2,4- microwave irradiation) and by using different solvents and cata-
triazole (1c) with aromatic aldehydes 2a–f and pyruvic acid lysts, such as HOAc, DMSO, primary alcohols with and with-
(3a) carried out in acetic acid at a room temperature under ultra- out the presence of HCl, Yb(OTf)3, or Et3N. In all these cases,
sonication for 120 min gave 7-((1H-1,2,4-triazol-5-yl)amino)-5- mixtures of triazolo[1,5-a]pyrimidines 4p–u and 5a–f in differ-
aryl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-7- ent ratios (the content of compounds 5a–f increased with the
carboxylic acids 4p–u in 34–76% yields (Scheme 4). In contrast elevation of temperature and time) with impurities of starting
to pyrazolyl-substituted pyrazolo[1,5-a]pyrimidine-7-carboxylic reagents and unidentified compounds were obtained.
acids 4d–o, triazolyl-substituted derivatives 4p–u were unstable
in protic solvents in the presence of water, and especially upon In contrast to tetrahydropyrimidines 4p–u, containing triazolyl
increasing the temperature gradually transformed into fragments, our attempts to obtain compounds 6 from pyrazolyl
7-hydroxytriazolo[1,5-a]pyrimidines 5a–f, which had been ob- derivatives 4b/c/e/f were unsuccessful. In particular, under the
tained earlier [5] by the three-component reaction of starting same conditions (prolonged stirring in acetic acid at tempera-
materials 1c, 2a–f, and 3a (HOAc, 65 °C, 48 h). This instability tures up to 70 °C), the starting tetrahydropyrazolopyrimidines
complicated the isolation and characterization of the hetero- 4b/c/e/f remained unchanged. Then, it was established that
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Beilstein J. Org. Chem. 2020, 16, 281–289.
compound 4e remained stable under refluxing in acetic acid for Structure elucidation
60 min, while heating for 120–180 min led to its decomposi- The purity and structures of the synthesized heterocycles were
tion. At the same time, compound 4b, after refluxing in acetic determined using elemental analysis, mass spectrometry, NMR
acid for ca. 120 min, was converted into 3-cyano-7-(4-methoxy- spectroscopy (1D and 2D NMR experiments), and X-ray
phenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylic diffraction analysis. The signals in the 1H and 13C NMR spec-
acid (7, yield 35%). The same carboxylic acid 7 was obtained tra of some of the compounds 4 were duplicated. This could
by counter synthesis through a three-component reaction in- have been caused by two reasons, namely by free rotation of the
volving 5-aminopyrazole-4-carbonitrile (1a), 4-methoxybenz- azolyl fragment in the position 7 or by the presence of a second
aldehyde (2b), and pyruvic acid (3a) under heating at reflux in diastereomer. To establish the reason of duplication, NMR
acetic acid for 240 min (yield 28%) or through two-component spectra were recorded at different temperatures. As the tempera-
heterocyclization of 5-aminopyrazole 1a and p-methoxyben- ture was increased from 25 °C to 130 °C, the peaks were still
zylidenepyruvic acid (8, obtained from p-methoxybenzalde- duplicated, proving the presence of two diastereomers.
hyde and pyruvic acid) under the same conditions in a much
shorter reaction time (10 min) with 66% yield (Scheme 5).
The 1H NMR spectra of 4a–o exhibited three signals of an
AMX system for the tetrahydropyrimidine ring (about
The results presented above indicate that the reaction possibly 2.27–2.48 ppm, 3.03–3.25 ppm, and 4.52–4.83 ppm), three
proceeded under kinetic and thermodynamic control, depending signals for protons of the NH groups (ca. 7.85–8.13 ppm for the
on the conditions. In particular, ultrasonication of the starting pyrimidine NH, 6.90–7.21 ppm for the NH pyrazolyl moiety,
materials 1a, 2b, and 3a for 90 min at room temperature provi- and 11.79–12.07 ppm for the aminopyrazole moiety), a CH
ded the kinetically controlled azolyltetrahydropyrimidine deriv- signal of the proton at position 2 of the pyrazolopyrimidine,
ative 4b (Scheme 4), while high-temperature treatment of signals of the aryl ring at 7.54–8.34 ppm, and signals corre-
the same starting materials (HOAc, refluxing at 118 °C for sponding to the alkyl substituent.
240 min) yielded the thermodynamically preferred dihydropyra-
zolopyrimidine-5-carboxylic acid 7 (Scheme 5).
The 1H NMR spectra of 4a–c/j/k/o showed a double set of
signals for the AMX system of the tetrahydropyrimidine ring,
The most probable pathway A (Scheme 6) to compounds 4 the NH protons, and the protons of the CH2CH3 moiety (in the
includes initial formation of the corresponding azomethines 9 case of esters) due to the presence of two isomers of 4.
and 10. A similar pathway was previously described and dis-
cussed in publications [31,32]. We cannot exclude other mecha- The 1H NMR and 13C NMR spectra of triazolyl derivatives
nisms, for example, via arylidenepyruvic acids (esters) 11 4p–u were more complicated, both due to the duplication of the
formed by water elimination from appropriate aldols (pathway signals and the fast decomposition of the compounds 4p–u in
B). However, our attempts to synthesize compound 4 by direct solutions. Therefore, 2D NMR and, in some cases, 13C NMR
reaction of unsaturated acid 8 and aminoazole 1a under differ- spectra were overcrowded and uninformative. Particularly,
ent conditions (ultrasonic activation and conventional heating) tetrahydropyrimidines 4s–u with hydroxy substituent in the aryl
were unsuccessful, and only dihydropyrimidine 7 was obtained. ring happened to be less stable than the derivatives 4p–r with
Scheme 5: Synthesis of 3-cyano-7-(4-methoxyphenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid (7).
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Beilstein J. Org. Chem. 2020, 16, 281–289.
Scheme 6: Proposed reaction mechanism.
the methoxy group; this explains the absence of 13C NMR spec- CH proton at position 5 with the pyrimidine NH group and
tra for compounds 4t/u in our work.
cross-peaks of the NH group with protons of the aromatic
system, thus excluding structure B (Figure 1).
The 1H NMR spectra of the products 4p–u exhibited a broad
singlet for the triazole NH and carboxyl groups at ca.
13.10–13.30 ppm, a broad singlet for the phenolic OH group at
9.40–9.70 ppm (for compounds 4s–u), singlets of pyrimidine
NH and CH groups of the triazolyl and triazole fragments in the
interval of 7.31–7.91 ppm, a singlet of the triazolylamino group
at 7.23–7.35 ppm, a multiplet for the CH proton in position 5 at
5.10–5.25 ppm (for the derivatives 4r/u with ortho-substituent
in the aryl ring) or at 4.60–4.90 ppm for the compounds
4p/q/s/t, multiplets for the CH2 group in position 6 at
2.90–3.60 ppm and 2.11–2.50 ppm, and multiplets of aromatic
protons at 6.65–7.45 ppm.
Figure 1: Alternative structures A and B for the tetrahydroazolopyrim-
idines 4.
The spectral data obtained for the tetrahydropyrimidines 4 most Eventually, the structure of tetrahydropyrimidines 4 was proven
likely corresponded to the possible regioisomers A and B by X-ray analysis carried out for a single crystal of one dia-
(Figure 1). Additional NOESY experiments, in particular for stereomer of compound 4g, which allowed assignment of the
compound 4k, showed the presence of cross-peaks between the structure as ethyl 5-(4-bromophenyl)-3-cyano-7-((4-cyano-1H-
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Beilstein J. Org. Chem. 2020, 16, 281–289.
pyrazol-5-yl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimi- In the crystal phase, molecules 4g formed centrosymmetric
dine-7-carboxylate (Figure 2).
dimers due to the N1–H···N4 intermolecular hydrogen bonds
(1 x, 1 y, 2 z; H···N 2.22 Å, N–H···N 164°). The dimers were
bound by a N6–H···O1 intermolecular hydrogen bond (x 1, y, z;
H···O 2.16 Å, N–H···O 162°), forming chains along the [100]
crystallographic direction (Figure 3).
Figure 2: Molecular structure of ethyl 5-(4-bromophenyl)-3-cyano-7-
((4-cyano-1H-pyrazol-5-yl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-7-carboxylate (4g) obtained from X-ray diffraction data.
Compound 4g existed as a solvate with acetonitrile in the
crystal lattice. The tetrahydropyrimidine ring adopted a half-
chair conformation (the puckering parameters [36] were: S =
0.70, Θ = 25.6°, Ψ = 21.6°). Deviations of the C2 and C3 atoms
Figure 3: Chains of 4g molecules in the crystal phase.
from the mean-plane of the remaining atoms of this ring were Conclusion
−0.26 Å and 0.35 Å, respectively. The phenyl substituent was In this study we disclosed a new direction for the multicompo-
located in an equatorial position and was slightly turned in rela- nent reaction of 5-aminopyrazole-4-carbonitriles or 3-amino-
tion to the N1–C3 endocyclic bond (the C4–N1–C3–C7 and 1,2,4-triazole with pyruvic acid or ethyl pyruvate and aromatic
N1–C3–C7–C12 torsion angles were −163.6(4)° and 19.7(7)°, aldehydes under ultrasonication, leading to 7-azolylamino-
respectively). Short intramolecular contacts appeared: the 4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines via a cascade of
H1(N)···H12 distance was 2.10 Å and the van der Waals radii elementary stages that is unusual for such transformations.
sum [37] was 2.34 Å, the H···N1 distance was 2.55 Å (and the Thus, we extended the molecular diversity of the compounds
van der Waals radii sum was 2.67 Å), while the H1···C12 dis- obtained by introducing an additional azolyl substituent to the
tance was 2.60 Å, with a van der Waals radii sum of 2.87 Å. pyrimidine ring.
The two vicinal substituents at the C1 atom had different orien-
tations in relation to the partially saturated cycle: the ester sub-
stituent was in an axial position, while the other substituent was
Supporting Information
found in an equatorial position (the C4–N3–C1–C18 and
Supporting Information File 1
C4–N3–C1–N5 torsion angles were −104.0(5)° and 139.6(5)°,
respectively). The carboxylic acid fragment was turned in rela-
tion to the N3–C1 endocyclic bond (the N3–C1–C18–O1
torsion angle was −131.4(5)°). The ethyl group was located in
an ap position to the C1–C18 bond and was almost orthogonal
to the C18–O2 bond (the C1–C18–O2–C19 and
C18–O2–C19–C20 torsion angles were −175.0(4)° and
85.1(7)°, respectively). The planar cyanopyrazolimino substitu-
ent was turned significantly to the N3–C1 endocyclic bond (the
N3–C1–N5–C14 torsion angle was −57.5(6)°).
Experimental and analytical data as well as X-ray
crystallographic information.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-27-S1.pdf]
Supporting Information File 2
1H and 13C NMR spectra.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-27-S2.pdf]
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Beilstein J. Org. Chem. 2020, 16, 281–289.
13.Zemlyanaya, N. I.; Karnozhitskaya, T. M.; Musatov, V. I.;
Funding
Konovalova, I. S.; Shishkina, S. V.; Lipson, V. V. Russ. J. Org. Chem.
2018, 54, 1241–1249. doi:10.1134/s1070428018080201
14.Lipson, V. V.; Karnozhitskaya, T. M.; Shishkina, S. V.; Shishkin, O. V.;
Turov, A. V. Russ. Chem. Bull. 2009, 58, 1441–1444.
doi:10.1007/s11172-009-0193-1
15.Bartashevich, E. V.; Plekhanov, P. V.; Rusinov, G. L.; Potemkin, V. A.;
Belik, A. V.; Chupakhin, O. N. Russ. Chem. Bull. 1999, 48, 1553–1557.
doi:10.1007/bf02496411
16.Sakhno, Y. I.; Desenko, S. M.; Shishkina, S. V.; Shishkin, O. V.;
Sysoyev, D. O.; Groth, U.; Kappe, C. O.; Chebanov, V. A. Tetrahedron
2008, 64, 11041–11049. doi:10.1016/j.tet.2008.09.089
17.Sakhno, Y. I.; Shishkina, S. V.; Shishkin, O. V.; Musatov, V. I.;
Vashchenko, E. V.; Desenko, S. M.; Chebanov, V. A. Mol. Diversity
2010, 14, 523–531. doi:10.1007/s11030-010-9226-9
18.Murlykina, M. V.; Sakhno, Ya. I.; Desenko, S. M.; Chebanov, V. A. In
Heterocyclic compounds chemistry. Recent aspects; Kartsev, V. G.,
Ed.; ICSPF Press: Moscow, Russia, 2014; pp 318–324.
19.Sakhno, Y. I.; Murlykina, M. V.; Morozova, A. D.; Kozyryev, A. V.;
Chebanov, V. A. Fr.-Ukr. J. Chem. 2015, 3, 1–20.
The authors thank the National Academy of Sciences of
Ukraine for financial support in the frame of the projects
"Creation of modern bases for obtaining and analyzing
substances and components of materials for pharmaceutical
purposes" (0119U100727) and "Investigation of structural
features of nitrogen containing heterocycles with potential
biological activity" (0119U100716). M. Murlykina was
supported by the Grant of National Academy of Sciences of
Ukraine for young scientists’ research laboratories and groups
(0118U100275).
ORCID® iDs
Sergey M. Desenko - https://orcid.org/0000-0001-8914-3232
Valentyn A. Chebanov - https://orcid.org/0000-0001-7564-778X
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