New one-pot synthesis of 4-hydroxyimino-5-polyfluoroalkylpyrazol-3-ones, their structure and biological activity

Article abstract of DOI:10.1007/s10593-019-02418-4

[Figure not available: see fulltext.] We propose different methods for the synthesis of 4-hydroxyimino-5-polyfluoroalkylpyrazol-3-ones. The simplest and most convenient procedure relies on sequential one-pot treatment of polyfluoroalkyl-3-oxoesters with hydrazine and sodium nitrite in acetic acid. It was established that 4-hydroxyimino-5-polyfluoroalkylpyrazol-3-ones exist in solid state and in solutions as mixtures of Z,Е-isomers of the hydroxyimine tautomer. The synthesized compounds were characterized with respect to in vivo analgesic activity and acute toxicity.

Full text of DOI:10.1007/s10593-019-02418-4

DOI 10.1007/s10593-019-02418-4
Chemistry of Heterocyclic Compounds 2019, 55(1), 52–59
New one-pot synthesis of
4-hydroxyimino-5-polyfluoroalkylpyrazol-3-ones,
their structure and biological activity
Yanina V. Burgart1,2, Natalya A. Agafonova1, Evgeny V. Shchegolkov1,2,
Vera V. Maslova3, Galina A. Triandafilova3, Sergey Yu. Solodnikov3,
Olga P. Krasnykh3, Victor I. Saloutin1,2*
1 I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22 S. Kovalevskoi / 20 Akademicheskaya St., Yekaterinburg 620990, Russia; e-mail: saloutin@ios.uran.ru
2 Ural Federal University named after the first President of Russia B. N. Yeltsin,
19 Mira St., Yekaterinburg 620002, Russia
3 Perm National Research Polytechnical University,
29 Komsomolsky Ave., Perm 614990, Russia; e-mail: ol.krasnykh@pstu.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(1), 52–59
Submitted November 14, 2018
Accepted December 21, 2018
We propose different methods for the synthesis of 4-hydroxyimino-5-polyfluoroalkylpyrazol-3-ones. The simplest and most convenient
procedure relies on sequential one-pot treatment of polyfluoroalkyl-3-oxoesters with hydrazine and sodium nitrite in acetic acid. It was
established that 4-hydroxyimino-5-polyfluoroalkylpyrazol-3-ones exist in solid state and in solutions as mixtures of Z,Е-isomers of the
hydroxyimine tautomer. The synthesized compounds were characterized with respect to in vivo analgesic activity and acute toxicity.
Keywords: 2-hydroxyimino-3-polyfluoroalkylpyrazol-5-ones, analgesic activity, nitrosation, tautomerism.
The importance of pyrazole derivatives is obvious from the
review articles published during the last 5 years, which consider
the issues related to their synthesis,1–3 ability of complex
formation,4–7 and biological properties.8–10 The pyrazole moiety
is found in many pharmaceutically relevant compounds (meta-
mizole, celecoxib, phenylbutazone, edavarone).
The significant interest of researchers in compounds
containing pyrazole ring is motivated by the broad
possibilities for its modification. Of particular importance
are 4-hydroxyiminopyrazol-5-ones, some of which have
been characterized as pesticides11 and bactericides,12 as
well as inhibitors of CDC25B phosphatases.13 These
compounds are important synthetic intermediates for the
preparation of azo dyes,14 heterocyclic products,15–17 and
4-aminopyrazoles serving as important intermediates for
the synthesis of biologically active compounds.18 Besides
that, 4-hydroxyiminopyrazolones are of interest to
researchers as chelating ligands for the design of
luminescent elements used in photovoltaic devices.19,20
The synthesis of 4-nitrosopyrazol-5-ones has been
achieved by nitrosation of existing pyrazolone nucleus with
NaNO2 in acetic11,12,15,18,21 or hydrochloric acid.14,22
The data available on trifluoromethyl-substituted 3-hydroxy-
iminopyrazoles are limited to two publications,20,23 even
though fluorinated derivatives have been recognized as
promising lead structures for the design of new medicinal
compounds and crop protection agents, as well as other
advanced materials of various nature. These possibilities are
largely due to the unique nature of fluorine24 that confers
interesting physicochemical properties, reactivity, and
biological effects to organofluorine compounds.24–26
The current work is devoted to the development of
effective methods for the synthesis of polyfluoroalkyl-
containing 4-hydroxyiminopyrazol-2-ones, characterization
of their tautomeric structure, as well as the study of their
biological properties.
4-Hydroxyimino-5-trifluoromethylpyrazol-3-one has
been previously prepared by our group using the cycli-
0009-3122/19/55(1)-0052©2019 Springer Science+Business Media, LLC
52

Chemistry of Heterocyclic Compounds 2019, 55(1), 52–59
Scheme 1
Method I
NaNO
AcOH
0–5°C, 30 min
NOH
O
RNHNH
2
RF
OEt
2
F
2 3 a
,
R = CF3 R = H
rt, 3–4 h
18–24%
F
b
RF
OEt
R = CF3, R = Ph
O
c RF= C2F5, R = H
d RF= C2F5, R = Ph
e RF= CF2CF2H, R = H
f RF= C3F7, R = H
OH
O
Method II
OH
N
1a RF = CF3
RNHNH
OH
RF
RF
NaNO2
0–5°C, 30 min
56–62%
2
RF
O
b RF = C4F9
g RF= C4F9, R = H
AcOH, , 3–4 h
N
N
N N
2a–j
F
R
h
i
R = C4F9, R = Ph
R
F
R = CF3, R = Me
j RF= C4F9, R = Me
Method III
NaNO2
OH
N N
3a–h
AcOH, H2O
0–5°C, 30 min
60–85%
R
zation of ethyl 2-hydroxyimino-4,4,4-trifluoro-3-oxo-
butanoate with hydrazine hydrate, including the inter-
mediate isolation of 5-hydroxy-4-hydroxyimino-5-trifluoro-
methylpyrazolidin-3-one with the formation of hydrated
hydrazide as a byproduct.27 However, the synthesis of
starting polyfluoroalkyl-containing 2-hydroxyimino-3-oxo-
esters was complicated due to their formation
predominantly as hydrates at the polyfluoroacyl moiety.23,27
In order to prepare 4-hydroxyiminopyrazolones con-
taining polyfluoroalkyl groups, in this work we explored the
possibilities of a one-pot procedure that we had previously
proposed for the synthesis of 4-nitroso-3-polyfluoro-
alkylpyrazoles from polyfluoroalkyl 1,3-diketones.28,29 It
was found that sequential treatment of 3-oxoesters 1a,b
with NaNO2 in AcOH followed by heterocyclization of the
hydroxyimine intermediate with hydrazines gave the target
4-hydroxyiminopyrazol-3-ones 2a,b,g,i in mediocre yields
(18–24%) (Scheme 1). The low productivity of this
approach motivated us to use a more effective approach to
the nitrosation of existing pyrazole rings. There is only a
single literature source describing the nitrosation of
1-pentafluorophenyl-3-trifluoromethylpyrazol-5-ol using
isoamyl nitrite in THF.20 We demonstrated that the
nitrosation of 3-polyfluoroalkylpyrazol-5-ols 3a–h with
NaNO2 in AcOH enabled convenient access to
4-hydroxyimino-5-polyfluoroalkylpyrazol-3-ones 2a–h in
up to 85% yields.
Scheme 2
H O
O
5
O H
N
N
N
H
RF
5
5 O
RF
RF
O
O
N N
N N
N N
2a–j
R
R
R
E-isomer
Z-isomer
Hydroxyimino tautomer
Nitroso tautomer
IR spectra of compounds 2a–j, which were recorded for
solid samples, featured a high frequency absorption band at
1704–1696 cm–1, indicating the presence of a carbonyl
group in the structure. According to the data of X-ray
structural analysis, crystals of compound 2j at room
temperature contained a Z,Е-isomer mixture of 4-hydroxy-
iminopyrazol-5-one tautomer (Fig. 1). This was observed
from the characteristic doubling of hydroxyimine group
atoms (N(3)(N(3A)), O(2)(O(2A)), H(2A)(H(2AA))).
The presence of hydroxyimine substituent was clearly
established from the arrangement of well-defined double
bonds in the pyrazole ring (one C=O bond and two C=N
bonds). Remarkably, this molecule lacked intramolecular
hydrogen bond between the hydrogen atom of
hydroxyimine substituent and the oxygen atom of carbonyl
group. Instead, one molecule of pyrazolone 2j was linked
by intermolecular hydrogen bonds (С=О···НON, bond
length 2.474 Å) with two other molecules, forming chains
of pyrazole molecules along the axis b (Fig. 2).
In order to synthesize pyrazoles 2, we further proposed
an approach relying on in situ one-pot preparation of
pyrazoles 3a–h from 3-oxoesters 1a,b and hydrazines in
AcOH, followed by treatment of the reaction mixture with
NaNO2. It was found that the target pyrazoles 2a,b,g,i,j
were formed under such conditions in good yields (56–
62%), therefore this method was recognized as the most
preferred option for the synthesis of similar compounds,
since it was possible to avoid the need for isolation of
pyrazoles 3a–h.
It should be noted that compounds 2a,c,e,f,g were
isolated as crystal hydrates containing one molecule of
water for each molecule of pyrazole.
In the case of compounds 2a–j, nitroso-oxime and keto-
enol tautomerism can occur, therefore they can exist as
nitroso form or Z,E-isomers of the hydroxyimine tautomer
(Scheme 2).
Figure 1. The molecular structure of compound 2j with atoms
represented by thermal vibration ellipsoids of 50% probability.
53

Chemistry of Heterocyclic Compounds 2019, 55(1), 52–59
Z,E-isomers were δZ 153–150 and δE 159–150 ppm, which
was also confirmed experimentally.30
Taking into account this trend, we assigned the isomers
of compounds 2a–j on the basis of 13C NMR spectra
(DMSO-d6), in which the isomers differed by the chemical
shifts of С-5 carbonyl carbon nucleus. Thus, the signal at
159–162 ppm was attributed to the carbonyl atom of
E-isomer which predominated in DMSO-d6, while the
signal at 150–153 ppm belonged to the С-5 atom of Z-form
(Scheme 2). The signals of α-CF3 or α-CF2 of poly-
fluoroalkyl substituents in Е-isomers of pyrazoles 2а–j
were generally observed at upfield positions relative to the
analogous signals of Z-form.
Figure 2. Interactions between the molecules of compound 2j.
Methylation of pyrazole 2b with dimethyl sulfate in the
presence of K2CO3 in MeCN led to the formation of
O-methylated product 4, which also existed as a mixture of
Z- and Е-isomers (Scheme 3). The formation of a single
product instead of two isomeric products due to
methylation at two different oxygen atoms was confirmed
by GC-MS analysis, as compound 4 gave only one
chromatographic peak with the retention time of 18.38 min
and m/z value of 271 [М+]. It should be noted that the
carbonyl carbon atoms of Z,Е-isomers of compound 4 gave
13C NMR signals in the same range (δЕ 158 and δZ 150 ppm)
as the carbonyl carbon atoms in Z,Е-isomers of the non-
methylated starting pyrazole 2b (Table 1). Furthermore, the
isomer ratio did not depend on the solvent used (DMSO-d6
or CDCl3), which could be apparently explained by the
lower possibility for intermolecular hydrogen bond
formation in methoxy product 4 compared to the starting
pyrazole 2b containing a hydroxy group.
IR spectra of heterocycle 2b in MeCN and CHCl3
solutions still contained the high frequency absorption
bands at 1735 and 1743 cm–1, respectively, arising from
carbonyl group vibrations. This indicated that the
molecular structure in solid samples and in solution phase
1
remained the same. According to the data of H and 19F
NMR spectroscopy, pyrazoles 2a–j existed in DMSO-d6
solutions as mixtures of two isomers (Table 1). The
analysis of NMR spectra of compounds 2b,d in CD3CN
and CDCl3 showed that the isomer ratio depended on the
nature of solvent, with a tendency for one isomer to
predominate when the less polar CDCl3 was used as
solvent.
The nitroso-hydroxyimine tautomerism of 5-alkylpyrazol-
3-ones has been studied by many research groups.22,30–32
Quantum-chemical calculations and experimental data were used
to show the preferred existence of 5-alkyl(phenyl)pyrazol-
3-ones in the form of hydroxyimine tautomer, with the Е-form
being predominant.31 The energy characteristics of various
isomers were calculated and 13C NMR spectra were simu-
lated using GIAO-ωb97xD/6-31G(d)//M06-2X/6-311++G(d,p)
method. The predicted 13C NMR chemical shifts for
In a continuation of our study, the biological properties
of the synthesized pyrazoles 2a,b,e,f,h,j were tested. The
possibilities for using functionalized pyrazoles as non-
steroidal anti-inflammatory drugs are well known.33 In
addition, the obtained pyrazoles 2a–j have a structural
Table 1. 19F and 13C NMR spectral data for compounds 2a–j, 4
Chemical shifts, δ, ppm
Z:E isomer ratio
RF
R
Е-isomer
Z-isomer
Compound
(solvent)
α-CF3
or α-CF2
α-CF3
or α-CF2
C=O
C=O
CF3
CF3
H
1.5:1 (DMSO-d6)
97.1
162.4
98.3
153.8
2a
2b
1:1 ((CD3)2CO)
97.223
98.323
Ph
1.3:1 (DMSO-d6)
1.1:1 (CD3CN)
0.3:1 (CDCl3)
97.1
97.0
95.0
159.2
98.5
98.3
96.8
150.3
C2F5
C2F5
H
Ph
1.4:1 (DMSO-d6)
1.6:1 (DMSO-d6)
8.2:1 (CDCl3)
49.0
49.0
46.8
162.1
158.9
51.9
51.6
49.3
153.6
150.2
2c
2d
CF2СF2H
C3F7
C4F9
H
H
H
1:1 (DMSO-d6)
2.2:1 (DMSO-d6)
2.3:1 (DMSO-d6)
2:1 ((CD3)2CO)
46.1
50.3
50.9
51.9
162.2
162.3
162.3
46.7
53.5
53.9
54.7
153.6
153.7
153.6
2e
2f
2g
C4F9
CF3
C4F9
Ph
Me
Me
2.8:1 (DMSO-d6)
1.3:1 (DMSO-d6)
2.9:1 (DMSO-d6)
13.2:1 (CDCl3)
51.1
97.3
51.1
49.3
158.9
160.5
160.5
53.9
98.6
53.9
51.5
150.2
151.8
151.7
2h
2i
2j
CF3
Ph
1.6:1 (DMSO-d6)
1.6:1 (CDCl3)
98.4
96.6
158.9
96.9
94.9
150.5
4
54

Chemistry of Heterocyclic Compounds 2019, 55(1), 52–59
Table 2. The analgesic activity and acute toxicity of compounds
Scheme 3
2a–j
Acute toxicity:
dose, mg/kg
(number of surviving
animals)
Analgesic activity:
increase in latency time
after 1 h (after 2 h), %
Compound
35.0*
at 25 mg/kg dose
62.4**
300 (1)
2a
2b
similarity with known analgesic drugs of antipyrine series,
therefore the majority of the synthesized pyrazoles
(compounds 2a,b,e,f,h,j) were tested for acute toxicity and
analgesic activity.
300 (0)
150 (2)
60 (3)***
150 (3)***
150 (3)
The acute toxicity was tested on CD-1 mice, using three
mice in each group for one dose of compound. The
compounds were introduced as single doses intra-
abdominally as suspensions in 1% starch mucus, after
which the animals were observed for 14 days.34,35 The
studied pyrazoles 2a,b,e,f,h,j were generally less toxic than
diclofenac, since the LD50 values for all of the tested
compounds were estimated to be in the range of 150–300
or above 300 mg/kg (Table 2). A decrease in toxicity was
observed upon lengthening of the carbon chain in the
polyfluoroalkyl substituent, namely, replacement of
trifluoromethyl group with a heptafluoropropyl group
(compounds 2a,b,f). An analogous trend was observed in
the series of 4-unsubstituted analogs36 where the
replacement of trifluoromethyl substituent with
pentafluoroethyl group also led to a slight decrease in
toxicity. In the case of compound 2b, it was shown that the
toxicity of that compound was lower via the route of gastric
administration.
Inactive
(89.5*4)
2e
Not tested
Inactive
(Inactive)
300 (2)
150 (3)
2f
2h
53.2*
150 (3)
2j
(69.1*5)
Diclofenac
56.0 10.336
LD50 74,37
intra-abdominal
administration
(83.4 18.1)36
at 10 mg/kg dose
* р < 0.05.
** р < 0.000001.
*** Intragastric administration via gastric tube.
*4 р < 0.01.
*5 р < 0.001.
Z,Е-isomers of the hydroxyimine tautomer. It was shown
that the synthesized pyrazoles exhibited moderate to strong
analgesic activity, which was comparable to the activity of
diclofenac.
The analgetic activity of pyrazoles 2a,b,e,h,j was
evaluated using in vivo experiments with SD rats at the
dose level of 15 or 25 mg/kg (Table 2), according to the hot
plate test. The compounds were introduced intra-abdo-
minally as a suspension in 1% starch mucus. Except for
compound 2h, all of the studied compounds exhibited mode-
rate analgesic activity, which in some cases approached the
activity of diclofenac at the dose level of 10 mg/kg. When
comparing compound 2h with its N-methyl derivative 2j, it
can be expected that the introduction of substituent at the
nitrogen atom of heterocycle should enhance the analgesic
activity. Such a trend was to some extent confirmed by the
results obtained from comparing compound 2а with
N-phenyl derivative 2b.
Pyrazoles 2a,b were tested for the presence of anti-
inflammatory activity using the model of carrageenan-
induced paw edema with Sprague Dawley rats.34
Compound 2a was found to be inactive at all experimental
data points (1, 3, and 5 h after the introduction of
carrageenan), while pyrazole 2b showed slight inhibition of
inflammation (17%, р < 0.05 compared to control) only in
the data point at 3 h.
Experimental
IR spectra were recorded on a PerkinElmer Spectrum
One FT-IR spectrometer over the wavenumber range of
4000–400 cm–1 using a diffuse reflectance accessory. H
1
and 19F NMR spectra were acquired on Bruker DRX-400
(400 and 376 MHz, respectively, compounds 2a,b,e,g,i)
and Bruker Avance 500 (500 and 470 MHz, respectively,
compounds 2c,d,f,h,j,4) spectrometers. 13C NMR spectra
were recorded on a Bruker Avance-500 (125 MHz).
Solvent was DMSO-d6. TMS was used as internal standard
for Н and 13С NMR spectra, and С6F6 was used as the
1
internal standard for 19F NMR spectra (δ –162.9 ppm).
Mass spectrum of compound 4 was recorded on an Agilent
7890A gas chromatograph coupled to Agilent 5975C Inert
XL EI/CI quadrupole mass spectrometric detector, using an
HP-5MS capillary fused silica column (polydimethyl-
siloxane, 5 mass % of phenyl groups, 30 m length, 0.25 mm
diameter, 0.25 µm film thickness. Mass spectra were
recorded in electron impact ionization mode (70 eV) while
scanning the total ion current over the mass range of 20–
1000 Da, carrier gas – helium. Injection volume was 1.0 µl,
sample solutions with 3–5 mg/ml concentration were
prepared in CHCl3. Elemental analysis was performed
using a PerkinElmer 2400 Series II CHN-O elemental
analyzer. Melting points were determined in open
capillaries on a Stuart SMP30 digital melting point
apparatus. Column chromatography was performed on
silica gel 60 (0.063–0.2 mm) from Alfa Aesar.
Thus, we have proposed alternative synthetic routes for
the preparation of 4-hydroxyimino-5-polyfluoroalkylpyrazol-
3-ones, among which the most effective method was based
on a one-pot treatment of polyfluoroalkyl-3-oxoesters with
hydrazine and sodium nitrite in acetic acid. It was
established that 4-hydroxyimino-5-polyfluoroalkylpyrazol-
3-ones in solid state and in solutions existed as mixtures of
55

Chemistry of Heterocyclic Compounds 2019, 55(1), 52–59
The starting polyfluoroalkyl-containing 3-oxoesters 138
19F NMR spectrum, δ, ppm: 97.1 (s, CF3 E-isomer); 98.5
(s, CF3 Z-isomer). Found, %: C 46.73; H 2.36; N 16.32.
C10H6F3N3O2. Calculated, %: C 46.70; H 2.35; N 16.34.
4-(Hydroxyimino)-5-(pentafluoroethyl)-2,4-dihydro-3H-
pyrazol-3-one hydrate (2c), a mixture of isomers, E:Z ratio
1.4:1. Yield 1.61 g (65%, method III), yellow powder,
mp 114–115°С. IR spectrum, ν, cm–1: 3675, 3400, 3221
(OH, NH), 1735 (C=O), 1642, 1555, 1505 (C=N, C=C),
1135–1059 (CF). 1Н NMR spectrum, δ, ppm: 12.63 (1Н, s,
NH E-isomer); 12.73 (1Н, s, NH Z-isomer); 15.19 (2H,
br. s, OH). 13С NMR spectrum, δ, ppm (J, Hz): 109.4 (qt,
J = 251.9, J = 39.4, CF2); 118.1 (tq, J = 286.7, J = 36.8,
CF3); 153.6 (C=O E-isomer); 162.1 (C=O Z-isomer).
19F NMR spectrum, δ, ppm (J, Hz): 49.0 (q, J = 2.5, CF2
E-isomer); 51.9 (q, J = 1.8, CF2 Z-isomer); 80.3 (t, J = 2.6,
CF3 E-isomer); 82.2 (unresolved t, CF3 Z-isomer). Found,
%: C 24.11; H 1.62; N 16.87. C5H2F5N3O2·H2O.
Calculated, %: C 24.03; H 1.57; N 18.69.
and pyrazolones 339 were synthesized according to known
procedures.
Synthesis of polyfluoroalkyl-containing 4-hydroxy-
iminopyrazol-5-ones 2a–j (General procedure). Method I.
A solution of 3-oxoester 1a,b,g,i (10 mmol) in AcOH
(10 ml) was cooled to 0–5°С with stirring and treated by
slow addition of NaNO2 (0.86 g, 12.5 mmol) as solution in
H2O (10 ml). The mixture was maintained for 30 min at 5–
10°С, treated with the appropriate hydrazine derivative
(11 mmol), and stirred at room temperature for 3–4 h.
Method II. A mixture of the appropriate 3-oxoester
1a,b,g,i,j (10 mmol) and the appropriate hydrazine
derivative (11 mmol) was refluxed in AcOH (10 ml) for 3–
4 h. The reaction mixture was then cooled to 0–5°С with
stirring and treated by slow addition of NaNO2 (1.72 g,
25 mmol) in H2O (15 ml). The mixture was then
maintained for 30 min at 5–10°С.
Method III. A solution of pyrazolone 3a–h (10 mmol) in
AcOH (10 ml) was cooled to 0–5°С with stirring and
treated by slow addition of NaNO2 (0.86 g, 12.5 mmol) in
H2O (10 ml). The mixture was maintained for 30 min at 5–
10°С.
In all of the cases, the reaction mixture was extracted
with Et2O (2×20 ml), the organic layer was washed with
saturated NaHCO3 solution to neutral pH, dried over
anhydrous Na2SO4, and evaporated at reduced pressure on
a rotary evaporator. The obtained precipitate was washed
with H2O, hexane, and air-dried.
4-(Hydroxyimino)-5-(trifluoromethyl)-2,4-dihydro-3H-
pyrazol-3-one hydrate (2а), a mixture of isomers, E:Z
ratio 1.5:1. Yield 0.47 g (24%, method I), 1.23 g (62%,
method II), 1.47 g (74%, method III), yellow powder,
mp 113–114°С (sublim.) (mp 110°С31). 1Н NMR spectrum,
δ, ppm: 12.50 (1Н, s, ОН Z-isomer); 12.60 (1Н, s, OН
E-isomer); 15.08 (1H, br. s, NH). 13С NMR spectrum,
δ, ppm (J, Hz): 119.1 (q, J = 270.0, CF3 Z-isomer); 119.2
(q, J = 268.5, CF3 E-isomer); 129.5 (q, J = 40.3, CCF3
E-isomer); 136.1 (q, J = 38.3, CCF3 Z-isomer); 138.6
(E-isomer); 140.0 (Z-isomer); 153.8 (C=O E-isomer);
162.4 (C=O Z-isomer). 19F NMR spectrum, δ, ppm: 97.1 (s,
CF3 E-isomer); 98.2 (s, CF3 Z-isomer). Found, %: C 24.38;
H 2.03; N 20.99. C4H2F3N3O2·H2O. Calculated, %:
C 24.13; H 2.03; N 21.11.
4-(Hydroxyimino)-5-(pentafluoroethyl)-2-phenyl-2,4-
dihydro-3H-pyrazol-3-one (2d), a mixture of isomers, E:Z
ratio 1.6:1. Yield 1.93 g (63%, method III), yellow powder,
mp 161–162°С. IR spectrum, ν, cm–1: 3125, 3047, 3017
(OH), 1707 (C=O), 1675, 1610, 1592, 1560 (C=N, C=C),
1
1140–1060 (CF). Н NMR spectrum, δ, ppm: 7.31–7.34,
7.49–7.53, 7.71–7.73 (5H, m, H Ph); the signal of OH
group was not observed due to deuterium exchange with
solvent. 13С NMR spectrum, δ, ppm (J, Hz): 109.5 (2С, qt,
J = 252.8, J = 39.6, CF2); 118.1 (2С, tq, J = 287.1,
J = 36.4, CF3); 119.5 (Z-isomer); 119.7 (E-isomer); 126.4
(E-isomer); 126.5 (Z-isomer); 129.1 (2С); 135.7 (2С, t,
J = 28.9, CCF2); 136.6 (Z-isomer); 136.7 (E-isomer); 139.2
(2С); 141.1; 150.2 (C=O E-isomer); 158.8 (C=O Z-isomer).
19F NMR spectrum, δ, ppm (J, Hz): 49.0 (br. s, CF2
E-isomer); 51.6 (br. s, CF2 Z-isomer); 80.5 (t, J = 2.7, CF3
E-isomer); 82.3 (unresolved t, CF3 Z-isomer). Found, %:
C 43.03; H 1.95; N 16.69. C11H6F5N3O2. Calculated, %:
C 43.01; H 1.97; N 13.68.
4-(Hydroxyimino)-5-(1,1,2,2-tetrafluoroethyl)-2,4-di-
hydro-3H-pyrazol-3-one hydrate (2e), a mixture of
isomers, E:Z ratio 1:1. Yield 1.66 g (72%, method III),
yellow powder, mp 50°С (sublim., PhMe). IR spectrum,
ν, cm–1: 3668, 3420, 3232, 1696 (OH, NH), 1746 (C=O),
1
1631, 1559, 1531 (C=N, C=C), 1102–1072 (CF). Н NMR
spectrum, δ, ppm (J, Hz): 6.83 (1H, tt, J = 51.8, J = 5.1
(CF2)2H Z-isomer); 6.85 (1H, tt, J = 51.8, J = 5.4, (CF2)2H
E-isomer); 12.48 (1Н, s, ОН Z-isomer); 12.60 (1Н, s, OН
E-isomer); 15.13 (1H, br. s, NH). 13С NMR spectrum,
δ, ppm (J, Hz): 106.9–113.5 (m, (CF2)2H); 129.1 (t,
J = 31.3, CCF2 Z-isomer); 135.1 (t, J = 29.6, CCF2
E-isomer); 138.1 (Z-isomer); 140.8 (E-isomer); 153.6
(E-isomer); (C=O E-isomer); 162.3 (C=O Z-isomer).
19F NMR spectrum, δ, ppm (J, Hz): 25.1 (2F, dt, J = 51.8,
J = 10.1, β-CF2 Z-isomer); 25.2 (2F, dt, J = 51.8, J = 8.7,
β-CF2 E-isomer); 46.0–46.1 (2F, m, γ-CF2 Z-isomer); 46.6–
46.7 (2F, m, γ-CF2 E-isomer). Found, %: C 26.05; H 2.41;
N 18.05. C5H3F4N3O2·H2O. Calculated, %: C 25.99;
H 2.18; N 18.18.
4-(Hydroxyimino)-5-(trifluoromethyl)-2-phenyl-2,4-di-
hydro-3H-pyrazol-3-one (2b), a mixture of isomers, E:Z
ratio 1.3:1. Yield 0.51 g (20%, method I), 1.52 g (59%,
method II), 2.11 g (82%, method III), orange powder,
mp 163–164°С. IR spectrum, ν, cm–1: 3131, 3057, 3007
(OH), 1704 (C=O), 1678, 1614, 1596, 1563 (C=N, C=C),
1
1145–1066 (CF). Н NMR spectrum, δ, ppm: 7.30–7.35,
7.48–7.53, 7.71–7.75 (5H, m, H Ph); the signal of OH
group was not observed due to deuterium exchange with
solvent. 13С NMR spectrum, δ, ppm (J, Hz): 119.2 (2С, q,
J = 269.5, CF3); 119.6 (E-isomer); 119.7 (Z-isomer); 126.5
(E-isomer); 129.1 (E-isomer); 129.7 (2С, q, J = 40.9,
CCF3); 136.8 (E-isomer); 126.4 (Z-isomer); 129.1
(Z-isomer); 136.8 (Z-isomer); 139.4 (E-isomer); 140.5
(Z-isomer); 150.3 (C=O E-isomer); 159.2 (C=O Z-isomer).
5-(Heptafluoropropyl)-4-(hydroxyimino)-2,4-dihydro-
3H-pyrazol-3-one hydrate (2f), a mixture of isomers, E:Z
56

Chemistry of Heterocyclic Compounds 2019, 55(1), 52–59
ratio 2.2:1. Yield 1.79 g (60%, method III), yellow powder,
ν, cm–1: 3510, 3446 (OH), 1705 (C=O), 1677, 1646, 1615
(C=N, C=C), 1213–1152 (CF). 1Н NMR spectrum, δ, ppm:
3.32 (3Н, s, CH3 Z-isomer); 3.34 (3Н, s, CH3 E-isomer);
the signal of OH group was not observed due to deuterium
exchange with solvent. 13С NMR spectrum, δ, ppm (J, Hz):
31.7 (CH3 E-isomer); 31.9 (CH3 Z-isomer); 119.0 (q,
J = 269.8, CF3 E-isomer); 119.1 (q, J = 268.4, CF3
Z-isomer); 127.7 (q, J = 40.7, CCF3 E-isomer); 134.4 (q,
J = 38.6, CCF3 Z-isomer); 138.7 (Z-isomer); 140.0
(E-isomer); 151.8 (C=O E-isomer); 160.5 (C=O Z-isomer).
19F NMR spectrum, δ, ppm: 97.3 (s, CF3 E-isomer); 98.6
(s, CF3 Z-isomer). Found, %: C 30.70; H 2.09; N 21.62.
C5H4F3N3O2. Calculated, %: C 30.78; H 2.07; N 21.54.
4-(Hydroxyimino)-2-methyl-5-(nonafluorobutyl)-2,4-di-
hydro-3H-pyrazol-3-one (2j), a mixture of isomers, E:Z
ratio 2.9:1. Yield 2.10 g (61%, method II), yellow crystals,
mp 130–131°С. IR spectrum, ν, cm–1: 3520, 3455 (OH),
1715 (C=O), 1670, 1645, 1605 (C=N, C=C), 1200–1105
(CF). 1Н NMR spectrum, δ, ppm: 3.36 (3Н, s, CH3
E-isomer); 3.37 (3Н, s, CH3 Z-isomer). 13С NMR spectrum,
δ, ppm (J, Hz): 31.8 (CH3 E-isomer); 32.1 (CH3 Z-isomer);
106.3–120.3 (m, C4F9); 127.1 (t, J = 31.3, CCF2 Z-isomer);
133.4 (t, J = 28.2, CCF2 E-isomer); 138.3 (Z-isomer); 140.9
(E-isomer); 151.7 (C=O E-isomer); 160.5 (C=O Z-isomer).
19F NMR spectrum, δ, ppm: 37.2–37.3 (2F, m, γ-CF2
E-isomer); 37.5–37.6 (2F, m, γ-CF2 Z-isomer); 40.4–40.5
(2F, m, β-CF2 E-isomer); 41.9–42.0 (2F, m, β-CF2
Z-isomer); 51.0–51.1 (2F, m, α-CF2 E-isomer); 53.9–54.0
(2F, m, α-CF2 Z-isomer); 82.1 (3F, t, J = 9.5, CF3
E-isomer); 82.2 (3F, t, J = 9.6, CF3 Z-isomer). Found, %:
C 27.84; H 1.17; N 12.18. C8H4F9N3O2. Calculated, %:
C 27.76; H 1.19; N 12.19.
mp 99–100°С (PhMe). IR spectrum, ν, cm-1: 3680, 3416,
3234, 1698 (OH, NH), 1749 (C=O), 1631, 1547, 1494
(C=N, C=C), 1124–1065 (CF). 1Н NMR spectrum, δ, ppm:
12.69 (1Н, s, OН E-isomer); 12.80 (1Н, s, ОН Z-isomer);
15.26 (1H, br. s, NH). 13С NMR spectrum, δ, ppm (J, Hz):
101.9–121.0 (C3F7); 131.4 (t, J = 31.7, CCF2 Z-isomer);
137.6 (t, J = 28.2, CCF2 E-isomer); 138.9 (Z-isomer); 140.6
(E-isomer); 153.7 (C=O E-isomer); 162.3 (C=O Z-isomer).
19F NMR spectrum, δ, ppm (J, Hz): 36.6–36.7 (2F, m,
γ-CF2 E-isomer); 38.3–38.4 (2F, m, γ-CF2 Z-isomer); 50.2–
50.3 (2F, m, β-CF2 E-isomer); 53.4–53.5 (2F, m, β-CF2
Z-isomer); 82.8 (3F, t, J = 9.2, CF3 E-isomer); 83.0 (3F, t,
J = 9.6, CF3 Z-isomer). Found, %: C 24.24; H 1.20;
N 14.02. C6H2F7N3O2·H2O. Calculated, %: C 24.09;
H 1.35; N 14.05.
4-(Hydroxyimino)-5-(nonafluorobutyl)-2,4-dihydro-3H-
pyrazol-3-one hydrate (2g), a mixture of isomers, E:Z
ratio 2.3:1. Yield 0.63 g (18%, method I), 2.16 g (62%,
method II), 2.97 g (85%, method III), yellow powder,
mp 126–127°С. IR spectrum, ν, cm–1: 3681, 3415, 3234,
2772 (OH, NH), 1745 (C=O), 1697, 1630, 1494 (C=N,
1
C=C), 1231–1138 (CF). Н NMR spectrum, δ, ppm: 12.69
(1Н, s, OН E-isomer); 12.80 (1Н, s, ОН Z-isomer); 15.25
(1H, br. s, NH). 13С NMR spectrum, δ, ppm (J, Hz): 106.0–
120.4 (m, C4F9); 129.1 (t, J = 31.3, CCF2 Z-isomer); 135.1
(t, J = 28.1, CCF2 E-isomer); 138.1 (Z-isomer); 140.8
(E-isomer); 153.6 (C=O E-isomer); 162.3 (C=O Z-isomer).
19F NMR spectrum, δ, ppm (J, Hz): 37.1–37.2 (2F, m,
γ-CF2 E-isomer); 37.5–37.6 (2F, m, γ-CF2 Z-isomer); 40.2–
40.3 (2F, m, β-CF2 E-isomer); 41.8–41.9 (2F, m, β-CF2
Z-isomer); 50.9 (2F, t, J =10.8, α-CF2 E-isomer,); 53.9–
54.0 (2F, m, α-CF2 Z-isomer), 82.2 (6F, t, J = 9.4, CF3).
Found, %: C 24.15; H 1.12; N 11.95. C7H2F9N3O2·H2O.
Calculated, %: C 24.08; H 1.15; N 12.04.
4-(Methoxyimino)-2-phenyl-5-(trifluoromethyl)-2,4-di-
hydro-3H-pyrazol-3-one (4), a mixture of isomers, E:Z
ratio 1.6:1. A mixture of oxime 2b (0.5 g, 1.9 mmol),
dimethyl sulfate (0.24 g, 1.9 mmol), and K2CO3 (0.39 g,
3 mmol) in MeCN (5 ml) was stirred at room temperature
for 4 h. The reaction mixture was then cooled, quenched
with H2O (5 ml), extracted with CHCl3 (2×10 ml),
evaporated at reduced pressure, and purified by column
chromatography, eluent CHCl3–hexane, 4:1. Yield 2.17 g
4-(Hydroxyimino)-5-(nonafluorobutyl)-2-phenyl-2,4-di-
hydro-3H-pyrazol-3-one (2h), a mixture of isomers, E:Z
ratio 2.8:1. Yield 3.34 g (82%, method III), yellow powder,
mp 127–128°С. IR spectrum, ν, cm–1: 3247, 3181 (NH),
1723 (C=O), 1704, 1616, 1595 (C=N, C=C), 1241–1129
1
(CF). Н NMR spectrum, δ, ppm: 7.20–7.25, 7.41–7.52,
7.83–7.93 (5H, m, H Ph). 13С NMR spectrum, δ, ppm
(J, Hz): 107.6–120.3 (C4F9); 119.4 (Z-isomer); 119.6
(E-isomer); 126.5 (E-isomer); 126.6 (Z-isomer); 129.1
(2С); 129.4 (t, J = 31.8, CCF2 Z-isomer); 135.8 (t, J = 28.4,
CCF2 E-isomer); 136.6 (Z-isomer); 136.7 (E-isomer); 138.8
(Z-isomer); 141.2 (E-isomer); 150.2 (C=O E-isomer);
158.9 (C=O Z-isomer). 19F NMR spectrum, δ, ppm (J, Hz):
37.3–37.4 (2F, m, γ-CF2 E-isomer); 37.5–37.6 (2F, m,
γ-CF2 Z-isomer); 40.7–40.8 (2F, m, β-CF2 E-isomer); 41.9–
42.0 (2F, m, β-CF2 Z-isomer); 51.0–51.1 (2F, m, α-CF2
E-isomer); 53.9–54.0 (2F, m, α-CF2 Z-isomer); 82.1 (3F, t,
J = 9.4, CF3 E-isomer); 82.2 (3F, t, J = 9.4, CF3 Z-isomer).
Found, %: C 38.30; H 1.42; N 10.43. C13H6F9N3O2.
Calculated, %: C 38.35; H 1.49; N 10.32.
(80%), orange powder, mp 82–83°С. Н NMR spectrum,
1
δ, ppm: 4.35 (3H, s, OCH3 Z-isomer); 4.36 (3H, s, OCH3
Е-isomer); 7.32–7.36, 7.49–7.53, 7.68–7.72 (5H, m, H Ph).
13С NMR spectrum, δ, ppm (J, Hz): 66.6 (Z-isomer); 67.0
(E-isomer); 118.7 (q, J = 270.8, CF3 E-isomer); 118.9 (q,
J = 269.3, CF3 Z-isomer); 119.6 (Z-isomer); 119.7
(E-isomer); 126.5 (E-isomer); 126.7 (Z-isomer); 129.1
(2C); 129.8 (q, J = 41.0, CCF3 Z-isomer); 135.7 (q,
J = 39.0, CCF3 E-isomer); 136.5 (2C); 138.2 (Z-isomer);
140.0 (E-isomer); 150.6 (C=O E-isomer); 158.1 (C=O
Z-isomer). 19F NMR spectrum, δ, ppm: 98.4 (s, CF3
E-isomer); 96.9 (s, CF3 Z-isomer). Mass spectrum, m/z
(Irel, %): 271 [M]+ (20). Calculated, %: C 48.72; H 2.97;
N 15.49. C11H8F3N3O2. Found, %: C 48.65; H 2.84; N 15.55.
X-ray structural analysis of compound 2j was
performed on an Xcalibur 3 automatic diffractometer
equipped with a CCD detector (graphite monochromator,
λ(MoKα) = 0.71073 Å, ω-scanning, temperature 295(2) K).
4-(Hydroxyimino)-2-methyl-5-(trifluoromethyl)-2,4-di-
hydro-3H-pyrazol-3-one (2i), a mixture of isomers, E:Z
ratio 1.3:1. Yield 0.43 g (22%, method I), 1.13 g (58%,
method II), yellow powder, mp 99–100°С. IR spectrum,
57

Chemistry of Heterocyclic Compounds 2019, 55(1), 52–59
Absorption was taken into account analytically according
using the carrageenan-induced paw edema model according
to the standard procedure.34 The study compounds were
administered intra-abdominally as suspensions in 1%
starch mucus (15 mg/kg) 30 min prior to the administration
of carrageenan. The volume of rat paws was measured
oncometrically across four time points: before the
administration of carrageenan, then 1, 3, and 5 h after its
administration using a TSE Volume Meter plethysmometer
(TSE Systems, Germany).
The obtained experimental data were processed by
Multiplet tests method using the GraphPad Prism 6
program. The results were interpreted as sufficiently
different at р < 0.05.
to the multifaceted crystal model using the CrysAlis RED
1.171.39.38a program.40 The crystal structure was solved
by direct method and refined with full-matrix method of
least squares by F2 using the SHELXTL software suite.41
Refinement for non-hydrogen atoms was performed in
anisotropic approximation, hydrogen atoms were placed in
geometrically calculated positions and included in the re-
finement according to the riding model in isotropic approxi-
mation with temperature parameters dependent on the
"parent" atoms. The crystallographic data for compound 2j
(crystals grown from CH2Cl2 solution): С8H4F9N3O2, М 345.14;
space group P21/c; monoclinic crystals; а 17.558(4),
b 5.4462(7), c 13.617(3) Å; β 105.40(2)°; V 1255.3(4) Å;
Z 4; dcalc 1.826 g/cm–3; μ 0.217 mm–1. A total of 7779
reflections were collected, of which 3087 were indepen-
dent, R factor 0.086, the number of refined parameters were
257. The complete crystallographic dataset for compound
2j was deposited at the Cambridge Crystallographic Data
Center (deposit CCDC 1878730).
This work was performed with financial support from
the Russian Science Foundation (grant 16-13-10255).
The equipment used was kindly provided by the
Collective Use Center ''Spectroscopy and Analysis of
Organic Compounds'', I. Ya. Postovsky Institute of Organic
Synthesis, Ural Branch of the Russian Academy of
Sciences.
The study of analgesic activity and acute toxicity of
compounds 2a,b,e,f,h,j. Laboratory animals (Sprague
Dawley rats and CD-1 mice) were obtained from the
Branch of the Institute of Biochemistry, Russian Academy
of Sciences, nursery "Pushchino". The second generation
of animals was used for the described experiments. The
animals were kept under natural light cycle in poly-
propylene rodent housing (Bioscape, Germany) on standard
animal bedding (RehoFix MK 2000, J. Rettenmaier &
Söhne, Germany), with the standard Chara chow for
conventional laboratory rodents (Assortiment-Agro, Russia
and BioPro, Russia) according to schedule and water ad
libitum. The work with laboratory animals was performed
by a professional veterinary doctor, pharmacologist, and
trained specialists according to bioethics regulations and
guidelines for human treatment of laboratory animals.34,42,43
The determination of acute toxicity was performed on
outbred albino mice of CD-1 line according to the standard
recommendations.34,35 The study compounds were
administered one time intra-abdominally as suspensions in
1% starch mucus, with each sample given to three animals.
The survival of mice in groups after the administration of
compounds was determined by close observation for 24 h
and subsequent general observation for 14 days.
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