Reactions of β-Carbonyl-Substituted 4H-chromenes and 1H-benzo[f]Chromenes with 5-aminopyrazoles

Article abstract of DOI:10.1007/s10593-021-02908-4

[Figure not available: see fulltext.] A method for the preparation of pyrazolo[1,5-a]pyrimidines containing a 2-hydroxybenzyl or (2-hydroxynaphthalen-1-yl)methyl group in position 6 based on the reaction of β-carbonyl-substituted 4H-chromenes and their benzo analogs with 5-aminopyrazoles is proposed. A new type of ring-chain tautomerism with the participation of 7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidines was discovered.

Full text of DOI:10.1007/s10593-021-02908-4

DOI 10.1007/s10593-021-02908-4
Chemistry of Heterocyclic Compounds 2021, 57(3), 305–313
Reactions of β-carbonyl-substituted 4H-chromenes
and 1H-benzo[f]chromenes with 5-aminopyrazoles
Vitaly А. Osyanin1*, Dmitry V. Osipov1, Kirill S. Korzhenko1,
Oleg P. Demidov2, Yuri N. Klimochkin1
1 Samara State Technical University,
244 Molodogvardeyskaya St., Samara 443100, Russia; е-mail: VOsyanin@mail.ru
2 North Caucasus Federal University,
1a Pushkina St., Stavropol 355009, Russia; е-mail: odemidov@gmail.com
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2021, 57(3), 305–313
Submitted October 26, 2020
Accepted November 26, 2020
A method for the preparation of pyrazolo[1,5-a]pyrimidines containing a 2-hydroxybenzyl or (2-hydroxynaphthalen-1-yl)methyl group
in position 6 based on the reaction of β-carbonyl-substituted 4H-chromenes and their benzo analogs with 5-aminopyrazoles is proposed.
A new type of ring-chain tautomerism with the participation of 7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidines was discovered.
Keywords: 5-amino-1H-pyrazoles, 1H-benzo[f]chromene, β-carbonyl-substituted chromene, 4H-chromene, pyrazolo[1,5-a]pyrimidines,
aza-Michael reaction, (3+3) cyclocondensation, tautomerism.
Pyrazolo[1,5-a]pyrimidines are traditionally regarded as
privileged structures in medicinal chemistry,1 and therefore
the development of new approaches to their preparation
attracts considerable interest.2 Examples of pharmaco-
logically active pyrazolo[1,5-a]pyrimidines include the
Z-drugs zaleplon, indiplon, and ocinaplon, which are non-
benzodiazepine sedatives,3 and the dipeptidyl peptidase 4
inhibitor anagliptin4 used in the treatment of type 2
diabetes (Fig. 1).
Azolopyrimidines are commonly synthesized by the
action of 1,3-dicarbonyl compounds or their synthetic
equivalents on aminoazoles.2,5 One of the drawbacks of a
number of existing methods is the formation of a mixture
of regioisomers in the case of asymmetric 1,3-bielectro-
philes.6 1-Unsubstituted 5-aminopyrazoles and acyclic
1,3-CCC-bielectrophiles are usually employed for the
preparation of pyrazolo[1,5-a]pyrimidines.7 At the same
Figure 1. Drugs based on pyrazolo[1,5-a]pyrimidines.
time, the use of heterocyclic compounds, for example,
3-carbonyl-substituted chromones, as three-carbon
synthons in the construction of this heterocyclic system is
much less common.8
In this work, we have shown that the less electrophilic,
in comparison with 3-formylchromones, β-carbonyl-
substituted 4H-chromenes and 1H-benzo[f]chromenes can
0009-3122/21/57(3)-0305©2021 Springer Science+Business Media, LLC
305

Chemistry of Heterocyclic Compounds 2021, 57(3), 305–313
be used to prepare pyrazolo[1,5-a]pyrimidine derivatives
containing the 2-hydroxybenzyl group at position 6. Such
an indirect method of C-hydroxybenzylation of hetero-
cyclic compounds is of interest because it is usually
impossible to directly introduce this group into π-electron-
deficient heterocycles.9
Figure 2. Ambident reactivity of β-carbonyl-substituted
4H-chromenes 1 and 5-aminopyrazoles 2.
The presence of two nonequivalent electrophilic centers
in acylchromenes 1 and four nonequivalent nucleophilic
centers in 5-aminopyrazoles 2 gives rise to a wide range of
products in the reaction of reagents 1 and 2 (Fig. 2). It is
believed that, in comparison with the nitrogen atom of the
amino group, the endocyclic nitrogen atom in 5-amino-
pyrazoles 2 is more basic and more sterically hindered as a
result of which it attacks the less hindered and more
electrophilic carbonyl carbon atom in conjugated systems.10
First, we investigated the reaction of 2-trifluoroacetyl-
1H-benzo[f]chromene (1a) with 5-amino-1H-pyrazoles 2a–c
containing the adamantane pharmacophore fragment as
well as a tert-butyl group. It turned out that when the
reaction was carried out in the absence of acidic catalysts in
CH2Cl2 at room temperature (method I), 7-(trifluoromethyl)-
4,7-dihydropyrazolo[1,5-a]pyrimidin-7-ols 3a–c (tautomeric
forms B) formed which are stable in the solid state.
Carrying out the reaction in boiling MeCN (method II)
significantly reduces the duration of the process, but the
yield of product 3а is somewhat lower. Deprotonation of
aminopyrazole 2a by the action of NaH in DMF (method III)
does not change the regioorientation of the reaction with
chromene 1a. In solution, the cyclic hemiaminal forms of
compounds 3a–c are in equilibrium with the corresponding
enamino ketones (tautomeric forms A) (Scheme 1).
The most characteristic signals in the 1H, 13C, and 19F NMR
spectra for tautomers A or B of compounds 3a–c are shown
in Figure 3.
Carrying out the reaction of trifluoroacetylchromenes 1a–с
and pyrazoles 2a,b in the presence of an acid catalyst
allows one to directly obtain 7-(trifluoromethyl)pyrazolo-
[1,5-a]pyrimidines 4a–c. i-PrOH in the presence of
BF3·OEt2 under reflux (method IV) or AcOH under reflux
(method V) can be used. In addition, pyrazolo[1,5-a]-
pyrimidine 4a was obtained by dehydration of hemiaminal
3а in i-PrOH in the presence of BF3·OEt2 (method VI), or
in MeOH in the presence of catalytic amounts of p-TsOH
under reflux (method VII) (Scheme 2 ).
–65.3, s
175.6, q, 2JCF = 30.5
12.20–12.26, d, 4J = 1.8
4.04–4.05, s
O
F3C
N
HN
R
5.77–5.80, d, 4J = 1.8
OH
N
H
89.3–89.9
11.10–11.14, s
10.09–10.10, d, 3J = 13.5
8.12, d, 3J = 13.5
In DMSO-d6 solution, form B of compounds 3a–c
predominates; however, in the first moment after dissolution,
according to 1H NMR spectroscopy data, the B to A ratio is
slightly higher than after 1–2 h. Therefore, it can be
assumed that in the solid state the compound exist in the
form of cyclic 4,7-dihydropyrazolo[1,5-a]pyrimidines 3а–с
(tautomers B).11 The ratio of tautomeric forms of products
3а–с can be calculated from the integral intensities of
singlet signals of fluorine atoms in the 19F NMR spectra or
the signals of the methylene protons in the 1H NMR spectra
and is approximately B:A = 6:4. The possibility of the
existence of ring-chain tautomerism is largely due to the
presence of an electron-withdrawing CF3 group, which
prevents easy elimination of H2O and the formation of
thermodynamically more stable pyrazolo[1,5-a]pyrimidines.
3a–c (A)
–76.2, s
3.83–3.85, s
84.5, q, 2JCF = 32.4
8.08–8.12, s
F3C OH
N
N
R
5.29–5.34, s
81.8–82.4
OH
N
H
9.55–9.58, s
8.89–8.91, d, 3J = 5.5
5.33–5.34, d, 3J = 5.5
3a–c (B)
Figure 3. Identification of tautomers A and B of products 3a–c
1
by characteristic signals in H (red), 13C (blue), and 19F (green)
NMR spectra (δ in ppm, J in Hz).
Scheme 1
Method I: CH2Cl2, rt, 20 h (for 3a–c)
Method II: MeCN, , 15 min (for 3a)
R
F3COC
H
COCF3
N
HN
+
N
H2N
2a–c
R
Method III: NaH, DMF, rt, 20 h (for 3a)
N
O
N
H
O
1a
H
F3C OH
COCF3
HN
~ H
N
N
N
R
69–86%
R
a R = adamantan-1-yl
b R = 3-hydroxyadamantan-1-yl
c R = t-Bu
OH
N
OH
N
H
H
3a–c (A)
3a–c (B)
306

Chemistry of Heterocyclic Compounds 2021, 57(3), 305–313
Me
Me
COCF3
Scheme 2
O
1b
CF3
CF3
1a
Me
Method IV
Methods IV, V
N
N
N
2a,b
N
1-Ad
1-Ad
83%
65–68%
Me
OH
N
R
OH
N
4a
Ph
4b
COCF3
< 136 ppm
74%
O
F3C
Methods VI, VII
N
1c
N
N
Method IV
F3C
N
> 145 ppm
3a
F3C
Ph CF3
Not formed
OH
N
N
N
Method IV: BF3·OEt2, i-PrOH, 8 h
Method V: AcOH, , 10 h
OH
N
4c
Method VI: BF3·OEt2, i-PrOH, 6 h
Method VII: p-TsOH, MeOH, , 2 h
The assignment of the obtained products to 5- or 7-tri-
fluoromethyl-substituted isomers is based on the fact that
the enamine carbon atom bonded to the trifluoromethyl
group and to the nitrogen atom with a single bond usually
appears at 136 ppm, while the signal of the azomethine
carbon atom bonded to the trifluoromethyl group resonates
further downfield (at 145 ppm) in the spectrum of
compounds with a fixed position of double bonds5a,10,12
(Scheme 2). In the 13C NMR spectra of compounds 4a–c,
the C-5 carbon atom of the pyrazolo[1,5-a]pyrimidine ring
appears at 151.2–153.6 ppm. The strong deshielding is due
to the acceptor effect of the neighboring pyridine-type
nitrogen atom. The trifluoromethyl carbon atom and carbon
atom C-7 are found as quartets at 121.2–121.7 ppm
(1JCF = 275.6 Hz) and 129.7–130.3 ppm (2JCF = 34.3 Hz),
respectively. These facts confirm the formation of
regioisomers with a trifluoromethyl group at position 7.
The carbon atom C-3 appears at 93.5–93.9 ppm.
of the endocyclic nitrogen atom of the pyrazole ring to the
carbonyl carbon atom, followed by dehydration in an acidic
medium.
The reaction of 1H-benzo[f]chromene-2-carbaldehydes
1d,e with 5-aminopyrazole 2d in AcOH under reflux is
complete in less than 15 min and leads to the formation of
pyrazolo[1,5-a]pyrimidines 4d,e in 73–79% yields. The
reaction with such a sluggish Michael acceptor as
2-benzoyl-1H-benzo[f]chromene (1f) proceeds much more
slowly and leads to product 4f in 58% yield (Scheme 3).
The formation of 7-phenyl-substituted derivative 4f is
confirmed by the presence in its 13C NMR spectrum of a
signal of the C-5 carbon atom at 155.4 ppm.13
The presence of an ester group in the structure of
pyrazole 2d, which is in direct conjugation with the amino
group, leads to a decrease in the nucleophilicity of the
latter, as
a result of which the reaction rate of
trifluoroacetylbenzochromenes 1a,g with compound 2d is
lower than that with 5-aminopyrazoles 2a–c. Moreover, in
contrast to pyrazolo[1,5-a]pyrimidines 4a–f, products 4g,h
exist in the solid state in the form of cyclic N,O-acetals
(tautomeric form B) (Scheme 3), which for compound 4g
was confirmed by X-ray structural analysis (Fig. 4). It
Isolation of intermediate products confirms the reaction
mechanism which encompasses the conjugated addition of
the exocyclic amino group of pyrazole 2 to the α-carbon
atom of the pyran ring of chromene 1, the opening of the
dihydropyran fragment, and then the nucleophilic addition
Scheme 3
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Chemistry of Heterocyclic Compounds 2021, 57(3), 305–313
Scheme 4
Figure 4. Molecular structure of compound 4g with atoms
represented as thermal vibration ellipsoids with 50% probability.
should also be noted that 4,9a-dihydro-6H-pyrano[3,2-e]-
pyrazolo[1,5-a]pyrimidine 4i (Scheme 3) and its various
arene-condensed variants were not previously described.
In the DMSO-d6 solution of compounds 4g,h, tautomer
B predominates, as well. The content of the minor isomers
4g,h (A) is about 20%, which can be easily determined
from the integrated intensities of signals of fluorine atoms
in the 19F NMR spectra which are detected at –60.0 (form
A) and –75.5 ppm (form B). Nevertheless, upon dissolution
of the colorless products 4g,h in DMSO-d6, the solution
acquires a yellow color characteristic of pyrazolo[1,5-a]-
pyrimidines. The ease of heterocyclization, in comparison
with compounds 4a–с, can be explained by the higher electro-
philicity of the C-7 carbon atom of the pyrazolo[1,5-a]-
pyrimidine ring due to the presence of an acceptor ester
group and the contribution of the corresponding resonance
structure to the distribution of electron density (Scheme 3).
1-Unsubstituted aminopyrazoles 2a–d act as 1,3-NCN-
binucleophiles in all the reactions presented above. At the
same time, 5-aminopyrazole 2e substituted at position 1
reacts with 2-trifluoroacetyl-1H-benzo[f]chromene (1a)
already as 1,3-NCC-binucleophile. This transformation was
carried out in DMF under reflux in the presence of catalytic
amounts of p-TsOH (Scheme 4). In the 13С NMR spectrum
of product 5, the presence of the quartet signal of the
carbon atom C-4 at 129.6 ppm (2JCF = 29.6 Hz) and the
strongly deshielded signal of the C-6 atom at 149.8 ppm
indicates the formation of 4-(trifluoromethyl)-1H-pyrazolo-
[3,4-b]pyridine 5 rather than its isomeric 6-trifluoromethyl
derivative.5a,14 Apparently, in this case, too, the initial step
of the reaction is the aza-Michael reaction with the
participation of an exocyclic amino group.
1
residual solvent signals (DMSO-d6: 2.50 ppm for Н nuclei,
1
39.5 ppm for 13С nuclei; СDCl3: 7.26 ppm for Н nuclei,
77.2 ppm for 13С nuclei) or CFCl3 (0.0 ppm for 19F nuclei)
as internal standards. Elemental analysis was performed on
a Euro Vector EA-3000 CHNS-analyzer. Melting points
were determined by the capillary method on an SRS
OptiMelt MPA100 apparatus. Monitoring of the reaction
progress and assessment of the purity of synthesized
compounds were done by TLC on Merck M60 F254 plates,
eluent CH2Cl2, visualization with UV light at 254 nm or by
iodine stain.
The starting chromenes 1a–g,15 as well as pyrazoles 2с16
and 2d17 were obtained by known methods.
3-(Adamantan-1-yl)-1Н-pyrazol-5-amine monohydrate
(2a). N2H4·H2O (100%, 10 ml) was added to a solution of
3-(adamantan-1-yl)-3-oxopropanenitrile (3.00 g, 15 mmol)
in EtOH (50 ml), and the resulting mixture was heated
under reflux for 5 h. The volatile components were
evaporated under reduced pressure. The residue was
coevaporated with PhMe (2×20 ml) and dissolved in cyclo-
hexane (10 ml) by heating, then H2O (0.3 ml, 17 mmol)
was added. The formed precipitate was filtered off, washed
with cyclohexane (2 ml), and dried in air at room
temperature. Yield 1.66 g (47%), colorless crystals,
mp 139–140°С. IR spectrum, ν, cm–1: 3400–3050 (NH,
NH2, H2O), 2904, 2846 (CH Ad), 1689, 1612, 1573, 1502,
1
1485, 1450, 1319, 1253, 1103, 991, 775, 713. H NMR
spectrum, δ, ppm: 1.69–1.77 (6H, m, 3CH2 Ad); 1.84–1.86
(6H, m, 3CH2 Ad); 2.03 (3H, br. s, 3CH Ad); 4.61 (5H, br. s,
NH, NH2, H2O); 5.41 (1H, s, H-4). 13C NMR spectrum,
δ, ppm: 28.4 (3CH Ad); 33.1 (C Ad); 36.6 (3CH2 Ad); 42.2
(3CH2 Ad); 88.9 (C-4); 154.1; 155.6. Found, %: C 66.25;
H 8.92; N 17.75. C13H19N3·H2O. Calculated, %: C 66.35;
H 8.99; N 17.86.
3-(5-Amino-1Н-pyrazol-3-yl)adamantan-1-ol (2b). A
mixture of 3-(3-hydroxyadamantan-1-yl)-3-oxopropane-
nitrile (0.90 g, 4.1 mmol), N2H4·H2O (100%, 3 ml), and
EtOH (15 ml) was heated under reflux for 5 h. The solvent
and excess N2H4·H2O were evaporated under reduced
pressure, and the residue was recrystallized from CHCl3–
MeOH, 10:1 mixture. Yield 0.82 g (86%), colorless
crystals, mp 143–145°С. IR spectrum, ν, cm–1: 3450–3050
(OH, NH, NH2), 2920, 2850 (CH Ad), 1612, 1566, 1492,
1454, 1338, 1315, 1257, 1118, 1080, 1033, 1002, 925, 798,
To conclude, we have demonstrated that β-carbonyl-
substituted chromenes act as masked 1,3-dicarbonyl
compounds in reactions with 5-aminopyrazoles and can be
effective precursors for the preparation of 6-(2-hydroxy-
benzyl)pyrazolo[1,5-a]pyrimidines.
Experimental
IR spectra were registered on a Shimadzu IRAffinity-1
Fourier transform spectrometer equipped with a Specac
Diamond ATR GS10800-B accessory. 1H, 13C, and 19F NMR
spectra (400, 100, and 376 MHz, respectively), as well as
DEPT-135 spectra were registered on a JEOL JNM-ECX400
spectrometer in DMSO-d6 (compounds 2b, 3a,b,c,
4a–e,g,h, 5) or CDCl3 (compounds 2a,e, 4f) using the
308

Chemistry of Heterocyclic Compounds 2021, 57(3), 305–313
1
648. H NMR spectrum, δ, ppm: 1.49 (2H, br. s, CH2 Ad);
1.53–1.65 (10H, m, 5CH2 Ad); 2.10 (2H, br. s, 2CH Ad);
4.37 (3H, br. s, NH2, OH); 5.10 (1H, s, H-4); 9.98 (1H, br. s,
NH). 13C NMR spectrum, δ, ppm: 30.6 (2CH Ad); 35.6
(CH2 Ad); 36.3 (C Ad); 41.4 (2CH2 Ad); 45.0 (2CH2 Ad);
50.3 (CH2 Ad); 67.0 (COH); 87.4 (C-4); 153.9 (2C).
Found, %: C 67.02; H 8.16; N 17.90. C13H19N3O.
Calculated, %: C 66.92; H 8.21; N 18.01.
J = 1.8, NH); tautomer B: 1.68 (6H, br. s, 3CH2 Ad); 1.81–
1.83 (6H, m, 3CH2 Ad); 1.97 (3H, br. s, 3CH Ad); 3.83
(2H, s, CH2); 5.29 (1H, s, H-3); 5.33 (1H, d, J = 5.5, H-5);
7.17–7.27 (2H, m, H Ar); 7.35 (1H, ddd, J = 8.2, J = 7.1,
J = 1.1, H Ar); 7.68 (1H, d, J = 9.0, H Ar); 7.74 (1H, d,
J = 7.8, H Ar); 7.83 (1H, d, J = 8.5, H Ar); 8.08 (1H, s,
C(CF3)OH); 8.89 (1H, d, J = 5.5, NH); 9.55 (1H, s, OH).
13C NMR spectrum, δ, ppm (J, Hz) (mixture of tautomers
A and B): 19.1 (CH2); 23.0 (CH2); 28.1 (3CH Ad, A); 28.6
(3CH Ad, B); 33.1 (C Ad, A); 34.4 (C Ad, B); 36.5 (3CH2
Ad, A); 37.0 (3CH2 Ad, B); 42.0 (3CH2 Ad, A); 42.6
(3CH2 Ad, B); 81.8 (C-3, B); 84.5 (q, 2JCF = 32.4, C-7, B);
89.3 (C-4, A); 101.5; 107.6; 116.2; 117.1; 118.0 (CH);
3-(Adamantan-1-yl)-1-methyl-1Н-pyrazol-5-amine (2е).
A mixture of 3-(adamantan-1-yl)-3-oxopropanenitrile (0.80 g,
3.9 mmol), MeNHNH2 (2 ml), and EtOH (10 ml) was
heated under reflux for 10 h. The solvent was evaporated
under reduced pressure, and the residue was recrystallized
from cyclohexane. Yield 0.51 g (56%), colorless crystals,
mp 199–200°С. IR spectrum, ν, cm–1: 3399, 3314, 3210
(NH2), 2904, 2847 (CH Ad), 1632, 1562, 1523, 1450,
1419, 1385, 1361, 1315, 1265, 1250, 1172, 1103, 991, 748.
1H NMR spectrum, δ, ppm: 1.71–1.75 (6H, m, 3CH2 Ad);
1.86–1.89 (6H, m, 3CH2 Ad); 2.00 (3H, br. s, 3CH Ad);
3.61 (3H, s, CH3); 3.67 (2H, br. s, NH2); 5.38 (1H, s, H-4).
13C NMR spectrum, δ, ppm: 28.7 (3CH Ad); 34.0 (C Ad);
34.1 (CH3); 36.9 (3CH2 Ad); 42.6 (3CH2 Ad); 87.5 (C-4);
144.9 (C-5); 161.0 (C-3). Found, %: C 72.76; H 9.11;
N 18.08. C14H21N3. Calculated, %: C 72.69; H 9.15; N 18.16.
2-(Adamantan-1-yl)-6-[(2-hydroxynaphthalen-1-yl)-
methyl]-7-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]-
pyrimidin-7-ol (3а). Method I. A solution of chromene 1a
(200 mg, 0.72 mmol) and pyrazole 2a (156 mg, 0.72 mmol)
in CH2Cl2 (5 ml) was kept without stirring at room
temperature for 20 h. The formed precipitate was filtered
off and recrystallized from EtOH.
Method II. A mixture of chromene 1a (200 mg,
0.72 mmol), pyrazole 2a (156 mg, 0.72 mmol), and MeCN
(5 ml) was heated under reflux for 15 min. The mixture
was cooled to 0°С, the formed precipitate was filtered off
and recrystallized from EtOH.
Method III. NaH as 60% dispersion in mineral oil (40 mg,
1.0 mmol) was added to a solution of pyrazole 2a (156 mg,
0.72 mmol) in DMF (4 ml). The mixture was stirred at
room temperature for 10 min until the evolution of H2
ceased, then chromene 1а (200 mg, 0.72 mmol) was added,
and the resulting mixture was kept without stirring at room
temperature for 20 h. The mixture was poured into H2O
(10 ml), and AcOH was added to pH 6. The formed
precipitate was filtered off, washed with H2O (3 ml), and
recrystallized from EtOH.
1
118.6 (CH); 118.7 (q, JCF = 291.8, CF3); 122.9 (CH);
123.5 (CH); 123.9 (CH); 124.0 (CH); 125.0 (q,
1JCF = 292.7, CF3); 125.0 (CH); 126.8 (CH); 127.0 (CH);
128.5 (CH); 128.7 (2C); 128.9 (2CH); 129.3; 133.9; 134.0;
4
140.5; 147.3 (q, JCF = 4.8, CH); 148.3; 151.3; 153.6;
2
155.4; 162.1; 175.7 (q, JCF = 30.5, C=O, A). 19F NMR
spectrum, δ, ppm: tautomer A (41%): –65.3 (s, CF3);
tautomer B (59%): –76.2 (s, CF3). Found, %: C 67.92;
H 5.65; N 8.36. C28H28F3N3O2. Calculated, %: C 67.87;
H 5.70; N 8.48.
2-(3-Hydroxyadamantan-1-yl)-6-[(2-hydroxynaphtha-
len-1-yl)methyl]-7-(trifluoromethyl)-4,7-dihydropyrazolo-
[1,5-a]pyrimidin-7-ol (3b) was obtained by method I of
the synthesis of compound 3а from chromene 1a
(200 mg, 0.72 mmol) and pyrazole 2b (168 mg,
0.72 mmol). Yield 255 mg (69%, method I), colorless
crystals, mp 201–202°С. IR spectrum, ν, cm–1: 3300–3050
(OH, NH), 2924, 2850 (CH Ad), 1659, 1597, 1566, 1489,
1462, 1415, 1333, 1311, 1230, 1196, 1138, 1087, 1026,
995, 960, 925, 903, 864, 814, 783, 744. 1H NMR spectrum,
δ, ppm (J, Hz): tautomer A: 1.50–1.70 (12H, m, 5CH2 Ad,
2CH Ad); 2.13 (2H, br. s, CH2 Ad); 4.04 (2H, s, CH2); 4.54
(1H, s, AdOH); 5.78 (1H, d, J = 1.8, H-4); 7.17–7.27 (2H,
m, H Ar); 7.38 (1H, ddd, J = 8.2, J = 6.9, J = 1.1, H Ar);
7.68 (1H, d, J = 8.9, H Ar); 7.74 (1H, d, J = 7.8, H Ar);
7.97 (1H, d, J = 8.5, H Ar); 8.12 (1H, d, J = 13.5,
=CHNH); 10.09 (1H, d, J = 13.5, =CHNH); 11.12 (1H, br.
s, OH); 12.22 (1H, d, J = 1.8, NH); tautomer B: 1.50–1.70
(12H, m, 5CH2 Ad, 2CH Ad); 2.13 (2H, br. s, CH2 Ad);
3.84 (2H, s, CH2); 4.40 (1H, s, Ad–OH); 5.29 (1H, s, H-3);
5.33 (1H, d, J = 5.5, H-5); 7.18–7.28 (2H, m, H Ar); 7.36
(1H, ddd, J = 8.2, J = 6.9, J = 1.1, H Ar); 7.68 (1H, d,
J = 8.9, H Ar); 7.74 (1H, d, J = 7.8, H Ar); 7.83 (1H, d,
J = 8.5, H Ar); 8.10 (1H, s, C(CF3)OH); 8.91 (1H, d,
J = 5.5, NH); 9.56 (1H, s, OH). 13C NMR spectrum, δ, ppm
(J, Hz) (mixture of tautomers A and B): 19.1 (CH2); 23.0
(CH2); 30.4 (2CH Ad); 30.7 (2CH Ad); 35.3 (CH2 Ad);
35.8 (CH2 Ad); 36.3 (C Ad); 37.7 (C Ad); 41.1 (2CH2 Ad);
41.7 (2CH2 Ad); 44.8 (2CH2 Ad); 45.1 (2CH2 Ad); 49.9
(CH2 Ad); 50.5 (CH2 Ad); 66.9 (C–OH); 67.3 (C–OH);
Yield 303 mg (85%, method I), 280 mg (78%, method II),
307 mg (86%, method III), colorless crystals, mp 209–
210°С. IR spectrum, ν, cm–1: 3233, 3144, 3117, 3047, 2985
(OH, NH), 2904, 2850 (CH Ad), 1659, 1618, 1597, 1566,
1489, 1462, 1415, 1333, 1315, 1230, 1196, 1138, 1026,
995, 964, 814, 787, 748. 1H NMR spectrum, δ, ppm
(J, Hz): tautomer A: 1.68 (6H, br. s, 3CH2 Ad); 1.81–1.83
(6H, m, 3CH2 Ad); 1.97 (3H, br. s, 3CH Ad); 4.04 (2H, s,
CH2); 5.77 (1H, d, J = 1.8, H-4); 7.17–7.27 (2H, m, H Ar);
7.38 (1H, ddd, J = 8.2, J = 7.1, J = 1.1, H Ar); 7.68 (1H, d,
J = 9.0, H Ar); 7.74 (1H, d, J = 7.8, H Ar); 7.97 (1H, d,
J = 8.5, H Ar); 8.12 (1H, d, J = 13.5, =CHNH); 10.09 (1H,
d, J = 13.5, =CHNH); 11.10 (1H, br. s, OH); 12.20 (1H, d,
2
81.9 (C-3, B); 84.5 (q, JCF = 32.4, C-7, B); 89.4 (C-4, A);
101.5; 107.6; 116.2; 117.1; 117.9 (CH); 118.6 (CH); 118.7
1
(q, JCF = 291.8, CF3); 122.9 (CH); 123.5 (CH); 123.9
1
(CH); 124.0 (CH); 124.6 (q, JCF = 292.7, CF3); 125.0
(CH); 126.8 (CH); 127.0 (CH); 128.5 (CH); 128.7 (2C);
128.9 (2CH); 129.3; 133.9; 134.0; 140.5; 147.2 (q, 4JCF = 4.8,
309

Chemistry of Heterocyclic Compounds 2021, 57(3), 305–313
CH); 148.2; 151.3; 153.6; 154.5; 161.2; 175.7 (q, 2JCF = 30.5,
Method VII. A crystal of p-TsOH was added to a
solution of compound 3a (99 mg, 0.20 mmol) in MeOH
(6 ml), and the resulting mixture was heated under reflux
for 2 h. The solvent was evaporated under reduced pressure,
and the residue was recrystallized from EtOH.
C=O, A). 19F NMR spectrum, δ, ppm: tautomer A (38%):
–65.3 (s, CF3); tautomer B (62%): –76.2 (s, CF3). Found, %:
C 65.71; H 5.45; N 8.16. C28H28F3N3O3. Calculated, %:
C 65.74; H 5.52; N 8.21.
2-(tert-Butyl)-6-[(2-hydroxynaphthalen-1-yl)methyl]-
7-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-
7-ol (3с) was obtained by method I of the synthesis of
compound 3а from chromene 1a (200 mg, 0.72 mmol) and
pyrazole 2c (100 mg, 0.72 mmol). Yield 240 mg (80%,
method I), colorless crystals, mp 216–218°С. IR spectrum,
ν, cm–1: 3219, 3148, 3119 (OH, NH), 2965, 2870, 1657,
1611, 1597, 1566, 1495, 1462, 1416, 1327, 1283, 1231,
1192, 1136, 1024, 995, 816, 789, 756, 745. 1H NMR
spectrum, δ, ppm (J, Hz): tautomer A: 1.21 (9H, s, (CH3)
C); 4.05 (2H, s, CH2); 5.80 (1H, d, J = 1.8, H-4); 7.18–7.27
(2H, m, H Ar); 7.38 (1H, ddd, J = 8.2, J = 7.1, J = 1.1,
H Ar); 7.68 (1H, d, J = 8.7, H Ar); 7.75 (1H, d, J = 8.0,
H Ar); 7.98 (1H, d, J = 8.5, H Ar); 8.13 (1H, d, J = 13.5,
=CHNH); 10.10 (1H, d, J = 13.5, =CHNH); 11.14 (1H, br. s,
OH); 12.26 (1H, d, J = 1.8, NH); tautomer B: 1.20 (9H, s,
(CH3)C); 3.85 (2H, s, CH2); 5.34–5.36 (2H, m, H-3,5); 7.18–
7.27 (2H, m, H Ar); 7.36 (1H, ddd, J = 8.2, J = 7.1, J = 1.1,
H Ar); 7.68 (1H, d, J = 8.7, H Ar); 7.75 (1H, d, J = 8.0,
H Ar); 7.83 (1H, d, J = 8.5, H Ar); 8.12 (1H, s, C(CF3)OH);
8.91 (1H, d, J = 5.3, NH); 9.58 (1H, s, OH). 13C NMR
spectrum, δ, ppm (J, Hz) (mixture of tautomers A and B):
19.0 (CH2); 23.0 (CH2); 30.2 (3CH3, A); 30.8 (3CH3, B);
Yield 235 mg (68%, method IV), 225 mg (65%, method V),
75 mg (80%, method VI), 78 mg (82%, method VII), light-
yellow crystals, mp 246–247°С. IR spectrum, ν, cm–1:
3209, 3070 (OH), 2904, 2850 (CH Ad), 1631, 1604, 1546,
1516, 1440, 1400, 1357, 1296, 1271, 1249, 1192, 1157,
1072, 1022, 987, 813, 786, 740. 1H NMR spectrum, δ, ppm
(J, Hz): 1.70 (6H, br. s, 3CH2 Ad); 1.93 (6H, br. s,
3СH2 Ad); 1.99 (3H, br. s, 3CH Ad); 4.57 (2H, s, CH2);
6.66 (1H, s, H-3); 7.20 (1H, d, J = 8.9, H Ar); 7.28 (1H, t,
J = 7.6, H Ar); 7.42 (1H, ddd, J = 8.2, J = 6.9, J = 1.1, H Ar);
7.76 (1H, d, J = 8.7, H Ar); 7.79–7.82 (2H, m, H-5, Н Ar);
7.86 (1H, d, J = 8.5, H Ar); 10.00 (1H, s, OH). 13C NMR
spectrum, δ, ppm (J, Hz): 23.8 (CH2); 28.4 (3CH Ad); 34.8
(C Ad); 36.7 (3CH2 Ad); 42.4 (3CH2 Ad); 93.5 (C-3);
1
114.8; 118.6 (CH); 120.7; 121.7 (q, JCF = 275.6, CF3);
122.7 (CH); 123.2 (CH); 127.5 (CH); 128.8; 129.2 (CH);
2
129.7 (q, JCF = 34.3, C-7); 129.7 (CH); 133.7; 148.2;
151.2 (C-5); 154.1; 167.4. 19F NMR spectrum, δ, ppm:
–60.4 (s, CF3). Found, %: C 70.50; H 5.41; N 8.77.
C28H26F3N3O. Calculated, %: C 70.43; H 5.49; N 8.80.
2-{[2-(Adamantan-1-yl)-7-(trifluoromethyl)pyrazolo-
[1,5-a]pyrimidin-6-yl]methyl}-4,5-dimethylphenol (4b)
was obtained by method IV of the synthesis of compound
4а from chromene 1b (184 mg, 0.72 mmol) and pyrazole
2a (156 mg, 0.72 mmol). Yield 270 mg (83%, method IV),
light-yellow crystals, mp 179–180°С (MeOH). IR spect-
rum, ν, cm–1: 3206 (OH), 2908, 2850 (CH Ad), 1601, 1547,
1516, 1462, 1431, 1415, 1354, 1292, 1250, 1188, 1157,
1080, 945, 887, 783. 1H NMR spectrum, δ, ppm: 1.71 (6H,
br. s, 3CH2 Ad); 1.94–2.05 (15H, m, 3CH2 Ad, 3CH Ad,
2CH3); 4.04 (2H, s, CH2); 6.56 (1H, s, H Ar); 6.64 (1H, s,
H Ar); 6.72 (1H, s, H-3); 8.40 (1H, s, H-5); 9.23 (1H, s,
OH). 13C NMR spectrum, δ, ppm (J, Hz): 18.9 (CH3); 19.7
(CH3); 28.4 (3CH Ad); 28.9 (CH2); 34.8 (C Ad); 36.7
(3CH2 Ad); 42.4 (3CH2 Ad); 93.6 (C-3); 116.9 (CH);
120.6; 121.3 (q, 1JCF = 275.6, CF3); 122.5; 126.8; 129.9 (q,
2JCF = 34.3, C-7); 130.8 (CH); 136.0; 148.6; 153.2; 153.6
(C-5); 167.3. 19F NMR spectrum, δ, ppm: –61.5 (s, CF3).
Found, %: C 68.47; H 6.21; N 9.15. C26H28F3N3O.
Calculated, %: C 68.56; H 6.20; N 9.22.
2
82.4 (C-3, B); 84.5 (q, JCF = 32.4, C-7, B); 89.9 (C-4, A);
101.5; 107.6; 116.2; 117.1; 117.9 (CH); 118.6 (CH); 118.7
1
(q, JCF = 291.8, CF3); 122.8 (CH); 123.5 (CH); 123.9
1
(CH); 124.0 (CH); 124.6 (q, JCF = 292.7, CF3); 125.0
(CH); 126.7 (CH); 126.9 (CH); 128.5 (CH); 128.6 (CH);
128.7; 128.9 (2CH); 129.3; 133.9; 134.0; 140.6; 147.3 (q,
4JCF = 4.8, CH); 148.2; 151.2; 153.5; 155.1; 161.8; 175.6
2
(q, JCF = 30.5, C=O, A). 19F NMR spectrum, δ, ppm:
tautomer A (36%): –65.3 (s, CF3); tautomer (B) (64%): –76.2
(s, CF3). Found, %: C 63.41; H 5.27; N 9.93. C22H22F3N3O2.
Calculated, %: C 63.30; H 5.31; N 10.07.
1-{[2-(Adamantan-1-yl)-7-(trifluoromethyl)pyrazolo-
[1,5-a]pyrimidin-6-yl]methyl}naphthalen-2-ol
(4а).
Method IV. BF3·OEt2 (20 μl, 20 mol %) was added to a
mixture of chromene 1a (200 mg, 0.72 mmol), pyrazole 2a
(156 mg, 0.72 mmol), and i-PrOH (5 ml), and the mixture
was heated under reflux for 8 h. The solvent was
evaporated under reduced pressure, the residue was
suspended at reflux in MeOH (2 ml), then kept at –30°С
for 2 h. The product was filtered off, washed with chilled
(–30°С) MeOH (2 ml), and recrystallized from EtOH.
Method V. A mixture of chromene 1a (200 mg,
0.72 mmol), pyrazole 2a (156 mg, 0.72 mmol), and AcOH
(5 ml) was heated under reflux for 10 h. The formed
precipitate was filtered off, washed with AcOH (2 ml), and
recrystallized from EtOH.
6-[(2-Hydroxyphenyl)(phenyl)methyl]-3-{7-(trifluoro-
methyl)pyrazolo[1,5-a]pyrimidin-2-yl}adamantan-1-ol
(4c) was obtained by method IV of the synthesis of
compound 4а from chromene 1c (219 mg, 0.72 mmol) and
pyrazole 2b (168 mg, 0.72 mmol). Yield 275 mg (74%,
1
method IV), light-yellow crystals, mp 229–231°С. H NMR
spectrum, δ, ppm (J, Hz): 1.52–1.66 (6H, m, 3CH2 Ad);
1.77–1.84 (6H, m, 2CH2 Ad, 2CH Ad); 2.17 (2H, br. s,
CH2 Ad); 4.51 (1H, s, Ad–OH); 6.22 (1H, s, CHPh); 6.67
(1H, dd, J = 7.6, J = 1.4, H Ar); 6.71–6.75 (1H, m, H Ar);
6.76 (1H, s, H-3); 6.79 (1H, d, J = 8.0, H Ar); 7.07–7.12
(3H, m, H Ar); 7.25 (1H, t, J = 7.3, H Ar); 7.30–7.34 (2H,
m, H Ar); 8.07 (1H, s, H-5); 9.67 (1H, s, OH). 13C NMR
spectrum, δ, ppm (J, Hz): 30.6 (2CH Ad); 35.5 (CH2 Ad);
Method VI. BF3·OEt2 (20 μl, 80 mol %) was added to a
solution of compound 3a (99 mg, 0.20 mmol) in i-PrOH
(3 ml), and the resulting mixture was heated under reflux
for 6 h. The solvent was evaporated under reduced
pressure, the residue was recrystallized from EtOH.
310

Chemistry of Heterocyclic Compounds 2021, 57(3), 305–313
4
38.2 (C Ad); 41.5 (2CH2 Ad); 42.9 (q, JCF = 3.8, CHPh);
(2Н, q, J = 7.1, СН2O); 4.41 (2Н, s, СН2); 7.09–7.13 (2Н,
m, H Ar); 7.19–7.23 (2Н, m, H Ar); 7.35 (1Н, d, J = 8.7,
H Ar); 7.62–7.66 (1Н, m, H Ar); 7.70–7.82 (5Н, m, H Ar);
8.55 (1Н, s, H-2); 8.75 (1Н, s, H-5); 9.63 (1Н, s, ОН).
13C NMR spectrum, δ, ppm: 14.6 (СН3); 24.2 (СН2); 60.6
(СН2O); 102.8; 116.7; 118.2 (СН); 122.2 (СН); 122.4;
122.8 (СН); 126.5 (СН); 128.9 (2С); 129.1 (2С); 129.2
(2СН); 130.2 (2СН); 131.3 (СН); 132.9; 146.0; 146.4;
147.3 (С-2); 152.6; 155.4 (С-5); 162.9 (С=О). Found, %:
C 73.79; H 4.95; N 9.83. C26H21N3O3. Calculated, %:
C 73.74; H 5.00; N 9.92.
44.9 (2CH2 Ad); 50.1 (CH2 Ad); 67.1 (COH); 93.9 (C-3);
115.8 (CH); 119.6 (CH); 121.2 (q, JCF = 275.6, CF3);
123.0; 127.4 (CH); 128.7; 129.0 (CH); 129.3 (2CH); 129.5
(2CH); 130.0 (CH); 130.3 (q, JCF = 34.3, C-7); 141.5;
1
2
148.5; 151.3 (C-5); 155.0; 167.0. 19F NMR spectrum, δ, ppm:
–60.8 (s, CF3). Found, %: C 69.42; H 5.40; N 7.98.
C30H28F3N3O2. Calculated, %: C 69.35; H 5.43; N 8.09.
Ethyl 6-[(2-hydroxynaphthalen-1-yl)methyl]pyrazolo-
[1,5-a]pyrimidine-3-carboxylate (4d). 1H-Benzo[f]chro-
mene-2-carbaldehyde (1d) (210 mg, 1.0 mmol) was added
to a solution of pyrazole 2d (155 mg, 1.0 mmol) in AcOH
(2 ml). The mixture was heated under reflux with vigorous
stirring for 15 min and cooled to room temperature. The
formed precipitate was filtered off and recrystallized from
EtOH–DMF, 4:1 mixture. Yield 255 mg (73%), light-
yellow crystals, mp 271–273°С. IR spectrum, ν, cm–1:
3246, 3055 (OH), 1720 (C=O), 1627, 1516, 1056, 808.
1H NMR spectrum, δ, ppm (J, Hz): 1.23 (3Н, t, J = 7.1,
СН3); 4.21 (2H, q, J = 7.1, СН2O); 4.42 (2H, s, CH2); 7.24–
7.28 (2Н, m, H Ar); 7.42 (1H, ddd, J = 8.5, J = 6.9, J = 1.4,
H Ar); 7.73 (1Н, d, J = 8.7, H Ar); 7.78 (1Н, d, J = 7.6,
H Ar); 8.04 (1Н, d, J = 8.9, H Ar); 8.49 (1Н, s, H-2); 8.77
(1Н, d, J = 2.1) and 8.94 (1Н, d, J = 2.1, H-5,7); 10.09 (1Н,
br. s, ОН). 13C NMR spectrum, δ, ppm: 14.9 (СН3); 24.6
(СН2); 60.0 (СН2O); 102.1; 116.4; 118.6 (СН); 123.0 (СН);
123.2 (СН); 124.8; 127.3 (СН); 128.8; 129.1 (СН); 129.3
(СН); 133.3; 134.8 (С-7); 146.1; 147.5 (С-2); 153.3; 155.3
(С-5); 162.1 (С=O). Found, %: C 69.22; H 4.88; N 12.01.
C20H17N3O3. Calculated, %: C 69.15; H 4.93; N 12.10.
Ethyl 6-[(6-bromo-2-hydroxynaphthalen-1-yl)methyl]-
pyrazolo[1,5-a]pyrimidine-3-carboxylate (4e) was obtained
by the method of the synthesis of compound 4d from
pyrazole 2d (155 mg, 1.0 mmol) and 8-bromo-1Н-benzo[f]-
chromene-2-carbaldehyde (1е) (289 mg, 1.0 mmol). Yield
335 mg (79%), light-yellow crystals, mp 300–302°С.
IR spectrum, ν, cm–1: 3240, 3051 (OH), 1708 (C=O), 1627,
1274, 1058. 1H NMR spectrum, δ, ppm (J, Hz): 1.24 (3Н, t,
J = 7.1, СН3); 4.22 (2Н, q, J = 7.1, СН2O); 4.41 (2Н, s,
СН2); 7.29 (1Н, d, J = 8.9, H-3 naphthalene); 7.51 (1Н, dd,
J = 9.1, J = 2.3, Н-7 naphthalene); 7.73 (1Н, d, J = 8.9, Н-4
naphthalene); 8.01 (1Н, J = 9.1, Н-8 naphthalene); 8.05
(1Н, d, J = 2.3, Н-5 naphthalene); 8.50 (1Н, s, Н-2); 8.74
(1Н, d, J = 2.1) and 8.93 (1Н, d, J = 2.1, Н-5,7); 10.27
(1Н, br. s, ОН). 13C NMR spectrum, δ, ppm: 14.9 (СН3);
24.6 (СН2); 60.0 (СН2O); 102.1; 116.1; 116.8; 119.9 (СН);
124.5; 125.6 (СН); 128.6 (СН); 130.0 (СН); 130.1; 130.8
(СН); 131.9; 134.8 (С-7); 146.2; 147.6 (С-2); 153.9; 155.2
(С-5); 162.1 (С=O). Found, %: C 56.30; H 3.83; N 9.75.
C20H16BrN3O3. Calculated, %: C 56.35; H 3.78; N 9.86.
Ethyl 6-[(2-hydroxynaphthalen-1-yl)methyl]-7-phenyl-
pyrazolo[1,5-a]pyrimidine-3-carboxylate (4f) was obtained
by the method of the synthesis of compound 4d from
pyrazole 2d (155 mg, 1.0 mmol) and (1Н-benzo[f]-
chromen-2-yl)(phenyl)methanone (1f) (286 mg, 1.0 mmol).
Reaction time 15 h. Yield 245 mg (58%), colorless
crystals, mp 270–272°С. IR spectrum, ν, cm–1: 3182, 3057
(OH), 1699 (C=O), 1529, 1246, 1056, 810. 1H NMR
spectrum, δ, ppm (J, Hz): 1.30 (3Н, t, J = 7.1, СН3); 4.37
Ethyl 13a-(trifluoromethyl)-4,13a-dihydro-6H-benzo-
[5,6]chromeno[3,2-e]pyrazolo[1,5-a]pyrimidine-3-carboxy-
late (4g) was obtained by the method of the synthesis of
compound 4d from pyrazole 2d (155 mg, 1.0 mmol) and
chromene 1a (278 mg, 1.0 mmol). Reaction time 15 h.
Yield 295 mg (71%), light-yellow crystals, mp 249–250°С
1
(EtOH). H NMR spectrum, δ, ppm (J, Hz): tautomer A:
1.21 (3H, t, J = 7.1, CH3); 4.20 (2H, q, J = 7.1, CH2O);
4.64 (2H, s, CH2); 7.17 (1H, d, J = 8.9, H Ar); 7.27–7.31
(1H, m, H Ar); 7.42–7.46 (1H, m, H Ar); 7.78 (1H, d,
J = 8.5, H Ar); 7.82 (1H, d, J = 8.7, H Ar); 7.89 (1H, d,
J = 8.5, H Ar); 8.19 (1H, s, H Ar); 8.68 (1H, s, H Ar);
10.05 (1H, s, OH); tautomer B: 1.25 (3H, t, J = 7.1, CH3);
3.76 (1H, d, J = 18.5, 6-CH2); 4.21 (2H, q, J = 7.1, CH2);
4.27 (1H, d, J = 18.5, 6-CH2); 7.16 (1H, d, J = 8.9, H-12);
7.22 (1H, d, J = 5.0, H-5); 7.40–7.44 (1H, m) and 7.54–
7.58 (1H, m, H-8,9); 7.77 (1H, d, J = 8.9, H Ar); 7.85 (1H,
d, J = 8.2, H Ar); 7.89 (1H, d, J = 8.5, H Ar); 7.97 (1H, s,
H-2); 10.19 (1H, d, J = 5.0, NH). 13C NMR spectrum, δ,
ppm (J, Hz): tautomer A: 14.8 (CH3); 24.1 (CH2); 60.4
(CH2O); 103.4; 114.3; 118.6 (CH); 122.7 (CH); 123.3
(CH); 123.8; 127.6 (CH); 128.8; 129.2 (CH); 130.0 (CH);
2
131.0 (q, JCF = 34.5, CCF3); 133.7; 146.9; 147.4 (C-2);
154.2; 155.9 (C-5); 161.8 (C=O) (the quartet signal of the
carbon atom of the CF3 group could not be recorded due to
its low intensity); tautomer B: 15.0 (CH3); 24.0 (C-6); 60.2
2
(CH2O); 84.6 (q, JCF = 34.3, C-13a); 94.2; 94.8; 114.2;
1
118.3 (CH); 122.9 (CH); 123.4 (q, JCF = 292.7, CF3);
125.0 (CH); 127.2 (CH); 127.5 (CH); 129.0 (CH); 129.1
(CH); 129.7; 131.7; 142.0; 142.5 (C-2); 148.7; 162.6
(C=O). 19F NMR spectrum, δ, ppm: tautomer A (22%):
–60.0 (s, CF3); tautomer B (78%): –75.5 (s, CF3). Found,
%: C 60.65; H 3.94; N 10.01. C21H16F3N3O3. Calculated,
%: C 60.72; H 3.88; N 10.12.
Ethyl
9-(adamantan-1-yl)-13a-(trifluoromethyl)-
4,13a-dihydro-6H-benzo[5,6]chromeno[3,2-e]pyrazolo-
[1,5-a]pyrimidine-3-carboxylate (4h) was obtained by the
method of the synthesis of compound 4d from pyrazole 2d
(155 mg, 1.0 mmol) and 1-[8-(adamantan-1-yl)-1H-benzo-
[f]chromen-2-yl]-2,2,2-trifluoroethan-1-one (1g) (412 mg,
1.0 mmol). Reaction time 15 h. Yield 410 mg (75%),
colorless crystals, mp 289–291°С (DMF). 1H NMR
spectrum, δ, ppm (J, Hz): tautomer A: 1.21 (3H, t, J = 7.1,
CH3); 1.71 (6H, br. s, 3CH2 Ad); 1.89 (6H, br. s, 3CH2
Ad); 2.03 (3H, br. s, 3CH Ad); 4.20 (2H, q, J = 7.1,
CH2O); 4.61 (2H, s, CH2); 7.16 (1H, d, J = 8.9, H Ar); 7.51
(1H, d, J = 8.9, H Ar); 7.67 (1H, s, H Ar); 7.75 (1H, d,
J = 8.7, H Ar); 7.80 (1H, d, J = 8.9, H Ar); 8.20 (1H, s,
311

Chemistry of Heterocyclic Compounds 2021, 57(3), 305–313
H Ar); 8.68 (1H, s, H Ar); 9.92 (1H, s, OH); tautomer B:
using the SHELXT program19 and solved employing the
SHELXL program,20 molecular graphics were rendered and
preparation of the material for publication was performed using
the OLEX2 software package.21 The full set of X-ray structural
data for compound 4g was deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 2038689).
1.25 (3H, t, J = 7.1, CH3); 1.71 (6H, br. s, 3CH2 Ad); 1.89
(6H, br. s, 3CH2 Ad); 2.03 (3H, br. s, 3CH Ad); 3.73 (1H,
d, J = 18.8, 6-CH2); 4.20–4.25 (3H, m, CH2O, 6-CH2); 7.11
(1H, d, J = 8.9, H-12); 7.21 (1H, d, J = 4.8, H-5); 7.63 (1H,
d, J = 8.9, H Ar); 7.70 (1H, s, H-10); 7.74 (1H, d, J = 8.7,
H Ar); 7.82 (1H, d, J = 8.9, H Ar); 7.96 (1H, s, H-2); 10.17
(1H, d, J = 4.8, NH). 13C NMR spectrum, δ, ppm (J, Hz):
tautomer A: 14.8 (CH3); 24.0 (CH2); 28.8 (3CH Ad); 36.0
(C Ad); 36.7 (3CH2 Ad); 43.0 (3CH2 Ad); 60.4 (CH2O);
103.4; 114.0; 118.4 (CH); 122.5 (CH); 123.9; 124.1 (CH);
Supplementary information file containing the synthetic
procedures and spectral-analytical characteristics of the
starting compounds for the preparation of adamantyl-
substituted pyrazoles 2a,b,e and the principal crystallo-
graphic data and parameters of the X-ray structural analysis
of compound 4g is available at the journal website at http://
link.springer.com/journal/10593.
2
128.8; 129.1 (CH); 130.0 (CH); 131.0 (q, JCF = 34.5,
CCF3); 131.9; 145.6; 146.9; 147.4 (C-2); 153.6; 156.0
(C-5); 161.8 (C=O) (the quartet signal of the carbon atom
of the CF3 group could not be recorded due to its low
intensity); tautomer B: 15.0 (CH3); 24.0 (C-6); 28.8 (3CH
Ad); 36.2 (C Ad); 36.7 (3CH2 Ad); 43.0 (3CH2 Ad); 60.1
This work was supported by the Russian Foundation for
Basic Research (grant 18-33-20249).
2
(CH2O); 84.6 (q, JCF = 34.3, C-13a); 94.4; 94.8; 113.9;
References
1
118.0 (CH); 122.7 (CH); 123.4 (q, JCF = 293.7, CF3);
1. Cherukupalli, S.; Karpoormath, R.; Chandrasekaran, B.;
Hampannavar, G. A.; Thapliyal, N.; Palakollu, V. N. Eur. J.
Med. Chem. 2017, 126, 298.
123.8 (CH); 125.5 (CH); 127.0 (CH); 129.1 (CH); 129.8;
129.9; 142.0; 142.4 (C-2); 147.4; 148.2; 162.6 (C=O).
19F NMR spectrum, δ, ppm: tautomer A (19%): –60.0 (s, CF3);
tautomer B (81%): –75.5 (s, CF3). Found, %: C 67.67;
H 5.53; N 7.55. C31H30F3N3O3. Calculated, %: C 67.75;
H 5.50; N 7.65.
2. (a) Salem, M. A.; Helal, M. H.; Gouda, M. A.; El-Gawad, H. H. A.;
Shehab, M. A. M.; El-Khalafawy, A. Synth. Commun. 2019,
49, 1750. (b) Al-Azmi, A. Curr. Org. Chem. 2019, 23, 721.
3. (a) Mirza, N. R.; Rodgers, R. J.; Mathiasen, L. S. J.
Pharmacol. Exp. Ther. 2006, 316, 1291. (b) Lippa, A.;
Czobor, P.; Stark, J.; Beer, B.; Kostakis, E.; Gravielle, M.;
Bandyopadhyay, S.; Russek, S. J.; Gibbs, T. T.; Farb, D. H.;
Skolnick, P. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 7380.
4. Kato, N.; Oka, M.; Murase, T.; Yoshida, M.; Sakairi, M.;
Yamashita, S.; Yasuda, Y.; Yoshikawa, A.; Hayashi, Y.;
Makino, M.; Takeda, M.; Mirensha, Y.; Kakigami, T. Bioorg.
Med. Chem. 2011, 19, 7221.
5. (a) Emelina, E. E.; Petrov, A. A. Russ. J. Org. Chem. 2009, 45,
417. [Zh. Org. Khim. 2009, 45, 427.] (b) Krasovsky, A. L.;
Moiseev, A. M.; Nenajdenko, V. G.; Balenkova, E. S.
Synthesis 2002, 901.
6. Filyakova, V. I.; Kuznetsova, O. A.; Ulomskii, E. N.;
Rybalova, T. V.; Gatilov, Yu. V.; Kodess, M. I.; Rusinov, V. L.;
Pashkevich, K. I. Russ. Chem. Bull., Int. Ed. 2002, 51, 332.
[Izv. Akad. Nauk, Ser. Khim. 2002, 313.]
1-{[3-(Adamantan-1-yl)-1-methyl-4-(trifluoromethyl)-
1Н-pyrazolo[3,4-b]pyridin-5-yl]methyl}naphthalen-2-ol
(5). A crystal of p-TsOH was added to a solution of
pyrazole 2e (169 mg, 0.73 mmol) and chromene 1a (200 mg,
0.72 mmol) in DMF (5 ml). The mixture was heated under
reflux for 12 h, cooled, and poured into H2O (10 ml) with
stirring. The formed precipitate was filtered off and
recrystallized from MeOH. Yield 120 mg (34%), light-
yellow crystals, mp 117–118°С. IR spectrum, ν, cm–1: 3500–
3150 (OH), 2904, 2850 (CH Ad), 1628, 1566, 1512, 1442,
1404, 1361, 1327, 1215, 1179, 1126, 1087, 1011, 987, 904,
1
810, 744, 705. H NMR spectrum, δ, ppm (J, Hz): 1.74
(6H, br. s, 3CH2 Ad); 2.06 (3H, br. s, 3СН Ad); 2.16 (6H,
br. s, 3CH2 Ad); 3.88 (3H, s, CH3); 4.59 (2H, s, CH2); 7.21–
7.27 (2H, m, H Ar); 7.33 (1H, ddd, J = 8.0, J = 6.9, J = 1.2,
H Ar); 7.55 (1H, d, J = 8.5, H Ar); 7.76–7.83 (3H, m, H Ar);
10.01 (1H, s, OH). 13C NMR spectrum (100°С), δ, ppm
(J, Hz): 26.3 (CH2); 29.0 (3CH Ad); 34.2 (CH3); 37.0
(3CH2 Ad); 38.5 (C Ad); 41.7 (3CH2 Ad); 107.5; 116.2;
118.9 (CH); 122.4 (CH); 123.1 (CH); 124.3 (q, 1JCF = 274.6,
CF3); 127.3 (CH); 128.5; 129.1 (CH, C); 129.4 (CH); 129.6
7. Shaabani, A.; Nazeri, M. T.; Afshari, R. Mol. Diversity 2019,
23, 751.
8. (a) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.;
Pipko, S. E.; Tolmachev, A. A. Heterocycles 2008, 75, 583.
(b) Quiroga, J.; Mejía, D.; Insuasty, B.; Abonía, R.; Nogueras, M.;
Sánchez, A.; Cobo, J.; Low, J. N. J. Heterocycl. Chem. 2002,
39, 51. (c) Zimmerman, J. R.; Myers, B. J.; Bouhall, S.;
McCarthy, A.; Johntony, O.; Manpadi, M. Tetrahedron Lett.
2014, 55, 936. (d) Santos, C. M. M.; Silva, V. L. M.;
Silva, A. M. S. Molecules 2017, 22, 1665/1.
9. Osipov, D. V.; Osyanin, V. A.; Klimochkin, Yu. N. In
Targets in Heterocyclic Systems: Chemistry and Properties;
Attanasi, O. A.; Merino, P.; Spinelli, D., Eds.; Società
Chimica Italiana: Rome, 2018, Vol. 22, p. 436.
10. Krasovsky, A. L.; Hartulyari, A. S.; Nenajdenko, V. G.;
Balenkova, E. S. Synthesis 2002, 133.
11. Goryaeva, M. V.; Burgart, Y. V.; Saloutin, V. I.; Sadchikova, E. V.;
Ulomskii, E. N. Heterocycles 2009, 78, 435.
12. (a) Emelina, E. E.; Petrov, A. A.; Selivanov, S. I.; Filyukov, D. V.
Russ. J. Org. Chem. 2008, 44, 251. [Zh. Org. Khim. 2008, 44,
259.] (b) Emelina, E. E.; Petrov, A. A.; Firsov, A. V. Russ. J.
Org. Chem. 2001, 37, 852. [Zh. Org. Khim. 2001, 37, 899.]
2
(q, JCF = 29.6, C-4); 133.9; 149.8 (C-6); 150.0; 151.3;
154.0. 19F NMR spectrum, δ, ppm: –52.4 (s, CF3). Found,
%: C 70.78; H 5.70; N 8.63. C29H28F3N3O. Calculated, %:
C 70.86; H 5.74; N 8.55.
X-ray structural analysis of compound 4g was
performed on an Agilent SuperNova diffractometer using a
microfocus X-ray source (CuKα radiation, λ 1.54060 Å)
and an Atlas S2 coordinate CCD detector. Crystals suitable
for structural analysis were obtained by slow evaporation at
room temperature of an EtOH solution of compound 4g.
The collection of reflections, solving and refinement of the
unit cell parameters was carried out using the CrysAlisPro
specialized software package.18 The structure was solved
312

Chemistry of Heterocyclic Compounds 2021, 57(3), 305–313
(c) Emelina, E. E.; Petrov, A. A.; Selivanov, S. I.; Nelyubina, Y. V.;
Lukashenko, A. V.; Osipov, D. V. Russ. Chem. Rev. 2021, 90,
324. [Usp. Khim. 2021, 90, 324.]
16. Magee, W. L.; Rao, C. B.; Glinka, J.; Hui, H.; Amick, T. J.;
Fiscus, D.; Kakodkar, S.; Nair, M.; Shechter, H. J. Org.
Chem. 1987, 52, 5538.
Antipin, M. Yu. J. Fluorine Chem. 2009, 130, 861.
13. Bharathi, Ch.; Prabahar, K. J.; Prasad, Ch. S.; Kumar, M. S.;
Magesh, S.; Handa, V. K.; Dandala, R.; Naidu, A. J. Pharm.
Biomed. Anal. 2007, 44, 101.
14. (a) Volochnyuk, D. M.; Pushechnikov, A. O.; Krotko, D. G.;
Sibgatulin, D. A.; Kovalyova, S. A.; Tolmachev, A. A.
Synthesis 2003, 1531. (b) Aggarwal, R.; Kumar, V.; Bansal, A.;
Sanz, D.; Claramunt, R. M. J. Fluorine Chem. 2012, 140, 31.
15. (a) Lukashenko, A. V.; Osyanin, V. A.; Osipov, D. V.;
Klimochkin, Yu. N. J. Org. Chem. 2017, 82, 1517.
(b) Lukashenko, A. V.; Osyanin, V. A.; Osipov, D. V.;
Klimochkin, Yu. N. Chem. Heterocycl. Compd. 2016, 52, 711.
[Khim. Geterotsikl. Soedin. 2016, 52, 711.] (с) Osyanin, V. A.;
17. Selvakumar, B.; Vaidyanathan, S. P.; Madhuri, S.; Elango, K. P.
J. Chem. Res. 2017, 41, 221.
18. CrysAlisPro, version 1.171.38.41; Rigaku Oxford Diffraction, 2015.
19. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Adv.
2015, A71, 3.
20. Sheldrick, G. M. Acta Crystallogr., Sect. C: Struct. Chem.
2015, C71, 3.
21. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339.
313