Features of two- and multicomponent heterocyclization reactions involving 3,4-disubstituted 5-aminopyrazoles and alkyl pyruvates

Article abstract of DOI:10.1016/j.tet.2017.12.031

Three-component heterocyclizations of pyruvic acids and their esters with 5-aminopyrazoles and aromatic aldehydes, in addition to the sequential versions of these reactions, under different activating conditions were studied. Under conventional heating, p

Full text of DOI:10.1016/j.tet.2017.12.031

Accepted Manuscript
Features of two- and multicomponent heterocyclization reactions involving 3,4-
disubstituted 5-aminopyrazoles and alkyl pyruvates
Yana I. Sakhno, Anton V. Kozyrev, Sergey M. Desenko, Svetlana V. Shishkina,
Vladimir I. Musatov, Dmytro O. Sysoiev, Valentin A. Chebanov
PII:
S0040-4020(17)31293-0
10.1016/j.tet.2017.12.031
TET 29187
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 August 2017
Revised Date: 10 December 2017
Accepted Date: 14 December 2017
Please cite this article as: Sakhno YI, Kozyrev AV, Desenko SM, Shishkina SV, Musatov VI, Sysoiev
DO, Chebanov VA, Features of two- and multicomponent heterocyclization reactions involving 3,4-
disubstituted 5-aminopyrazoles and alkyl pyruvates, Tetrahedron (2018), doi: 10.1016/j.tet.2017.12.031.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Features of two- and multicomponent
heterocyclization reactions involving 3,4-
disubstituted 5-aminopyrazoles and alkyl
pyruvates
Leave this area blank for abstract info.
Yana I. Sakhno, Anton V. Kozyrev, Sergey M. Desenko, Svetlana V. Shishkina, Vladimir I. Musatov,
Dmytro O. Sysoiev, and Valentin A. Chebanov
SSI “Institute for Single Crystals” NAS of Ukraine, Nauky Ave. 60, 61072, Kharkiv, Ukraine

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Features of two- and multicomponent heterocyclization reactions involving 3,4-
disubstituted 5-aminopyrazoles and alkyl pyruvates
Yana I. Sakhnoa, Anton V. Kozyreva, Sergey M. Desenkoa, b, Svetlana V. Shishkinaa, b, Vladimir I.
Musatova, Dmytro O. Sysoievc, and Valentin A. Chebanova, b
a Division of Chemistry of Functional Materials, State Scientific Institution “Institute for Single Crystals” of National Academy of Sciences of Ukraine,
Nauky Ave. 60, 61072 Kharkiv, Ukraine
b Faculty of Chemistry, V. N. Karazin Kharkiv National University, Svobody Sq. 4, 61077 Kharkiv, Ukraine
c Fachbereich Chemie, University of Konstanz, Fach M-720, Universitaetsstrasse 10, 78457 Konstanz, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Three-component heterocyclizations of pyruvic acids and their esters with 5-aminopyrazoles and
aromatic aldehydes, in addition to the sequential versions of these reactions, under different
activating conditions were studied. Under conventional heating, pyrazolopyrimidine derivatives
containing a hydroxyl group in the 6-position were formed in both two- and three-component
treatments. Whereas the application of an inert atmosphere did not influence the outcome of
these reactions, the use of ultrasonic irradiation led to the formation of 7-hydroxy-
Available online
Keywords:
tetrahydropyrazolopyrimidines
in
multi-component
reactions
and
6-hydroxy-
Aminoazole
Alkyl pyruvates
Ethyl p-methoxybenzylidenepyruvate
Ultrasonication
Multicomponent reaction
dihydropyrazolopyrimidines in the case of a step-by-step approach. The products of the latter
treatment were further transformed into heteroaromatized 6-hydroxy-pyrazolopyrimidines by
conventional heating.
2017 Elsevier Ltd. All rights reserved
.
1. Introduction
resulted in a mixture of dihydropyrazolopyrimidines VI and
dihydopyrazolopyridines VII and heteroaromatic
pyrazolopyridines VIII (Scheme 1). Application of
The reactions of pyruvic acid derivatives have been used for
the synthesis of various heterocyclic compounds since the
beginning of the twentieth century. Among these processes, the
most thoroughly studied were those dealing with benzylidene-
and acetylpyruvic acids.1-18 A series of our previous publications
was also devoted to two- and multicomponent reactions (MCRs)
involving pyruvic acids and different aminoazoles, such as 5-
amino-1,2,4-triazoles,1,19-23 5-aminotetrazole,2,19 5-amino-3-
methylisoxazole,24 5-aminopyrazoles7,8,10,25 and tuning the
selectivity of these heterocyclizations.7,10,20,25
ultrasonication in
a
two-component reaction yielded
dihydropyrazolopyrimidines VI selectively (Scheme 1).7 On the
other hand, the introduction of a carboxamide substituent in the
4-position of 5-aminopyrazole led to exclusively pyrimidine
acids IX both in two-component and three-component reactions
with
pyruvic
acid
derivatives
(Scheme
1).
Tetrahydropyrazolopyrimidines X were formed when ultrasonic
irradiation was applied in a three-component reaction of 5-
amino-4-ethyl-3(4’-fluorophenyl)pyrazole, pyruvic acid, and
aromatic aldehydes (Scheme 1).21
Interest in the mechanism and outcome of these reactions
arose due to the proven biological activity of the final
products21,25,26 and their multi-vector character.19-25 In particular,
in the case of pyruvic acid heterocyclizations with different
aminopyrazoles, the approach based on the application of specific
catalytic systems and non-classical activation methods
(microwave and ultrasonic irradiation), gave the opportunity to
develop selective synthetic procedures to afford various classes
It should be noted that using alkyl pyruvates as starting
reagents in the three-component reaction with substituted
aminopyrazoles I (R2 = H), and aldehydes led to the formation
of a set of reaction products which were similar to the
compounds isolated from the MCRs involving pyruvic acid with
aminoazoles and aromatic aldehydes.8,27-29
of
heterocyclic
compounds.7,8,10,19-25
For
instance,
The sequential and multicomponent reactions of aromatic
anilines with pyruvic acid based β,γ-unsaturated ester or with
pyruvates and aromatic aldehydes yielding 2- or 4-substituted
quinolines and pyrrol-2-ones have been studied. The formation of
different reaction products was described depending on whether
the reaction is sequential or a multicomponent, and on specific
reaction conditions.30-32
pyrazolopyridine acids IV were formed when 3-aryl-5-
aminopyrazole was used as a reagent in the MCRs with aromatic
aldehydes II and pyruvic acid III (Scheme 1).8 However,
applying benzylidenepyruvic acid and its substituted derivatives
V and 3-aryl-5-aminopyrazole in two-component reactions

2
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 1. Some sequential and multicomponent reactions involving pyruvic acids and different 5-aminopyrazoles.
On the other hand, MCR of the same reagents 1a-c, 2a-e and
3a,b under ultrasonication in acetic acid at room temperature for
6 hours redirected the reaction towards the formation of alkyl 7-
hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-
2. Results and discussion
The present paper is devoted to the study of some features of
MCRs between 3-aryl-4-alkyl-substituted 5-aminopyrazoles,
aromatic aldehydes, and alkyl pyruvates as well as of the
sequential version of these treatments under conventional heating
and ultrasonication.
carboxylates 5a-e (Scheme 2, Table 1). Replacement of
ultrasonication by mechanical stirring at room temperature
allowed us to obtain compounds 5a-e in a much longer reaction
time (20 h) and with lower yields and purity (TLC and NMR
control). It is believed, that the cavitation effect and the specific
influence of ultrasonication on the mass transfer enhance the
reaction and its overall efficiency.33-37Compounds 5 were
transformed into substances 4 upon boiling in acetic acid for 9
hours. The same transformations for similar compounds had been
described in our previous publications.10,20,25
In particular, it was established that the three-component
reaction of an equimolar mixture of 5-aminopyrazoles 1a-c,
aromatic aldehydes 2a-e, and pyruvic acid esters 3a,b under
conventional heating at reflux in acetic acid for 7 hours led to the
formation of a pyrimidine ring followed by an oxidative
heteroaromatization process which finally gave alkyl 6-hydroxy-
2,7-diphenylpyrazolo[1,5-a]pyrimidine-5-carboxylates
4a-s,
In our previous work8 it was found that three-component
reactions of 5-amino-3-methylpyrazole or 5-amino-3-
(Scheme 2, Table 1, Method A). It is worth noting that the same
treatment under an inert atmosphere also yielded compounds 4a-s
while neither dihydropyrazolopyrimidine nor the compound
without a hydroxyl-group were observed. This experimental fact
shows that the oxidation occurs irrespective of the presence of
oxygen in the reaction mixture and may be connected with more
complex processes such as disproportionation.8,21 Indeed, the
yields of pyrimidine derivatives were always lower than 50%,
both under atmospheric and inert conditions.
arylpyrazole (R2
=
H) with aromatic aldehydes and ethyl
pyruvate under conventional heating at reflux always led to the
formation of heteroaromatized pyrazolopyridines with no
hydroxy-group in the pyridine ring (e.g. compound IV, Scheme
1).

3
ACCEPTED MANUSCRIPT
R
OH
N
N
R1
O
, 7 h
OAlk
4a-s
R3
N
R2
H
Method A
O
2a-e
R1
N
R2
NH2
O
AcOH, , 9 h
Me
AcOH
OAlk
Me
O
OAlk
OH
N
Me
O
H
O
Me
1a-c
N
N
N
3a,b
NH
N
R1
O
O
))), r.t., 6 h
O
N
R3
6
Me
R2
H
5a-e
side-product
Scheme 2. Multicomponent reactions of 5-aminopyrazoles 1a-c, aldehydes 2a-e, and alkyl pyruvates 3a,b.
Table 1. Three-component reactions of 5-aminopyrazoles 1a-c, aldehydes 2a-e, and alkyl pyruvates 3a,b (See Scheme 2).
Building block
Product
Aminoazole
R1
Aldehyde
Pyruvic Acid Esters
Yield
(%)
N
R2
N
R3
N
Alk
C2H5
N
1a
1b
1c
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
1a
1a
1a
1a
1a
C6H5
C2H5
C2H5
CH3
2a
2a
2a
2b
2c
2d
2e
2b
2c
2d
2e
2c
2d
2b
2c
2d
2e
2a
2d
2a
2b
2c
2d
2e
4-CH3O-С6H4
4-CH3O-С6H4
4-CH3O-С6H4
C6H5
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3a
3a
3a
3a
3b
3b
3a
3a
3a
3a
3a
4a
4b
4c
4d
4e
4f
23
4-F-C6H4
4-CH3-C6H4
C6H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
i-C3H7
i-C3H7
C2H5
C2H5
C2H5
C2H5
i-C3H7
i-C3H7
C2H5
C2H5
C2H5
C2H5
C2H5
32
17
18
27
24
17
23
27
29
18
19
17
22
21
25
18
18
19
50
50
52
50
49
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
C6H5
4-F-C6H4
C6H5
4-Cl-C6H4
4-COOCH3-C6H4
C6H5
C6H5
4g
4h
4i
4-F-C6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
C6H5
4-F-C6H4
4-Cl-C6H4
4-COOCH3-C6H4
4-F-C6H4
4j
4k
4l
4-Cl-C6H4
C6H5
4m
4n
4o
4p
4q
4r
4s
CH3
4-F-C6H4
CH3
4-Cl-C6H4
4-COOCH3-C6H4
4-CH3O-С6H4
4-Cl-C6H4
4-CH3O-С6H4
C6H5
CH3
CH3
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
5a
5b
5c
5d
5e
C6H5
C6H5
4-F-C6H4
C6H5
4-Cl-C6H4
4-COOCH3-C6H4
C6H5

4
Tetrahedron
ACCEPTED MANUSCRIPT
To identify the cause of the low yields of products 4a-s the
corresponding mother liquors were examined by 1H NMR
spectroscopy and it was determined that the reaction solution
contained unreacted aromatic aldehyde and an additional
compound which was identified as a diacylation product 6. The
structure of compound 6 was proven by counter synthesis. To
avoid the formation of the unwanted side-product 6, different
reaction conditions were tested with application of several protic
and aprotic solvents containing acid and base catalysts as well as
microwave irradiation. However, all of these efforts were in vain.
It should be noted that heterocyclization reactions leading to
the formation of 6-hydroxy-containing azoloazines were
discussed only in a few publications38-40 and never for MCRs. For
instance, Desenko et al.40 described the two-component treatment
of 5-amino-3-methylpyrazole (7) with α,β-unsaturated ketone 8:
the reagents were heated in DMF under an argon atmosphere and
a mixture of four products 9, 10, 11, 12 was formed (Scheme 3).
Scheme 4. The sequential reaction of 5-aminopyrazoles 1a-c
with ethyl p-methoxybenzylidenepyruvate (13).
Table 2. The two-component reactions of 5-aminopyrazoles 1a-c
with ethyl p-methoxybenzylidenepyruvate (13) (See Scheme 4).
Activation method
Aminoazole
Heating
R2
Ultrasonication
Yield
(%)
Scheme 3. The two-component reaction of 5-amino-3-
methylpyrazole (7) with α,β-unsaturated ketone 8.40
Yield
(%)
N
R1
N
N
B
C
Compound 9 was obtained under an inert atmosphere and its
reaction with oxygen led to formation of substance 10 while
further oxidation led to product 12. Attempts at the dehydration
of compound 10 in different solvents (DMF, alcohols with HCl,
KOH, ZnCl2 or p-TsOH) were unsuccessful.
C6H5
C2H5
C2H5
CH3
31 75
37 64
28 72
42
1a
1b
1c
4a
4b
4c
14a
4-FC6H4
4-CH3C6H4
49
41
14b + 4b
14c + 4c
Therefore, the next step of the study was to apply a sequential
reaction instead of the three-component one. The linear pathway
included the two-step synthesis of β,γ-unsaturated ketoester 13
starting from 4-methoxybenzaldehyde 2a and pyruvic acid III,
followed by reaction with ethanol and acetyl chloride.41-43 Further
reactions of 3-aryl-4-alkylsubstituted 5-aminopyrazoles 1a-c with
the ethyl ester of p-methoxybenzylidenepyruvic acid 13 under
conventional heating gave pyrazolopyrimidine carboxylic acid
esters 4a-c (Scheme 4, Method B), which were identical to the
compounds isolated from the MCR of 5-aminopyrazoles 1a-c,
aromatic aldehydes 2a-e, and pyruvic acid esters 3a,b (Scheme
2). The yields were rather low (28-37%) as in the case of the
MCR (Table 2). Application of an inert atmosphere had no
influence on the outcome of the reaction, as was stated above for
the MCR.
3. Structure elucidation
Purity and structures of the synthesized compounds were
established by elemental analysis, mass-spectrometry, 1H and 13
C
NMR spectroscopy, and by X-ray diffraction study (see
Experimental part).
For instance, the 1H NMR spectra of 6-hydroxy-
pyrazolopyrimidines 4a-s exhibited a broad singlet for the OH-
group at 9.8-10.2 ppm, peaks of aromatic protons at 7.2-8.45
ppm and signals corresponding to the alkyl substituent. However,
this spectral data is not enough to establish the structure of
compounds 4a-s and to identify one of two possible isomers XI
and XII (Fig. 1).
On the other hand, carrying out the same treatment under
ultrasonic irradiation for 2 hours at room temperature instead of
compounds 5 (Scheme 2), led to other heterocyclic compounds ˗
ethyl
6-hydroxy-7-(4-methoxyphenyl)-3-alkyl-2-aryl-6,7-
dihydropyrazolo[1,5-a]pyrimidine-5-carboxylates 14a-c which in
cases of aminoazoles 1b,c were accompanied by small amounts
of the heterocycles 4b,c (Scheme 4, Table 2). All attempts to
separate these mixtures by crystallization were unsuccessful and
only heteroaromatized pyrimidines 4 were isolated. It should be
noted that compound 14a and a mixture of pyrimidines 14b,c and
4b,c were transformed into individual substances 4a-c upon
boiling in acetic acid for 2 hours open to the air (Method C).
Fig. 1. Alternative structures XI and XII for 6-
hyrdoxypyrazolopyrimidines 4a-s.
Therefore, the structure of compounds 4a-s was additionally
proven by an X-ray analysis of compound 4o (Fig. 2).

compounds
4
were isolated from the reaction of 5-
ACCEPTED MANUSCRIPT
aminopyrazoles 1 with p-methoxybenzylidenepyruvic acid ethyl
ester (13).
5. Experimental section
5.1. General experimental details
The starting β,γ-unsaturated ketoester 1341-43, 3,4-substituted
5-aminopyrazoles 1a-c44 and isopropyl 2-oxopropanoate (3b)45
were synthesized according to the known literature methods.
Ethyl 2-oxopropanoate (3a) is commercially available.
Fig. 2. Molecular structure of ethyl 7-(4-fluorophenyl)-6-
hydroxy-3-methyl-2-(p-tolyl)-pyrazolo[1,5-a]pyrimidine-5-
carboxylate (4o) according to X-ray diffraction analysis.
Melting points of all the compounds synthesized were
determined with a Kofler melting point apparatus and are
uncorrected. The NMR spectra were recorded in DMSO-d6 and
CDCl3 at 400 MHz with a Varian MR-400 spectrometer, at 400
MHz (100 MHz for 13C) and at 600 MHz (150 MHz for 13C) with
a Bruker Avance DRX600. The mass spectra were measured on a
GS-MS Varian 1200L (direct input of sample, ionizing voltage
70 eV) instrument. Elemental analysis was performed on a Euro
Vector EA-3000.
1
The H NMR spectra of ethyl carboxylates 5a-e exhibited a
multiplet for the CH2-group at ca. 1.95-2.38 ppm, a broad signal
for the NH-group at 7.21-7.30 ppm, a broad singlet of the OH-
group at 6.40-6.60 ppm, a multiplet for the CH-group at position
5 at 4.46-4.76 ppm and a multiplet of aromatic protons at 6.88-
8.07. The spectra also contained signals of an ethyl ester group as
well as a quartet of the CH2-group at 4.05-4.26 and a triplet of the
methyl group at 1.16-1.17 ppm and signals for the other terminal
Ultrasonication was performed using the standard US-bath
(SELDI, Ukraine) with a working frequency of 44.2 kHz.
Microwave experiments were carried out using the EmrysTM
Creator EXP synthesizer from Biotage AB (Uppsala, Sweden)
possessing a single-mode microwave cavity producing controlled
irradiation at 2.45 MHz. Experiments were carried out in sealed
microwave process vials utilizing the high absorbance level. The
reaction time reflects irradiation times at the set reaction
temperature (fixed hold times).
substituents.
The
spectral
data
obtained
for
the
pyrazolopyrimidines 5 may also correspond to two possible
isomers XIII and XIV (Fig. 3). Additional NOE experiments,
confirming the spatial closeness of the CH-proton at position 5
with the pyrimidine NH-group, allowed us to exclude structure
XIV. Also, the structure of compounds 5a-e was additionally
1
confirmed from the H NMR spectra by their comparison with
literature data for similar pyrimidines.21,25
5.2. General procedure for the synthesis of alkyl 6-hydroxy-2,7-
diphenylpyrazolo[1,5-a]pyrimidine-5-carboxylates 4
O
N
OAlk
OH
R3
N
N
N
R1
OH
O
R1
(Method A)
A mixture of appropriate 3-aryl-4-alkyl-
OAlk
N
H
substituted 5-aminopyrazole 1 (0.54 mmol), aromatic aldehyde 2
(0.54 mmol) and alkyl pyruvate 3 (0.54 mmol) in 2 mL of acetic
acid was heated at reflux under argon atmosphere for 7 hours.
The mixture was allowed to stand until a precipitate formed. The
precipitate was then filtered off and dried in vacuo.
N
R3
R2
R2
H
XIV
XIII
Fig. 3. Alternative structures XIII and XIV for pyrimidines 5.
The 1H-NMR spectra of pyrimidines 14a-c exhibited a doublet
for the OH-group at 6.61 ppm (J 4.6 Hz), doublet (J 1.1 Hz) for
the CH group at 5.57, a doublet of doublets (J 5.3, 1.1 Hz) for the
CH group at 4.79, and peaks for aromatic protons around 6.64-
7.75 ppm. For ethyl esters of compounds 14, the quartet of the
CH2-group was around 4.10-4.41 and triplet of the methyl-group
was at 1.26 ppm. Therefore spectral data confirmed the structure
of compounds 14 as 6-hydroxy-6,7-dihydropyrazolo[1,5-
a]pyrimidines.
(Method B) A mixture of the appropriate 5-aminopyrazole 1
(0.54 mmol) and the ethyl (E)-4-(4-methoxyphenyl)-2-oxobut-3-
enoate (13) (0.12 g, 0.54 mmol) in 2 mL of acetic acid was
heated at reflux for 4 h. After cooling, the precipitate was filtered
off and vacuum dried.
(Method С) Compound 14 was heated at reflux for 2 h in 2
mL of acetic acid. After cooling, the precipitate was filtered off
and vacuum dried.
5.2.1. Ethyl 3-ethyl-6-hydroxy-7-(4-methoxyphenyl)-2-
phenylpyrazolo[1,5-a]pyrimidine-5-carboxylate (4a)
Yellow solid (0.05 g, 23%), m.p. 149-150 °C; [Found: C,
68.91; H, 5.61; N, 10.18. C24H23N3O4 requires C, 69.05; H, 5.55;
4. Conclusion
In summary, the multicomponent and sequential reactions
involving 3-aryl-4-alkylsubstituted 5-aminopyrazoles, aromatic
aldehydes and p-methoxybenzylidenepyruvic esters or pyruvic
acid esters were studied. Multicomponent heterocyclization of
pyrazoles 1 and aromatic aldehydes 2 with ethyl pyruvate under
ultrasonication in contrast to two-component reactions involving
β,γ-unsaturated ketoester 13 proceeded with the formation of
tetrahydropyrimidine ring (compounds 5) instead of
dihydropyrimidines 14. On the other hand, MCRs under
conventional heating at reflux yielded ethyl 6-hydroxy-2,7-
diphenylpyrazolo[1,5-a]pyrimidine-5-carboxylates 4 containing
an OH-group in the 6-position of heterocycle. The same
N, 10.07%]; δH (400 MHz, CDCl3) 10.32 (s, 1H, OH), 7.02-8.16
(m, 9Н, Ar), 4.62 (q, J 7.1 Hz, 2H, ОCH2CH3), 3.92 (s, 3H,
OCH3), 3.14 (q, J 7.5 Hz, 2H, CH2CH3), 1.56 (t, J 7.1 Hz, 3H,
ОCH2CH3), 1.37 (t, J 7.5 Hz, 3H, CH2CH3); δC (150 MHz,
CDCl3) 169.0, 160.9, 153.7, 143.6, 141.3, 134.0, 132.4, 131.7,
128.5, 131.0, 128.4, 128.2, 119.3, 113.5, 112.0, 63.1, 55.4, 16.7,
14.9, 14.2; MS (EI, 70 eV), m/z (%): 418 (26.8), 417 (99.9)
[M+], 356 (25.9), 314 (25.4).
5.2.2. Ethyl 3-ethyl-2-(4-fluorophenyl)-6-hydroxy-7-(4-
methoxyphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (4b)

6
Tetrahedron
ACCEPTED MANUSCRIPT
Yellow solid (0.08 g, 32%), m.p. 193-194 °C; [Found: C,
(m, 9Н, Ar), 4.46 (q, J 7.2 Hz, 2H, ОCH2CH3), 3.89 (s, 3H,
65.86; H, 5.15; N, 10.05. C24H22FN3O4 requires C, 66.2; H, 5.09;
N, 9.65%] δH (400 MHz, DMSO-d6) 10.05 (s, 1H, OH), 7.00-
OCH3), 2.98 (q, J 7.4 Hz, 2H, CH2CH3), 1.37 (t, J 7.1 Hz, 3H,
ОCH2CH3), 1.22 (t, J 7.4 Hz, 3H, CH2CH3); δC (150 MHz,
CDCl3) 166.0, 165.9, 152.3, 142.7, 138.8, 138.7, 133.3, 132.2,
131.6, 131.1, 130.7, 128.8, 128.4, 127.9, 110.6, 62.4, 52.4, 16.0,
14.9, 14.1; MS (EI, 70 eV), m/z (%): 445 (88.2) [M+], 430
(39.5), 399 (45.6), 342 (99.9).
;
7.90 (m, 8Н, Ar), 4.44 (q, J 7.2 Hz, 2H, ОCH2CH3), 3.81 (s, 3H,
OCH3), 2.96 (q, J 7.5 Hz, 2H, CH2CH3), 1.37 (t, J 7.0 Hz, 3H,
ОCH2CH3), 1.21 (t, J 7.5 Hz, 3H, CH2CH3); δC (150 MHz,
CDCl3) 166.7, 162.6 (d, JC-F 245.7 Hz), 160.9, 151.8, 143.3,
141.7, 138.6, 138.5, 133.5, 132.7, 130.4 (d, JC-F 8.4 Hz), 119.6,
116.1 (d, JC-F 21.5 Hz), 114.0, 110.5, 62.7, 55.8, 16.4, 15.3, 14.5;
MS (EI, 70 eV), m/z (%): 435 (99.9) [M+], 388 (92.7), 332
(86.2).
5.2.8. Ethyl 3-ethyl-2-(4-fluorophenyl)-6-hydroxy-7-
phenylpyrazolo[1,5-a]pyrimidine-5-carboxylate (4h)
Yellow solid (0.05 g, 23%), m.p. 168-169 °C; [Found: C,
68.03; H, 5.17; N, 10.47. C23H20FN3O3 requires C, 68.14; H,
4.97; N, 10.36%]; δH (400 MHz, DMSO-d6) 9.99 (s, 1H, OH),
7.22-7.89 (m, 9Н, Ar), 4.44 (q, J 7.2 Hz, 2H, ОCH2CH3), 2.95 (q,
J 7.4 Hz, 2H, CH2CH3), 1.36 (t, J 7.1 Hz, 3H, ОCH2CH3), 1.21 (t,
J 7.3 Hz, 3H, CH2CH3); δC (150 MHz, CDCl3) 168.9, 162.9 (d,
JC-F 247.8 Hz), 152.9, 143.5, 141.5, 131.7, 131.3, 130.6, 130.3,
130.0 (d, JC-F 8.2 Hz), 129.9, 128.1, 127.1, 115.5 (d, JC-F 21.5
Hz), 111.9, 63.2, 16.6, 14.8, 14.2; MS (EI, 70 eV), m/z (%): 406
(30.3), 405 (99.9) [M+], 344 (26.5).
5.2.3. Ethyl 6-hydroxy-7-(4-methoxyphenyl)-3-methyl-2-(p-
tolyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (4c)
Yellow solid (0.04 g, 17%), m.p. 179-180 °C; [Found: C,
68.92; H, 5.68; N, 10.17. C24H23N3O4 requires C, 69.05; H, 5.55;
N, 10.07%]; δH (400 MHz, DMSO-d6) 10.06 (s, 1H, OH), 6.86-
8.45 (m, 8Н, Ar), 4.45 (q, J 7.2 Hz, 2H, ОCH2CH3), 3.85 (s, 3H,
OCH3), 2.47 (s, 3H, CH3), 2.33 (s, 3H, CH3), 1.38 (t, J 7.1 Hz,
3H, ОCH2CH3); δC (150 MHz, CDCl3) 168.9, 160.9, 154.0,
144.0, 141.2, 138.1, 131.7, 130.9, 128.6, 127.5, 123.7, 121.0,
119.3, 111.1, 105.1, 63.2, 55.4, 21.3, 14.1, 9.04; MS (EI, 70 eV),
m/z (%): 417 (99.9) [M+], 370 (86.7).
5.2.9. Ethyl 3-ethyl-2,7-bis(4-fluorophenyl)-6-
hydroxypyrazolo[1,5-a]pyrimidine-5-carboxylate (4i)
Yellow solid (0.06 g, 27%), m.p. 187-188 °C; [Found: C,
65.09; H, 4.67; N, 10.07. C23H19F2N3O3 requires C, 65.24; H,
4.52; N, 9.92%]; δH (400 MHz, DMSO-d6) 10.03 (s, 1H, OH),
7.21-7.99 (m, 8Н, Ar), 4.45 (q, J 7.2 Hz, 2H, ОCH2CH3), 2.95 (q,
J 7.3 Hz, 2H, CH2CH3), 1.36 (t, J 7.1 Hz, 3H, ОCH2CH3), 1.20 (t,
J 7.4 Hz, 3H, CH2CH3); δC (150 MHz, CDCl3) 168.8, 163.5 (d,
JC-F 251.7 Hz), 162.8 (d, JC-F 247.7 Hz), 152.9, 143.5, 141.5,
132.9 (d, JC-F 8.5 Hz), 131.3, 130.6, 130.0 (d, JC-F 8.2 Hz), 129.8,
123.1, 115.6 (d, JC-F 21.6 Hz), 115.3 (d, JC-F 21.8 Hz), 112.1,
63.2, 16.6, 14.8, 14.1; MS (EI, 70 eV), m/z (%): 424 (27.7), 423
(99.9) [M+], 362 (20.2).
5.2.4. Ethyl 3-ethyl-6-hydroxy-2,7-diphenylpyrazolo[1,5-
a]pyrimidine-5-carboxylate (4d)
Yellow solid (0.04 g, 18%), m.p. 141-142 °C; [Found: C,
72.21; H, 6.10; N, 11.38. C23H21N3O3 requires C, 71.3; H, 5.46;
N, 10.85%]; δH (400 MHz, DMSO-d6) 9.99 (s, 1H, OH), 7.20-8.0
(m, 10Н, Ar), 4.45 (q, J 7.0 Hz, 2H, ОCH2CH3), 2.97 (q, J 7.7
Hz, 2H, CH2CH3), 1.37 (t, J 7.1 Hz, 3H, ОCH2CH3), 1.22 (t, J 7.4
Hz, 3H, CH2CH3); δC (150 MHz, CDCl3) 168.9, 153.8, 143.5,
141.4, 140.8, 136.6, 133.7, 131.6, 131.1, 128.4, 126.9, 123.7,
112.4, 112.2, 109.2, 63.1, 16.6, 14.9, 14.1; MS (EI, 70 eV), m/z
(%): 387 (58.7) [M+], 372 (56.1), 341 (99.9), 284 (58.8).
5.2.10. Ethyl 7-(4-chlorophenyl)-3-ethyl-2-(4-fluorophenyl)-6-
hydroxypyrazolo[1,5-a]pyrimidine-5-carboxylate (4j)
5.2.5. Ethyl 3-ethyl-7-(4-fluorophenyl)-6-hydroxy-2-
phenylpyrazolo[1,5-a]pyrimidine-5-carboxylate (4e)
Yellow solid (0.07 g, 29%), m.p. 239-240 °C; [Found: C,
62.62; H, 4.47; N, 9.69. C23H19ClFN3O3 requires C, 62.8; H,
4.35; N, 9.55%]; δH (400 MHz, DMSO-d6) 9.95 (s, 1H, OH),
7.16-7.96 (m, 8Н, Ar), 4.44 (q, J 7.0 Hz, 2H, ОCH2CH3), 2.95 (q,
J 7.2 Hz, 2H, CH2CH3), 1.36 (t, J 7.2 Hz, 3H, ОCH2CH3), 1.20 (t,
J 7.2 Hz, 3H, CH2CH3); δC (150 MHz, CDCl3) 168.8, 162.9 (d,
JC-F 248.2 Hz), 152.9, 143.5, 141.5, 136.2, 132.1, 131.3, 130.4,
130.0 (d, JC-F 8.1 Hz), 129.8, 128.4, 125.5, 115.6 (d, JC-F 21.5
Hz), 112.2, 63.3, 16.6, 14.8, 14.2; MS (EI, 70 eV), m/z (%): 441
(24.9), 439 (76.4) [M+], 424 (45.5), 395 (25.5), 393 (99.9), 336
(62.0).
Yellow solid (0.06 g, 27%), m.p. 152-153 °C; [Found: C,
68.08; H, 5.08; N, 10.40. C23H20FN3O3 requires C, 68.14; H,
4.97; N, 10.36%]; δH (400 MHz, DMSO-d6) 9.83 (s, 1H, OH),
7.17-8.19 (m, 9Н, Ar), 4.45 (q, J 7.1 Hz, 2H, ОCH2CH3), 2.97 (q,
J 7.5 Hz, 2H, CH2CH3), 1.37 (t, J 7.1 Hz, 3H, ОCH2CH3), 1.22 (t,
J 7.9 Hz, 3H, CH2CH3); δC (150 MHz, CDCl3) 168.5, 162.7 (d,
JC-F 159.2 Hz), 153.5, 147.0, 144.3, 143.1, 141.0, 133.2, 132.6,
132.5, 130.7, 130.2, 128.0 (d, JC-F 34.5 Hz), 114.9 (d, JC-F 21.8
Hz), 112.0, 62.8, 16.3, 14.5, 13.8; MS (EI, 70 eV), m/z (%): 405
(40.2) [M+], 390 (40.8), 359 (99.9), 302 (88.6).
5.2.11. Ethyl 3-ethyl-2-(4-fluorophenyl)-6-hydroxy-7-(4-
(methoxycarbonyl)phenyl)pyrazolo[1,5-a]pyrimidine-5-
carboxylate (4k)
5.2.6. Ethyl 7-(4-chlorophenyl)-3-ethyl-6-hydroxy-2-
phenylpyrazolo[1,5-a]pyrimidine-5-carboxylate (4f)
Yellow solid (0.05 g, 18%), m.p. 222-223 °C; [Found: C,
64.52; H, 4.98; N, 9.56. C25H22FN3O5 requires C, 64.79; H, 4.78;
N, 9.27%]; δH (400 MHz, DMSO-d6) 9.99 (s, 1H, OH), 7.15-8.18
(m, 8Н, Ar), 4.45 (q, J 7.2 Hz, 2H, ОCH2CH3), 3.89 (s, 3H,
OCH3), 2.96 (q, J 7.3 Hz, 2H, CH2CH3), 1.37 (t, J 7.1 Hz, 3H,
CH2CH3), 1.21 (t, J 7.3 Hz, 3H, CH2CH3); δC (150 MHz, DMSO-
d6) 166.4, 166.3 , 162.8 (d, JC-F 246.0 Hz), 152.3, 143.4, 139.1,
132.6, 132.2, 131.6, 131.4, 130.4 (d, JC-F 8.3 Hz), 130.2, 129.6,
129.1, 115. 9 (d, JC-F 21.5 Hz), 111.3, 62.7, 52.5, 16.4, 14.9, 14.3;
MS (EI, 70 eV), m/z (%): 464 (31.9), 463 (99.9) [M+], 360
(29.2).
Yellow solid (0.06 g, 24%), m.p. 157-158 °C; [Found: C,
65.39; H, 4.86; N, 10.04. C23H20ClN3O3 requires C, 65.48; H,
4.78; N, 9.96%]; δH (400 MHz, DMSO-d6) 10.35 (s, 1H, OH),
7.25-8.11 (m, 9Н, Ar), 4.45 (q, J 7.0 Hz, 2H, ОCH2CH3), 2.97 (q,
J 7.4 Hz, 2H, CH2CH3), 1.37 (t, J 7.1 Hz, 3H, ОCH2CH3), 1.22 (t,
J 7.5 Hz, 3H, CH2CH3); δC (150 MHz, CDCl3) 168.8, 153.8,
143.5, 141.4, 136.1, 133.6, 132.7, 131.5, 131.1, 130.3, 128.8,
127.8, 125.5, 125.3, 112.4, 63.1, 16.6, 14.8, 14.1; MS (EI, 70
eV), m/z (%): 423 (47.2), 422 (34), 421 (99.9) [M+], 360 (38.7),
332 (31.0).
5.2.7. Ethyl 3-ethyl-6-hydroxy-7-(4-(methoxycarbonyl)phenyl)-2-
5.2.12. Isopropyl 3-ethyl-2,7-bis(4-fluorophenyl)-6-
phenylpyrazolo[1,5-a]pyrimidine-5-carboxylate (4g)
hydroxypyrazolo[1,5-a]pyrimidine-5-carboxylate (4l)
Yellow solid (0.05 g, 19%), m.p. 182-183 °C; [Found: C,
65.78; H, 4.92; N, 9.66. C24H21F2N3O3 requires C, 65.90; H, 4.84;
Yellow solid (0.04 g, 17%), m.p. 168-169 °C; [Found: C,
67.31; H, 5.34; N, 9.53. C25H23N3O5 requires C, 67.41; H, 5.2; N,
9.43%]; δH (400 MHz, DMSO-d6) 9.96 (s, 1H, OH), 6.69-8.48

N, 9.61%]; δH
153.5, 144.1, 134.1, 132.6, 131.7, 130.0, 127.4, 127.1, 126.9,
126.1, 122.8, 112.8, 106.2, 61.9, 52.7, 21.3, 8.7; MS (EI, 70 eV),
m/z (%): 445 (49.7) [M+], 399 (29.8), 371 (22.5), 343 (27.4).
(400 MHz, DMSO-d ) 10.04 (As, C1HC, EOHP)T, 6E.8D5- MANUSCRIPT
6
8.39 (m, 8Н, Ar), 5.23 (gept, J 6.3 Hz, 1H, CH(CH3)2), 2.96 (q, J
7.3 Hz, 2H, CH2CH3), 1.37 (d, J 6.2 Hz, 6H, CH(CH3)2), 1.21 (t,
J 7.9 Hz, 3H, CH2CH3); δC (100 MHz, DMSO-d6) 168.4, 163.5
(d, JC-F 251.0 Hz), 162.9 (d, JC-F 247.7 Hz), 152.7, 143.5, 141.4,
132.9 (d, JC-F 8.8 Hz), 131.6, 130.6, 129.9 (d, JC-F 8.4 Hz), 129.8,
123.0, 115.5 (d, JC-F 21.8 Hz), 115.2 (d, JC-F 22.2 Hz), 112.0,
71.4, 21.7, 16.6, 14.7; MS (EI, 70 eV), m/z (%): 437 (86.8) [M+],
377 (99.9), 320 (40.8).
5.2.18. Isopropyl 6-hydroxy-7-(4-methoxyphenyl)-3-methyl-2-(p-
tolyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (4r)
Yellow solid (0.04 g, 18%), m.p. 199-200 °C; [Found: C,
69.51; H, 5.92; N, 9.77. C25H25N3O4 requires C, 69.59; H, 5.84;
N, 9.74%]; δH (400 MHz, DMSO-d6) 10.02 (s, 1H, OH), 7.04-
7.99 (m, 8Н, Ar), 5.30 (gept, J 6.1 Hz, 1H, CH(CH3)2), 3.85 (s,
3H, OCH3), 2.46 (s, 3H, CH3), 2.34 (s, 3H, CH3), 1.39 (d, J 6.3
Hz, 6H, CH(CH3)2); δC (100 MHz, DMSO-d6) 171.8, 166.4,
160.8, 142.1, 140.8, 135.1, 133.4, 132.6, 129.6, 128.0, 126.9,
126.1, 122.3, 114.1, 113.9, 106.2, 70.8, 55.8, 21.9, 21.3, 9.0; MS
(EI, 70 eV), m/z (%): 431 (93.9) [M+], 371 (41.1), 300 (27.8).
5.2.13. Isopropyl 7-(4-chlorophenyl)-3-ethyl-2-(4-fluorophenyl)-
6-hydroxypyrazolo[1,5-a]pyrimidine-5-carboxylate (4m)
Yellow solid (0.04 g, 17%), m.p. 181-182 °C; [Found: C,
63.42; H, 4.72; N, 9.35. C24H21ClFN3O3 requires C, 63.51; H,
4.66; N, 9.26%]; δH (400 MHz, DMSO-d6) 9.87 (s, 1H, OH),
6.98-8.41 (m, 8Н, Ar), 5.27 (gept, J 6.4 Hz, 1H, CH(CH3)2), 2.96
(q, J 7.6 Hz, 2H, CH2CH3), 1.38 (d, J 6.3 Hz, 6H, CH(CH3)2),
1.21 (t, J 7.5 Hz, 3H, CH2CH3); δC (150 MHz, CDCl3) 168.0,
162.4 (d, JC-F 240.8 Hz), 152.4, 143.1, 141.1, 135.7, 131.7, 131.2,
129.8 (d, JC-F 8.5 Hz), 129.8, 129.4, 128.1, 125.1, 115.2 (d, JC-F
21.7 Hz), 111.8, 71.2, 21.3, 16.2, 14.4; MS (EI, 70 eV), m/z (%):
455 (5.5), 453 (17.4) [M+], 413 (52.1), 411(99.9), 336 (41.5).
5.2.19. Isopropyl 7-(4-chlorophenyl)-6-hydroxy-3-methyl-2-(p-
tolyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (4s)
Yellow solid (0.05 g, 19%), m.p. 215-216 °C; [Found: C,
66.05; H, 5.15; N, 9.72. C24H22ClN3O3 requires C, 66.13; H, 5.09;
N, 9.64%]; δH (400 MHz, CDCl3) 10.43 (s, 1H, OH), 6.84-8.39
(m, 8Н, Ar), 5.40 (gept, J 6.1 Hz, 1H, CH(CH3)2), 2.64 (s, 3H,
CH3), 2.41 (s, 3H, CH3), 1.54 (d, J 5.9 Hz, 6H, CH(CH3)2); δC
(100 MHz, DMSO-d6) 168.1, 153.5, 144.6, 141.0, 137.8, 136.56,
135.6, 131.8, 131.0, 130.3, 129.8, 128.9, 128.0, 127.6, 125.2,
105.2, 71.3, 21.3, 21.0, 8.7; MS (EI, 70 eV), m/z (%): 437 (20.1),
435 (47.7) [M+], 377 (41.5), 351 (22.8), 350 (29.0), 348 (33.2),
347 (38.6), 320 (42.7), 319 (42.7), 319 (34.5), 318 (99.9), 304
(41.3).
5.2.14. Ethyl
tolyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (4n)
6-hydroxy-3-methyl-7-phenyl-2-(p-
Orange solid (0.05 g, 22%), m.p. 203-204 °C; [Found: C,
71.22; H, 5.52; N, 10.97. C23H21N3O3 requires C, 71.3; H, 5.46;
N, 10.85%]; δH (400 MHz, CDCl3) 10.27 (s, 1H, OH), 6.89-8.23
(m, 9Н, Ar), 4.61 (q, J 4.9 Hz, 2H, ОCH2CH3), 2.65 (s, 3H, CH3),
2.40 (s, 3H, CH3), 1.56 (t, J 5.0 Hz, 3H, CH2CH3); δC (150 MHz,
CDCl3) 168.5, 153.7, 143.6, 140.9, 137.8, 131.3, 130.6, 130.4,
130.3, 129.9, 128.8, 127.7, 127.6, 126.7, 104.9, 62.9, 21.0, 13.8,
8.7; MS (EI, 70 eV), m/z (%): 387 (99.9) [M+], 341 (33.3), 284
(40.5), 270 (47.0).
5.3. General procedure for the synthesis of ethyl 3-ethyl-7-
hydroxy-2-phenyl-5-aryl-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-7-carboxylates 5
A mixture of 3-phenyl-4-ethyl 5-aminopyrazole 1a (0.1 g,
0.54 mmol), aromatic aldehyde 2 (0.54 mmol) and ethyl pyruvate
3a (0.06 g, 0.54 mmol) in 2 mL of acetic acid was ultrasonicated
at room temperature for 6 h. The mixture was allowed to stand
overnight. The solid precipitated was collected by filtration and
vacuum dried.
5.2.15. Ethyl
7-(4-fluorophenyl)-6-hydroxy-3-methyl-2-(p-
tolyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (4o)
Orange solid (0.05 g, 21%), m.p. 195-196 °C; [Found: C,
68.09; H, 5.06; N, 10.48. C23H20FN3O3 requires C, 68.14; H,
4.97; N, 10.36%]; δH (400 MHz, DMSO-d6) 10.21 (s, 1H, OH),
6.97-8.19 (m, 8Н, Ar), 4.46 (q, J 7.0 Hz, 2H, ОCH2CH3), 2.47 (s,
3H, CH3), 2.35 (s, 3H, CH3), 1.39 (t, J 7.0 Hz, 3H, CH2CH3); δC
(100 MHz, CDCl3) 168.8, 163.0 (d, JC-F 249.1 Hz), 154.0, 143.8,
141.2, 138.2, 132.7, 130.9, 130.7, 130.5 (d, JC-F 8.2 Hz), 129.2,
128.9, 123.0, 115.1 (d, JC-F 23.2 Hz), 105.4, 63.3, 28.7, 23.4, 8.0;
MS (EI, 70 eV), m/z (%): 405 (33.6) [M+], 359 (23.3), 289
(22.3), 288 (99.9).
5.3.1. Ethyl 3-ethyl-7-hydroxy-5-(4-methoxyphenyl)-2-phenyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylate (5a)
White solid (0.11 g, 50%), m.p. 139-140 °C; [Found: C,
68.27; H, 6.52; N, 10.10. C24H27N3O4 requires C, 68.39; H, 6.46;
N, 9.97%]; δH (400 MHz, DMSO-d6) 6.88-7.61 (m, 9Н, Ar), 7.27
(d, J 6.9 Hz, 1H, NH), 6.43 (s, 1H, OH), 4.46-4.69 (m, 1H, CH),
4.18 (q, J 6.9 Hz, 2H, ОCH2CH3), 3.74 (s, 3H, OCH3), 2.42 (q, J
7.2 Hz, 2H, CH2CH3), 1.95-2.35 (m, 2H, CH2), 1.17 (t, J 7.0 Hz,
3H, ОCH2CH3), 1.00 (t, J 7.2 Hz, 3H, CH2CH3); δC (100 MHz,
DMSO-d6) 169.6, 158.9, 148.7, 144.3, 134.9, 134.0, 128.2,
128.1, 127.1, 113.9, 98.2, 82.0, 61.5, 55.2, 50.2, 42.1, 15.2, 14.9,
14.0; MS (EI, 70 eV), m/z (%): 421 (89.1) [MH+], 348 (48.3),
306 (49.0), 187 (61.3), 172 (90.1), 161 (99.9).
5.2.16. Ethyl 7-(4-chlorophenyl)-6-hydroxy-3-methyl-2-(p-
tolyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (4p)
Yellow solid (0.06 g, 25%), m.p. 194-195 °C; [Found: C,
65.39; H, 4.84; N, 10.01. C23H20ClN3O3 requires C, 65.48; H,
4.78; N, 9.96%]; δH (400 MHz, DMSO-d6) 10.21 (s, 1H, OH),
6.97-8.19 (m, 8Н, Ar), 4.46 (q, J 7.0 Hz, 2H, ОCH2CH3), 2.47 (s,
3H, CH3), 2.35 (s, 3H, CH3), 1.39 (t, J 7.0 Hz, 3H, CH2CH3); δC
(150 MHz, CDCl3) 168.8, 154.1, 143.9, 141.3, 138.3, 136.1,
132.2, 131.0, 130.6, 130.4, 129.8, 128.4, 128.0, 125.6, 105.6,
63.3, 21.3, 14.1, 9.1; MS (EI, 70 eV), m/z (%): 423 (32.8), 421
(84.3) [M+], 320 (48.7), 319 (32.9), 318(99.9).
5.3.2. Ethyl 3-ethyl-7-hydroxy-2,5-diphenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylate (5b)
Pale yellow solid (0.12 g, 50%), m.p. 136-137 °C; [Found: C,
70.49; H, 6.37; N, 10.65. C23H25N3O3 requires C, 70.57; H, 6.44;
N, 10.73%]; δH (400 MHz, DMSO-d6) 7.20-7.61 (m, 10Н, Ar),
7.30 (d, J 7.1 Hz, 1H, NH), 6.51 (s, 1H, OH), 4.49-4.74 (m, 1H,
CH), 4.18 (q, J 7.2 Hz, 2H, ОCH2CH3), 2.43 (q, J 7.3 Hz, 2H,
CH2CH3), 2.05-2.36 (m, 2H, CH2), 1.17 (t, J 7.1 Hz, 3H,
ОCH2CH3), 1.01 (t, J 7.2 Hz, 3H, CH2CH3); δC (100 MHz,
DMSO-d6) 169.6, 148.7, 148.4, 144.3, 134.9, 128.5, 128.3,
127.7, 127.1, 126.9, 104.8, 98.3, 82.0, 61.5, 50.8, 42.1, 15.3,
14.9, 14.0; MS (EI, 70 eV), m/z (%): 392 (99.9) [MH+], 344
(90.5), 276 (10).
5.2.17. Ethyl
6-hydroxy-7-(4-(methoxycarbonyl)phenyl)-3-
methyl-2-(p-tolyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (4q)
Yellow solid (0.04 g, 18%), m.p. 225-226 °C; [Found C,
67.37; H, 5.26; N, 9.37. C25H23N3O5 requires C, 67.41; H, 5.20;
N, 9.43%]; δH (400 MHz, DMSO-d6) 10.36 (s, 1H, OH), 6.62-
8.99 (m, 8Н, Ar), 4.63 (q, J 8.0 Hz, 2H, ОCH2CH3), 3.98 (s, 3H,
CH3), 2.66 (s, 3H, CH3), 2.40 (s, 3H, CH3), 1.55 (t, J 7.9 Hz, 3H,
CH2CH3); δC (100 MHz, DMSO-d6) 169.8, 166.2, 160.6, 155.6,

8
Tetrahedron
5.3.3. Ethyl 3-ethyl-5-(4-fluorophenyl)-7-hydroxy-2-phenyl-
individual product. Compounds 14b and 14c were obtained as
ACCEPTED MANUSCRIPT
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylate (5c)
mixtures with 4b and 4c respectively.
Pale yellow (0.12 g, 52%), m.p. 128-129 °C; [Found: C,
67.41; H, 5.83; N, 10.28. C23H24FN3O3 requires C, 67.47; H,
5.91; N, 10.26%]; δH (400 MHz, DMSO-d6) 7.23-7.59 (m, 9Н,
Ar), 7.20 (d, J 8.2 Hz, 1H, NH), 6.49 (s, 1H, OH), 4.53-4.75 (m,
1H, CH), 4.18 (q, J 7.3 Hz, 2H, ОCH2CH3), 2.50 (q, J 7.4 Hz,
2H, CH2CH3), 2.0-2.35 (m, 2H, CH2), 1.17 (t, J 7.3 Hz, 3H,
ОCH2CH3), 1.01 (t, J 7.3 Hz, 3H, CH2CH3); δC (100 MHz,
DMSO-d6) 169.9, 162.0 (d, JC-F 250.0 Hz), 160.8, 149.2, 144.6,
138.7, 135.2, 129.3 (d, JC-F 8.4 Hz), 128.7, 127.5, 115.6 (d, JC-F
21.4 Hz), 98.8, 82.4, 62.0, 50.5, 42.4, 15.7, 15.4, 14.4; MS (EI,
70 eV), m/z (%): 410 (99.9) [MH+], 362 (90.1), 294 (12.5).
5.5.1. Ethyl 3-ethyl-6-hydroxy-7-(4-methoxyphenyl)-2-phenyl-
6,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylate (14a)
Pale yellow solid (0.1 g, 42%), m.p. 163-164 °C; [Found: C,
68.61; H, 6.18; N, 10.09. C24H25N3O4 requires C, 68.72; H, 6.01;
N, 10.02%]; δH (400 MHz, DMSO-d6) 6.64-7.85 (m, 9Н, Ar),
6.61 (d, J 5.3 Hz, 1H, OH), 5.57 (d, J 1.1 Hz, 1H, CH), 4.79 (dd,
J 5.3, 1.1 Hz, 1H, CH), 4.25 (q, J 7.0 Hz, 2H, ОCH2CH3), 3.67
(s, 3H, OCH3), 2.86 (q, J 7.3 Hz, 2H, CH2CH3), 1.26 (t, J 7.1 Hz,
3H, ОCH2CH3), 1.16 (t, J 7.4 Hz, 3H, CH2CH3); δC (100 MHz,
DMSO-d6) 163.4, 159.1, 153.8, 149.5, 140.7, 133.4, 128.7,
127.9, 126.9, 128.6, 126.7, 119.1, 114.5, 65.7, 64.5, 62.0, 55.1,
16.1, 15.2,14.1; MS (EI, 70 eV), m/z (%): 419 (99.9) [M+], 390
(49.6), 316 (57.1).
5.3.4. Ethyl 5-(4-chlorophenyl)-3-ethyl-7-hydroxy-2-phenyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylate (5d)
Pale yellow solid (0.12 g, 50%), m.p. 126-127 °C; [Found: C,
64.72; H, 5.78; N, 9.82. C23H24ClN3O3 requires C, 64.86; H, 5.68;
N, 9.87%]; δH (400 MHz, DMSO-d6) 7.23-7.59 (m, 9Н, Ar), 7.30
(d, J 6.1 Hz, 1H, NH), 6.52 (s, 1H, OH), 4.46-4.76 (m, 1H, CH),
4.18 (q, J 7.1 Hz, 2H, ОCH2CH3), 2.43 (q, J 7.3 Hz, 2H,
CH2CH3), 2.05-2.34 (m, 2H, CH2), 1.17 (t, J 7.2 Hz, 3H,
ОCH2CH3), 1.01 (t, J 7.3 Hz, 3H, CH2CH3); δC (100 MHz,
DMSO-d6) 169.9, 149.2, 148.4, 144.5, 141.6, 136.5, 129.3,
128.9, 128.7, 127.6, 127.5, 98.8, 82.3, 62.0, 50.6, 42.3, 15.7,
15.4, 14.5; MS (EI, 70 eV), m/z (%): 426 (100) [MH+].
5.5.2. Ethyl 3-ethyl-2-(4-fluorophenyl)-6-hydroxy-7-(4-
methoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-5-
carboxylate (14b)
δH (400 MHz, DMSO-d6) 6.64-7.85 (m, 8Н, Ar), 6.60 (d, J 5.1
Hz, 1H, OH), 5.57 (br s, 1H, CH), 4.76-4.83 (m, 1H, CH), 4.25
(q, J 7.2 Hz, 2H, ОCH2CH3), 3.67 (s, 3H, OCH3), 2.86 (q, J 7.5
Hz, 2H, CH2CH3), 1.21 (t, J 7.3 Hz, 3H, ОCH2CH3), 1.13 (t, J 7.5
Hz, 3H, CH2CH3); δC (100 MHz, DMSO-d6) 163.2, 162.2 (d, JC-F
244.7 Hz), 157.9, 155.2, 147.0, 144.9, 136.5, 130.6 (d, JC-F 8.6
Hz), 128.2, 119.2, 116.2 (d, JC-F 21.0 Hz), 115.7, 114.2, 66.2,
65.8, 62.2, 55.4, 16.2, 15.1,14.3.
5.3.5. Ethyl 3-ethyl-7-hydroxy-5-(4-(methoxycarbonyl)phenyl)-2-
phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-
carboxylate (5e)
5.5.3. Ethyl 6-hydroxy-7-(4-methoxyphenyl)-3-methyl-2-(p-tolyl)-
6,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylate (14c)
Pale yellow solid (0.12 g, 49%), m.p. 71-72 °C; [Found: C,
66.69; H, 6.19; N, 9.42. C25H27N3O5 requires C, 66.80; H, 6.05;
N, 9.35%]; δH (400 MHz, DMSO-d6) 7.21-8.07 (m, 9Н, Ar), 7.28
(d, J 6.4 Hz, 1H, NH), 6.60 (s, 1H, OH), 4.56-4.82 (m, 1H, CH),
4.18 (q, J 7.1 Hz, 2H, ОCH2CH3), 3.85 (s, 3H, OCH3), 2.40 (q, J
7.3 Hz, 2H, CH2CH3), 2.09-2.36 (m, 2H, CH2), 1.16 (t, J 7.1 Hz,
3H, ОCH2CH3), 1.02 (t, J 7.4 Hz, 3H, CH2CH3); δC (100 MHz,
DMSO-d6) 169.4, 166.0, 148.8, 147.7, 144.0, 134.8, 129.4,
129.0, 128.3, 127.3, 127.2, 127.1, 125.7, 98.5, 81.9, 61.6, 52.2,
50.6, 41.8, 15.3, 14.9, 14.0; MS (EI, 70 eV), m/z (%): 450 (100)
[MH+].
δH (400 MHz, DMSO-d6) 6.64-7.64 (m, 8Н, Ar), 6.59 (d, J 5.2
Hz, 1H, OH), 5.56 (br s, 1H, CH), 4.75-4.81 (m, 1H, CH), 4.25
(q, J 7.3 Hz, 2H, ОCH2CH3), 3.67 (s, 3H, OCH3), 2.37 (s, 3H,
CH3), 2.32 (s, 3H, CH3), 1.26 (t, J 7.3 Hz, 3H, OCH2CH3); δC
(100 MHz, DMSO-d6) 163.6, 156.9, 147.2, 144.6, 136.4, 131.0,
130.0, 129.6, 128.9, 125.4, 117.1, 114.5, 109.2, 65.5, 64.6, 62.8,
55.6, 21.6, 15.2, 6.7.
5.6. X-ray diffraction study
The colourless crystals of 4o (C23H20O3N3F) are monoclinic. At
293 K a = 4.9357(2), b = 19.131(1), c = 21.240(1) Å, β =
91.375(4)°, V = 2005.0(2) Ǻ3, Mr = 405.42, Z = 4, space
5.4. Procedure for the synthesis of N-(4-methyl-1-(2-
oxopropanoyl)-3-(p-tolyl)-1H-pyrazol-5-yl)-2-oxopropanamide
(6)
group P21/c, dcalc = 1.343 g/сm3,
µ
(MoK )
=
0.097 mm-1,
α
F(000)
=
848. Intensities of 18554 reflections (3514
A mixture of 5-aminopyrazole 1c (0.1 g, 0.54 mmol) and ethyl
pyruvate (3a) (0.06 g, 0.54 mmol) in 2 mL of acetic acid was
heated at reflux for 6 h. The mixture was concentrated to 1 mL
and allowed to stand overnight. The precipitated solid was
collected by filtration and vacuum dried. White solid (0.12 g,
41%), m.p. 218-219 °C; [Found: C, 62.21; H, 5.29; N, 12.94.
C17H17N3O4 requires C, 62.38; H, 5.23; N, 12.84%]; δH (400
MHz, DMSO-d6) 9.65 (s, 1H, NH), 7.21-7.48 (m, 4Н, Ar), 2.32
(s, 3H, CH3), 2.01 (s, 3H, CH3), 1.93 (s, 3H, CH3), 1.89 (s, 3H,
CH3); δC (100 MHz, DMSO-d6) 196.6, 193.6, 169.2, 168.7,
153.9, 153.7, 137.4, 137.1, 129.8, 126.9, 91.5, 23.1, 21.5, 21.2,
9.4; MS (EI, 70 eV), m/z (%): 327 (53.0) [M+], 229 (99.9),
187(75.7).
independent, Rint = 0.042) were measured on the «Xcalibur-3»
diffractometer (graphite monochromated MoKα radiation, CCD
detector, ω-scaning, 2Θmax = 50°). The structure was solved by
direct method using SHELXTL package46. Positions of the
hydrogen atoms were located from electron density difference
maps and refined using “riding” model with Uiso = nUeq of the
carrier atom (n = 1.5 for methyl and hydroxyl groups and n =
1.2 for other hydrogen atoms). Full-matrix least-squares
refinement against F2 in anisotropic approximation for non-
hydrogen atoms using 3514 reflections was converged to wR2
0.190 (R1 0.068 for 2227 reflections with F>4σ(F), S
=
=
=
1.454). The final atomic coordinates, and crystallographic data
for molecule 4o have been deposited to the Cambridge
Crystallographic Data Centre, 12 Union Road, CB2 1EZ, UK
(fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk) and
are available on request quoting the deposition numbers CCDC
1566003).
5.5. Procedure for the synthesis of ethyl 6-hydroxy-7-(4-
methoxyphenyl)-3-alkyl-2-phenyl-6,7-dihydropyrazolo[1,5-
a]pyrimidine-5-carboxylates 14
A mixture of the appropriate 5-aminopyrazole 1 (0.54 mmol)
and ethyl (E)-4-(4-methoxyphenyl)-2-oxobut-3-enoate (13) (0.12
g, 0.54 mmol) in 2 mL of acetic acid was ultrasonicated at room
temperature for 2 h. After cooling, the precipitate formed was
filtered off and vacuum dried. Compound 14a was isolated as
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