Alternative approaches to the synthesis of polyfluoroalkyl-containing 1-methyl-4-nitrosopyrazoles

Article abstract of DOI:10.1007/s11172-021-3195-2

We studied different approaches to the synthesis of polyfluoroalkyl-containing 1-methyl-4-nitrosopyrazoles, which are based on the cyclization of 4,4,4-trifluoro-3,3-dihydroxy-2-hydroxyimino-1-R-butan-1-ones or 2-hydroxyimino-1,3-diketones with methylhydrazine and on a one-pot sequential treatment of 1,3-diketones with sodium nitrite and methylhydrazine. It was found that the regioselectivity of the formation of 1-methyl-4-nitrosopyrazoles is affected by the steric factors of 1,3-dicarbonyl reagents. The study of the mycostatic effect of 4-nitrosopyrazoles showed that the introduction of a bulky polyfluoroalkyl or tert-butyl substituent leads to a decrease in their activity.

Full text of DOI:10.1007/s11172-021-3195-2

Russian Chemical Bulletin, International Edition, Vol. 70, No. 6, pp. 1135—1140, June, 2021
1135
Alternative approaches to the synthesis of polyfluoroalkyl-containing
1-methyl-4-nitrosopyrazoles
N. A. Agafonova,a Ya. V. Burgart,a N. А. Gerasimova,b N. P. Evstigneeva,b and V. I. Saloutina
aI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 ul. Sof´i Kovalevskoi, 620108 Ekaterinburg, Russian Federation.
E-mail: saloutin@ios.uran.ru
bUral Research Institute of Dermatovenerology and Immunopathology,
8 ul. Shcherbakova, 620076 Ekaterinburg, Russian Federation
We studied different approaches to the synthesis of polyfluoroalkyl-containing 1-methyl-
4-nitrosopyrazoles, which are based on the cyclization of 4,4,4-trifluoro-3,3-dihydroxy-2-
hydroxyimino-1-R-butan-1-ones or 2-hydroxyimino-1,3-diketones with methylhydrazine and
on a one-pot sequential treatment of 1,3-diketones with sodium nitrite and methylhydrazine.
It was found that the regioselectivity of the formation of 1-methyl-4-nitrosopyrazoles is affec-
ted by the steric factors of 1,3-dicarbonyl reagents. The study of the mycostatic effect of 4-nitro-
sopyrazoles showed that the introduction of a bulky polyfluoroalkyl or tert-butyl substituent
leads to a decrease in their activity.
Key words: 4,4,4-trifluoro-3,3-dihydroxy-2-(hydroxyimino)butan-1-ones, polyfluoroalkyl-
2-hydroxyimino-1,3-diketones, 1-methyl-4-nitrosopyrazoles, mycostatic activity.
The pyrazole framework provides rich opportunities
for the design of physiologically active molecules, since
its functionalization allows one to obtain multifunctional
compounds capable of binding to biological targets, which
leads to different pharmacological activities.1—5 Fluorine-
containing pyrazoles are of particular interest for the
preparation of biologically active molecules6—8 due to the
presence of electron-withdrawing fluorine atoms, which
affect the properties of compounds containing this ele-
ment, changing their physicochemical and biological
parameters.9—12
Recently, among trifluoromethyl-containing 1-methyl-
4-nitrosopyrazoles we found compounds with high anti-
mycotic activity in combination with moderate acute
toxicity.13 We suggest that the nitroso group makes
a significant contribution to the antifungal effect, since
these compounds may act as antimicrobial agents of the
nitrofuran group, the exact mechanism of action of which
is unknown.14 Apparently, nitrofurazone and nitroimid-
azoles (for example, metronidazole, ornidazole, etc.) are
metabolized by reduction of the nitro group with the for-
mation of reactive forms, which can covalently bind to
bacterial enzymes, disrupting the DNA of microbial cells.15
To synthesize trifluoromethyl-containing 4-nitroso-
pyrazoles, we used the cyclization of 2-hydroxyimino-1,3-
diketones 2 with hydrazines (method A)16 or a one-pot
sequential treatment of 1,3-diketones 1 with sodium nitrite
and hydrazines (method B).17,18 However, we have earlier
found that the synthesis of trifluoromethyl-containing
2-hydroxyimino-1,3-diketones 2 by nitrosation of 1,3-di-
ketones 1 with sodium nitrite in aqueous solutions of or-
ganic acids is complicated by their isolation as hydrates 3
at the trifluoroacetyl fragment.19
In this connection, in the present work we studied the
possibility of synthesizing 1-methyl-4-nitrosopyrazoles 4
by the reaction of 4,4,4-trifluoro-3,3-dihydroxy-2-
(hydroxyimino)butan-1-ones 3 with methylhydrazine
and compared the outcome with the results of the syn-
thesis of the target compounds by a one-pot three-com-
ponent cyclization of 1,3-diketones 1 and cyclocon-
densation of polyfluoroalkyl-2-hydroxyimino-1,3-di-
ketones 2.
It was found that hydrates 3a—с having (het)aryl sub-
stituents undergo cyclization with methylhydrazine to form
3-trifluoromethyl-substituted 4-nitrosopyrazoles 4a—c
(Scheme 1, method A), similar to those obtained earlier
from the corresponding 1,3-diketones 1а—с or their
lithium salts using a one-pot approach (method В).13
However, compound 3d containing a tert-butyl sub-
stituent reacts with methylhydrazine to give 5-trifluoro-
methyl-substituted 4-nitrosopyrazole 5а (see Scheme 1,
method A). The direction of cyclization was not changed
when the one-pot approach, i.e., the sequential nitrosation
of 1,3-diketone 1d and condensation with methylhydrazine
(method B) was used.
* Dedicated to Academician of the Russian Academy of Sciences
V. N. Charushin on the occasion of his 70th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1135—1140, June, 2021.
1066-5285/21/7006-1135 © 2021 Springer Science+Business Media LLC

Agafonova et al.
1136
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 6, June, 2021
Scheme 1
Method A
reflux
Method B
1, 3, 4: R = Ph (a), thiophen-2-yl (b), furan-2-yl (c), But (d)
Note that we previously observed the formation of
1,3-dimethyl-4-nitroso-5-trifluoromethylpyrazole (5b) in
small amounts only in the one-pot reaction of lithium
trifluoropentenoate with methylhydrazine. Compound 5b
was formed in a mixture with the predominant 3-trifluo-
romethyl-substituted isomer in a ratio of ∼1 : 2.13
In contrast to trifluoromethyl-substituted diketones
1a—d,19 their polyfluoroalkyl-containing analogs 1e,f do
not form hydrates upon nitrosation with sodium nitrite in
acetic acid, rather giving 2-hydroxyimino-1,3-diketones
2a,b (Scheme 2). The 13C NMR spectrum of compound
2a, which exists in solution in CDCl3 as a single isomer,
exhibits a triplet at δ 178.58 corresponding to the carbonyl
carbon atom of the C(O)CF2 fragment. The stability of
the carbonyl group at the polyfluoroalkyl substituent may
be due to its lower electron-withdrawing ability as com-
pared to a trifluoromethyl residue.
2-Hydroxyimino-1,3-diketones 2a,b, regardless of the
length of the polyfluoroalkyl substituent and the nature of
the non-fluorinated residue, give 3-polyfluoroalkyl-1-
methyl-4-nitrosopyrazoles 4d,e. One-pot transformations
of 1,3-diketones 1e,f lead to the same pyrazoles 4d,e (see
Scheme 2).
Note that 4-nitrosopyrazoles cannot be synthesized by
nitrosation of preliminary obtained 3-polyfluoroalkylpyr-
azoles, whereas the most efficient method for the synthe-
sis of 4-hydroxyimino-5-polyfluoroalkylpyrazol-3-ones is
the nitrosation of 3-polyfluoroalkylpyrazol-5-ols.20
The regioisomeric structure of 3-trifluoromethyl-
substituted 4-nitrosopyrazoles 4a—c has been established
by us earlier13 based on the 1H, 13C, and 19F NMR spec-
troscopy data.
In the determination of the regioisomeric structure of
5-trifluoromethyl-substituted pyrazole 5а, its 1H and
19F NMR spectra, which differed from the spectra of
3-trifluoromethylpyrazoles 4а—c in the signal splitting
patterns of the СF3 and N(1)Me groups, were the most
informative. Thus, the signals for the СF3 and N(1)Me
groups of compound 5а were observed as quartets with
spin-spin coupling constants of 1.7 Hz due to the coupling
between the fluorine atoms and the protons of the neigh-
boring Ме substituent (see Experimental), while the signals
for these groups in the spectra of pyrazoles 4а—с were
observed as singlets.13
Scheme 2
In the 1H NMR spectra of 3-polyfluoroalkyl-4-nitro-
sopyrazoles 4d,е, the protons of the N(1)Me group reso-
nate as singlets, which indicates their remoteness from
perfluoroalkyl substituents.
The regioisomeric structure of 3-pentafluoroethyl-
substituted pyrazole 4d was additionally confirmed by
X-ray diffraction analysis (Fig. 1).
RF = C2F5, R = Ph (1e, 2a, 4d), RF = C4F9, R = Me (1f, 2b, 4e)
From the data obtained, it can be concluded that the
method for the synthesis of 4-nitrosopyrazoles 4a—d and
5а does not affect their regioisomeric structure. It is obvi-
ous that the regioselectivity of cyclization is determined
Reagents and conditions: i. NaNO2, AcOH, H2O, 0 °C, 15 min,
then 20 °С, 1—2 h; ii (method В). 1) NaNO2, AcOH,
10 °С, 2) NH2NHMe, EtOH; iii (method А). NH2NHMe, EtOH,
reflux.

Polyfluoroalkylated 1-methyl-4-nitrosopyrazoles
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 6, June, 2021
1137
Comparing the efficiency of the methods used, we can
note the expectedly higher yields of the target 4-nitroso-
pyrazoles 4 and 5 in the synthesis from hydroxyimines 2
or 3 by method A (Table 1), but this advantage can be
neutralized by the stage of their isolation and purification.
As mentioned above, 3-trifluoromethyl-substituted
4-nitrosopyrazoles 4a—c possess a pronounced ability to
inhibit the growth of pathogenic dermatophyte fungi, while
5-trifluoromethyl-substituted 4-nitrosopyrazole 5b is less
efficient (Table 2).
We investigated the antimycotic and antibacterial
activity of pyrazoles 4d and 5a against eight test strains of
pathogenic dermatophytes and yeast-like fungi Candida
albicans. A reference drug was the known antifungal agent
fluconazole. It turned out that the replacement of the
trifluoromethyl substituent in compound 4а with a penta-
fluoroethyl group led to a decrease in the antimycotic
effect of pyrazole 4d, which exhibited a moderate activity
(MIC 25 μg mL–1) against fungi of the strain T. inter-
digitale, a weak inhibitory effect (MIC 50 μg mL–1) against
T. rubrum, T. violaceum, E. floccosum, and had no effect
(MIC 100 μg mL–1) against T. tonsurans, T. schonleinii,
M. canis.
Fig. 1. General view of the molecule of 4-nitrosopyrazole 4d
according to X-ray diffraction analysis. Thermal ellipsoids are
shown with a 50% probability.
by the structure of the substituents at the 1,3-dicarbonyl
fragment of the starting reagents 1—3. In most cases, the
more nucleophilic MeNH group of methylhydrazine reacts
with the carbonyl group at the non-fluorinated substituent
of the 1,3-dicarbonyl agent as the most electrophilic posi-
tion.8 A dramatic change in the direction of the reaction
we observed only in the case of compounds 1d and 3d
having a bulky tert-butyl substituent, which hinders the
attack by a MeNH group on the neighboring carbonyl
function.
A comparison of the antifungal effect of 5-trifluoro-
methyl-containing pyrazoles 5a and 5b showed that the
Table 1. Yields of compounds 2—5
Hydroxy-
imine 2, 3
Yield
of 2, 3 (%)
4-Nitroso-
pyrazole
Yield of compounds 4, 5 (%)
from hydroxyimines 2, 3
(method A)
total yield
from 1,3-diketone 1
(method B)
on two stepsa
3a19
3b19
3c19
2a
55b, 84c
52b, 87c
71b, 78c
72
4a
4b
4c
4d
4e
5а
76
68
89
77
38
77
42b 64c
35b, 59c
63b, 69c
55
68
59
84
44
21
68
2b
77
29
3d19
49b, 78c
37b, 60c
a Calculated on the corresponding starting 1,3-diketone 1.
b For synthesis of hydroxyimines 3 in aqueous AcOH.
c For synthesis of hydroxyimines 3 in aqueous citric acid.
Table 2. Fungistatic activity of 4-nitrosopyrazoles 4 and 5
Com-
pound
MIC (mg mL–1) for inhibition of fungal strains
T. rubrum T. gypseum T. tonsurans T. violaceum T. interdigitale T. schonleinii E. floccosum M. canis C. albicans
4a
4b
4c
4d
5a
5b
12.5
12.5
12.5
50
>200
12.5
25
50
3.12
50
6.25
—*
6.25
50
200
100
1.95
12.5
25
—*
—*
0.38
50
12.5
50
200
100
1.56
100
25
12.5
100
>200
100
3.12
—*
25
50
12.5
100
>200
25
25
—*
н/а
>200
>200
25
25
100
200
—*
>200
>200
>200
1.56
>200
100
0.78
Flucon- 3.12
azole
6.25
6.25
1.56
* Not tested.

Agafonova et al.
1138
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 6, June, 2021
5,5,6,6,7,7,8,8,8-Nonafluoro-3-(hydroxyimino)heptane-2,4-
dione (2b). The yield was 77% (after column chromatography,
eluent CHCl3), colorless crystals, m.p. 49—50 °C. A mixture of
E- and Z-isomers in the ratio of 86 : 14 (1Н NMR spectroscopy
data). IR (ATR), ν/cm–1: 3241 (О—Н), 1719, 1639 (C=O), 1591
(C=N), 1224—1190 (C—F). 1H NMR (CDCl3), δ, E-isomer:
2.48 (s, 3 H, Me); 10.16 (br.s, 1 H, OH); Z-isomer: 2.49 (s, 3 H,
Me); 11.39 (br.s, 1 H, OH). 19F NMR (CDCl3), δ, E-isomer:
36.0, 39.2, 42.1 (all m, 2 F each, CF2); 80.9 (tt, 3 F, CF3,
J = 9.7 Hz, J = 2.4 Hz); Z-isomer: 36.1, 40.4, 42.1 (all m,
2 F each, CF2), 81.0 (tt, 3 F, CF3, J = 9.7 Hz, J = 2.4 Hz).
Found (%): C, 28.72; H, 1.34; N, 4.31. С8Н4F9NО3. Calculat-
ed (%): C, 28.85; H, 1.21; N, 4.20.
Synthesis of 4-nitrosopyrazoles 4a—e and 5а (general proce-
dure). Method A. Methylhydrazine (0.46 mg, 10 mmol) was
added to a solution of hydrate 3a—d or 2-hydroxyimino-1,3-
diketone 2a,b (10 mmol) in ethanol (20 mL) and the mixture was
refluxed for 3—4 h. After cooling to room temperature, the sol-
vent was evaporated, the residue was extracted with diethyl ether
(2×20 mL), the organic layer was washed with saturated aqueous
sodium bicarbonate until the washings were neutral, dried with
sodium sulfate, and concentrated in vacuo. The residue was
washed with water (10 mL), hexane (10 mL) and dried.
Method B. A solution of 1,3-diketone 1a—f (10 mmol) in
acetic acid (10 mL) was cooled to 10 °C, followed by a dropwise
addition over 30 min of a solution of sodium nitrite (0.86 g,
12.5 mmol) in water (10 mL) with stirring. Then, a solution of
methylhydrazine (0.51 g, 11 mmol) in ethanol was added and
the mixture was stirred at room temperature for 3—4 h. The
products were isolated as in method А.
1-Methyl-4-nitroso-5-phenyl-3-trifluoromethyl-1H-pyrazole
(4а) was purified by column chromatography (eluent chloroform).
The yield was 76% (method А), 68% (method B), blue crystals,
m.p. 97—98 °C (cf. Ref. 17: m.p. 97—98 °C). The spectral
data agree with those published earlier.17 13C NMR (CDCl3), δ:
38.08 (Me), 119.69 (q, CF3, J = 269.7 Hz); 126.46 (q, CCF3,
J = 40.6 Hz); 125.73, 129.14, 130.64, 131.22 (Ph), 150.12, 155.12
(CNO, CPh).
1-Methyl-4-nitroso-5-(thiophen-2-yl)-3-trifluoromethyl-1H-
pyrazole (4b) was purified by column chromatography (eluent
chloroform—diethyl ether—hexane, 2 : 2 : 1). The yield was 68%
(method А), 59% (method B), green crystals, m.p. 102—103 °C
(cf. Ref. 13: m.p. 102—103 °C). The IR, 1H and 19F NMR spec-
tral data agree with those published earlier.13
replacement of the methyl group at position C(3) with
a bulky tert-butyl substituent leads to a complete loss of
the antimycotic effect.
In conclusion, we showed the possibility of using
4,4,4-trifluoro-3,3-dihydroxy-2-hydroxyimino-1-R-but-
an-1-ones formed by nitrosation of trifluoromethyl-1,3-
diketones in aqueous solutions of organic acids19 for the
synthesis of 4-nitrosopyrazoles. In contrast to trifluoro-
methyl analogs, the nitrosation of polyfluoroalkyl-1,3-
diketones yielded 2-hydroxyimino-1,3-diketones, which
were also converted to 4-nitrosopyrazoles. It was found
that the regioselectivity of the formation of 4-nitrosopyr-
azoles is affected by the structure of the 1,3-dicarbonyl
agent, and not by the method of its preparation. The study
of the antifungal effect of 4-nitrosopyrazoles showed that
the introduction of a bulky polyfluoroalkyl or tert-butyl
substituent leads to a decrease in their inhibitory activity.
Experimental
Melting points were determined in open capillaries on a Stuart
SMP30 apparatus. IR spectra in the 4000—400 cm–1 range were
recorded on a Spectrum Two infrared Fourier-transform spectro-
meter equipped with a diamond attenuated total reflectance
(ATR) attachment (Perkin Elmer, USA). 1H, 19F, and 13C NMR
spectra were recorded on Bruker DRX-400 and Bruker Avance
500 spectrometers in DMSO-d6 or CDCl3, using Me4Si (1H)
and C6F6 (19F) as internal standards. Elemental analysis (C, H,
N) was performed on a PerkinElmer PE 2400 series II CHN-O
EA 1108 or Carlo Erba CHNS-O EA 1108 elemental analyzers.
Column chromatography was performed on Macherey-Nagel
silica gel 60 (0.063—0.2 mm). The reaction progress was moni-
tored by TLC on ALUGRAM® Xtra SIL G/UV254 plates.
4,4,4-Trifluoro-3,3-dihydroxy-2-hydroxyimino-1-R-butan-
1-ones 3a—d were obtained by the procedure described in the
work.19
Synthesis of 2-hydroxyimino-1,3-diketones (2a,b) (general
procedure). A solution of sodium nitrite (0.41 mg, 6 mmol) in
water (5 mL) was added dropwise over 10—15 min to a cooled
to 0 °C solution of 1,3-diketone 1e,f (5 mmol) in acetic acid
(3—5 mL) with stirring. Then the reaction mixture was stirred
at room temperature for 1—2 h, neutralized with saturated aqueous
sodium bicarbonate, and extracted with diethyl ether (2×15 mL).
The organic layers were combined, dried, and concentrated. The
target compounds were isolated by a suitable method.
4,4,5,5,5-Pentafluoro-2-hydroxyimino-1-phenylpentane-1,3-
dione (2a). The yield was 72% (washed with hexane), colorless
crystals, m.p. 119—120 °C. IR (ATR), ν/cm–1: 3242 (О—Н),
1721, 1644 (C=O), 1593 (C=N), 1222—1192 (C—F). 1H NMR
(CDCl3), δ: 7.52—7.56, 7.67—7.70, 7.80—7.82 (all m, 5 H, Ph);
9.33 (br.s, 1 H, OH). 13С NMR (CDCl3), δ: 107.75 (tq, CF2,
J = 269.7 Hz, J = 37.5 Hz); 117.67 (qt, CF3, J = 287.8 Hz,
J = 34.1 Hz); 128.90, 129.52, 133.54, 135.44 (Ph); 152.22 (C=O);
178.58 (t, CF2C=O, J = 26.1 Hz); 189.66 (C=N). 19F NMR
(CDCl3), δ: 44.32 (q, 2 F, CF2, J = 0.9 Hz), 80.70 (s, 3 F, CF3).
Found (%): C, 44.92; H, 1.95; N, 4.84. С11Н6F5NО3. Calculat-
ed (%): C, 44.76; H, 2.05; N, 4.75.
5-(Furan-2-yl)-1-methyl-4-nitroso-3-trifluoromethyl-1H-
pyrazole (4c). The yield was 89% (method А), 84% (method B),
a light green powder, m.p. 95 °C (cf. Ref. 13: m.p. 95 °C). The
IR, 1H and 19F NMR spectral data agree with those published
earlier.13
3-tert-Butyl-1-methyl-4-nitroso-5-trifluoromethyl-1H-pyr-
azole (5а) was purified by column chromatography (eluent
chloroform). The yield was 77% (method А), 68% (method B),
a blue oil. IR, ν/cm–1: 1523, 1487, 1451, 1431 (C=N, C=C,
N=O); 1149—1090 (C—F). 1H NMR (CDCl3), δ: 1.42 (s, 9 H,
But); 4.04 (q, 3 H, NMe, J = 1.7 Hz). 13C NMR (CDCl3), δ:
29.16 (But), 33.95 (CMe3), 39.92 (q, NMe, J = 3.0 Hz); 119.20
(q, CF3, J = 271.9 Hz); 126.18 (q, CCF3, J = 41.1 Hz); 153.31,
157.09 (CNO, C—But). 19F NMR (CDCl3), δ: 103.62 (q, CF3,
J = 1.7 Hz). Found (%): C, 46.48; H, 5.36; N, 18.65. C9H12F3N3O.
Calculated (%): C, 45.96; H, 5.14; N, 17.87.

Polyfluoroalkylated 1-methyl-4-nitrosopyrazoles
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 6, June, 2021
1139
1-Methyl-4-nitroso-3-pentafluoroethyl-5-phenyl-1H-pyr-
azole (4d). The yield was 77% (method А), 44% (method B), light
blue crystals, m.p 107—109 °C. IR, ν/cm–1: 1602, 1519, 1478,
1454 (C=N, C=C, N=O); 1125—1109 (C—F). 1H NMR
(CDCl3), δ: 3.96 (s, 3 H, Me); 7.62 (m, 5 Н, Ph). 13C NMR
(CDCl3), δ: 38.04 (Me), 110.20 (tq, CF2, J = 253.2 Hz,
J = 39.5 Hz); 118.69 (qt, CF3, J = 286.8 Hz, J = 36.5 Hz); 125.78,
129.08, 130.43, 131.10 (Ph), 146.31, 156.04 (signals for the CNO,
CPh, CCF2 carbons overlap with signals for carbon atoms of Ph
group). 19F NMR (CDCl3), δ: 49.0 (q, CF2, J = 2.2 Hz), 78.9
(t, CF3, J = 2.2 Hz). Found (%): C, 47.33; H, 2.72; N, 27.39.
C12H8F5N3O. Calculated (%): C, 47.22; H, 2.64; N, 13.77.
1,5-Dimethyl-4-nitroso-3-nonafluorobutyl-1H-pyrazole (4e).
The yield was 38% (method А), 21% (method B), a green oil. IR,
ν/cm–1: 1694, 1563, 1479, 1455 (C=N, C=C, N=O). 1H NMR
(CDCl3), δ: 2.54 (s, 3 H, Me); 3.91 (s, 3 H, NMe). 19F NMR
(CDCl3), δ: 36.1 (m, 2 F, γ-CF2), 39.7 (m, 2 F, β-CF2); 53.1
(m, 2 F, α-CF2); 80.8 (tt, 3 F, CF3, J = 9.7 Hz, J = 2.7 Hz).
Found (%): C, 31.44; H, 1.73; N, 12.33. C9H6F9N3O. Calculat-
ed (%): C, 31.50; H, 1.76; N, 12.25.
This work does not involve human participants and
animal subjects.
The authors declare no competing interest.
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X-ray diffraction analysis of compound 4d. Single crystals of
compound 4d were obtained by crystallization from diethyl ether,
C12H8F5N3O, M = 305.21, single crystals are monoclinic, space
group P21/n, a = 13.3053(16) Å; b = 7.7036(7) Å; c = 13.5295(19) Å;
α = 90.000°, β = 112.029°, γ = 90.000°, V = 1285.5(3) Å3, Z = 4,
dcalc = 1.577 g cm–3, μ(MoKα) = 0.153 cm–1, F(000) = 616.
A 9003 total number of reflections was measured on a Xcalibur
3 diffractometer at 295(2) K (MoKα radiation, graphite mono-
chromator, CCD detector, ω/2θ scan technique), the number
of independent reflections was 3517 (Rint = 0.0423), the number
of reflections with I ≥ 2σ(I) was 1563. The crystal structure was
solved by direct methods and refined using the SHELXL-97
program21 by the least squares method in the anisotropic full-
matrix approximation for all nonhydrogen atoms to R1 = 0.0522,
wR2 = 0.1346 and GOOF = 1.006 (for reflections with I ≥ 2σ(I)).
A complete set of crystallographic data was deposited with
the Cambridge Crystallographic Data Center (CCDC 2063016)
and is available at http://www.ccdc.cam.ac.uk/conts/retrieving.
html (12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033; e-mail: deposit@ccdc.cam.ac.uk).
Microbiological study of compounds 4d and 5а. The micro-
biological study was carried out at the Ural Research Institute of
Dermatovenerology and Immunopathology. The following test
strains of dermatophyte fungi were used in the study: Trichophyton
rubrum (RKPG (Russian collection of pathogenic fungi) F 1408),
Trichophyton mentagrophytes var. gypseum (RKPG F 1425),
Trichophyton tonsurans (RKPG F 1396/228), Trichophiton viol-
aceum (RKPG F 1211), Trichophyton mentagrophytes var. inter-
digitale (RKPG F 1459/11044), Trichophyton schoenleinii (RKPG
F 235/25), Epidermophyton floccosum (RKPG F 1659/17),
Microsporum canis (RKPG F 1643/1585) and yeast-like fungi
Candida albicans (RKPG Y 401/NCTC 885/653). Antimicrobial
properties were assessed using the serial dilution method recom-
mended by the Clinical and Laboratory Standards Institute
(CLSI, 2014) according to the procedure described in the work.13
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The work was carried out in the framework of the
Russian state assignment АААА-А19-119011790134-1,
using the equipment of the Centre for Joint Use "Spectro-
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Received February 16, 2021;
in revised form March 23, 2021;
accepted March 24, 2021