Regiocontrolled N-, O- and C-methylation of 1-phenyl-3-polyfluoroalkyl-1H-pyrazol-5-ols

Article abstract of DOI:10.1016/j.jfluchem.2017.12.011

The approaches for regiocontrolled N-, O- and C-methylation of 1-phenyl-3-polyfluoroalkyl-1H-pyrazol-5-ols have been developed. The chemoselective N-methylation proved to be an efficient method for the synthesis of polyfluorinated antipyrine analogs. In addition, we reinvestigated the structure of 3-polyfluoroalkyl-1-phenylpyrazol-5-ols by the X-Ray analysis. The quantum-chemical calculations were used for an explanation of methylation processes. The preliminary biological testing revealed a significant analgesic activity of trifluoromethyl-containing antipyrine.

Full text of DOI:10.1016/j.jfluchem.2017.12.011

Accepted Manuscript
Title: Regiocontrolled N-, O- and C-methylation of
1-phenyl-3-polyfluoroalkyl-1H-pyrazol-5-ols
Authors: N.A. Nemytova, E.V. Shchegol’kov, Ya.V. Burgart,
P.A. Slepukhin, S.S Borisevich, S.L. Khursan, V.I. Saloutin
PII:
S0022-1139(17)30497-9
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2017.12.011
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12-12-2017
12-12-2017
Please cite this article as: N.A.Nemytova, E.V.Shchegol’kov, Ya.V.Burgart,
P.A.Slepukhin, S.S Borisevich, S.L.Khursan, V.I.Saloutin, Regiocontrolled N-, O- and
C-methylation of 1-phenyl-3-polyfluoroalkyl-1H-pyrazol-5-ols, Journal of Fluorine
Chemistry https://doi.org/10.1016/j.jfluchem.2017.12.011
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Regiocontrolled N-, O- and C-methylation of 1-phenyl-3-polyfluoroalkyl-
1H-pyrazol-5-ols
N.A. Nemytova1, E.V. Shchegol’kov*1, Ya.V. Burgart1, P.A. Slepukhin1,2,
S.S. Borisevich3, S.L. Khursan3, V.I. Saloutin1
1Postovsky Institute of Organic Synthesis of Ural Branch of Russian Academy of Science, S. Kovalevskoy Str.,
22, Ekaterinburg 620990, Russia;
2Ural Federal University, 19 Mira Street, 620002 Ekaterinburg, Russia;
3Ufa Institute of Chemistry of Russian Academy of Science, Octyabrya Av., 71, Ufa 450078, Russia
Email: schegolkov@ios.uran.ru
* Corresponding author
Graphical abstract
HIGHLIGHTS


Regiocontrolled N-, O- and C-methylation of 1-phenyl-3-(polyfluoroalkyl)-1H-pyrazol-5-ols is
developed.
The chemoselective N-methylation is an efficient method for the synthesis of polyfluorinated
antipyrine analogs.


The quantum-chemical calculations are presented for an explanation of methylation processes.
Trifluoromethylantipyrine has a powerful analgesic properties.
Abstract
The approaches for regiocontrolled N-, O- and C-methylation of 1-phenyl-3-polyfluoroalkyl-1H-pyrazol-
5-ols have been developed. The chemoselective N-methylation proved to be an efficient method for the synthesis
1

of polyfluorinated antipyrine analogs. In addition, we reinvestigated the structure of 3-polyfluoroalkyl-1-
phenylpyrazol-5-ols by the X-Ray analysis. The quantum-chemical calculations were used for an explanation of
methylation processes. The preliminary biological testing revealed a significant analgesic activity of
trifluoromethyl-containing antipyrine.
Keywords: 1H-Pyrazol-5-ols; Methylation; Polyfluorinated antipyrine; Chemoselectivity; Quantum-
chemical calculations; Analgesic activity
1. Introduction
The pyrazoles are the preferred structures in the bioactive molecules design because
their derivatives have the various biological properties [1–8]. According to SciFinder® search
data, over 40 review articles on the synthesis and properties of pyrazoles have been published
in the last 5 years. Among them the most perspective objects are the pyrazolone derivatives due
to their practical application in medicine. Recently, 3-methyl-1-phenylpyrazol-5-one
(Edaravone, the brand names Radicava® and Radicut®) was found to be a free radical
scavenger [9]. Today, Edaravone is used as nootropic drug which helps the recovery after
ischemic stroke [10] and treat the amyotrophic lateral sclerosis [11]. However, its methylated
derivative, 1,2-dihydro-1,5-dimethyl-2-phenyl-3H-pyrazol-3-one (antipyrine, phenazone), is
being used in medicine more than 100 years (see DrugBank) as a nonsteroidal anti-
inflammatory drug (NSAID). A series of NSAIDs (aminophenazone, propyphenazone,
metamizole, etc.) was developed based on antipyrine (Fig. 1).
Figure 1. Pyrazol-containing drugs
These data show that the introduction of a methyl substituent has a significant value for
the appearance of different biological activity in molecules. The methyl group is considered to
be very important in the molecular recognition of endogenous and exogenous organic
compounds by bioreceptors. Methyl groups have stereoelectronic effects on micromolecules
and biomacromolecules, thereby leading to diverse biological effects, including selectivity
among bioreceptors, increased potency, and protection against enzyme metabolism [12].
Cognizant of the methyl group’s importance in molecular recognition, C. Wermuth wrote: “The
2

methyl group, so often considered as chemically inert, is able to alter deeply the
pharmacological properties of a molecule” [13].
To introduce the methyl substituent in organic compounds, the methylation is used. The
presence of several functional groups in an initial substrate needs to develop conditions for the
chemoselective methylation. So, regioselective N-methylation of 3-methyl-1-phenylpyrazol-5-
one is carried out with dimethyl sulphate or methyl iodide that allows to obtain antipyrine [14].
The use of a base in this reaction yields to a mixture of N-, O-, C-methylated products [15]. The
selective O-methylation of non-fluorinated pyrazole is carried out with methanol under
Mitsunobu reaction conditions [16–18], with diazomethane [19] or via chlorination of the initial
pyrazole followed by chlorine substitution on the methoxy group in the methanol with alkali
[20].
Herein, we have developed the methods for regiocontrolled N-, O- and C-methylation
of 1-phenyl-3-polyfluoroalkyl-1H-pyrazol-5-ols since fluorinated derivatives have the great
promising to obtain the biologically active compounds. For example, one of the last “bestseller”
on the drug market is Celebrex® (Celecoxib) having the structure of 4-[5-(4-methylphenyl)-3-
(trifluoromethyl)-1H-pyrazol-1-yl]benzene-1-sulfonamide (Fig. 1) [21]. It has the selective
activity to COX-2 inhibition, whereas the non-fluorinated analogs are either inactive or inhibit
both COX-1 and COX-2 isoenzymes [21].
Data on methylation of polyfluoroalkylpyrazolones are limited by only two works,
which described obtaining of N-methylated derivatives [22, 23]. Synthesis of 1-phenyl-2-
methyl-3-trifluoromethyl-5-pyrazolone (trifluoromethylantipyrine) in a yield 72 % was
described in 1958 year by N-methylation of 1-phenyl-3-trifluoromethyl-5-pyrazolone with 4.7-
fold excess of dimethyl sulphate at 110-120 ºC for 1.5 h [22]. Later, the
trifluoromethylantipyrine analog containing second trifluoromethyl-group in phenyl substituent
was obtained in a yield 58% by the reaction of the corresponding pyrazole with 10-fold excess
of dimethyl sulphate [23]. Both publications do not contain the data on the structure and
biological properties of trifluoromethylantipyrines.
2. Results and Discussion
To find out the optimal conditions for chemoselective N- and O-methylation of 1-
phenyl-3-trifluoromethyl-5-pyrazolone 1a, a thorough study of this reaction with the used
various methylating agents (MeI – methyl iodide, Me2SO4 – dimethyl sulphate, DMF-DMA –
N,N-dimethylformamide dimethyl acetal, (MeO)2CO – dimethyl carbonate [24]) was carried
out.
3

We have found that under regioselective N-methylation conditions of 3-methyl-1-
phenylpyrazol-5-one with methyl iodide in refluxing acetonitrile the initial pyrazole 1a was
isolated (Table 1, Entry 1). The using of equimolar quantities of MeI and K2CO3 as a base
resulted in a mixture of N- and O-methyl substituted pyrazoles 2a and 3a (Table 1, Entry 2). In
all cases, the reaction of pyrazole 1a and MeI in the presence of K2CO3 resulted in predominant
formation of O-isomer 3a (Table 1, Entry 2-5). The use of proton-donating methanol as a
solvent led to reducing of 3a content compared with the reactions in acetonitrile (Entry 2, 3, 5).
Employment of 5-fold excess of MeI substantially increased the content of 3a (Entry 5).
The methylation of pyrazole 1a with Me2SO4 in the presence of various inorganic bases
also was non-selective (Entry 7-9). However, 100 % formation of pyrazole 3a was obtained
from 1 equiv of Me2SO4, 1.5 equiv of K2CO3 and acetonitrile as a solvent (Entry 6), but
increasing of the methylating reagent to 5 equiv resulted in a significantly decrease of
compound 3a content (Entry 10).
Scheme 1
Under methylation with equimolar quantities of Me2SO4 without base, the increasing of
N-methyl isomer 2a was observed in MeCN (Entry 11). However, complete conversion of the
initial pyrazole 1a did not occur with 2 equiv of Me2SO4 (Entry 12). The 5-fold excess of
Me2SO4 without a base was found to be an effective for regioselective formation of N-methyl
isomer 2a (Entry 13). Obviously, Me2SO4 in the large excess is not only a reagent but also a
polar solvent. In contrast, the conversion of the reaction is 56% in nonpolar toluene after the
same period of time (Entry 14) and it became less regioselective in proton-donating methanol
(Entry 15).
4

aThe ratio of products was determined by 19F NMR spectra (CDCl3) after the heating of initial
pyrazoles 1a-d for 6-7 h in corresponding conditions.
Reaction with (MeO)2CO did not occur without a base (Entry 16), although the same
methylation conditions for non-fluorinated pyrazole resulted in N- and O-substituted products
in ratio 73:21 [25]. However, full conversion of pyrazole 1a into the O-isomer 3a was not
achieved (Entry 17-18). (MeO)2CO seems to be a weak methylating agent [26] same as MeI
compared to Me2SO4.
The reaction of pyrazole 1a with DMF-DMA in the presence of a base led to complex
mixture of products (Entry 19). However, the reaction of heterocycle 1a with DMF-DMA in
refluxing MeCN (Entry 20) resulted in 4-[(dimethylamino)methylene]-2,4-dihydro-5-
(trifluoromethyl)-3H-pyrazol-3-one 4a instead of expected products 2a and 3a (Scheme 1).
Obviously, compound 4a formed as a result of the aminomethylidation of pyrazole 1a with
DMF-DMA at CH-center similar to non-fluorinated analogs [27]. It is noted that the substance
4a exists in solutions as one of possible isomers which is confirmed by NMR spectra that
contain a one set of signals. Based on X-Ray analysis data (Fig. 2, CCDC 1553333) the structure
of compound 4a corresponds to Z-isomer. The crystal packing are characterized by the short
contacts between two molecules with distances F1…C10’ 3.138(4) Å, F2…H—C8’ 2.525 Å.
Figure 2. The ORTEP view of molecule 4a.
Figure 3. The ORTEP view of molecule 2a.
After a series of experiments, we have revealed the optimal conditions (Scheme 1) for
chemoselective synthesis of the N-methylpyrazolone 2a (heating with 5 equiv of Me2SO4, Entry
15), O-methylpyrazole 3a (refluxing in acetonitrile with 1 equiv of Me2SO4 and 1.5 equiv of
K2CO3, Entry 6), and C-aminomethylated derivative 4a (refluxing in acetonitrile with 2 equiv
of DMF-DMA, Entry 20).
5

It was found that the using of 10-fold of excess of dimethyl sulphate (as described in a
patent [23]) is impractical because it led to the product yield decreasing.
In contrast to non-fluorinated pyrazolone, the selective O-methylation of fluorinated
pyrazoles occurs under the use of the inorganic base and Me2SO4. It can be explained by the
formation of a stable salt from polyfluoroalkyl pyrazolole 1a due to the more acidic nature of
its hydroxyl proton. More acidic nature of the fluorinated alcohols is well-known [28].
An application of optimal conditions allowed to carry out chemoselective N- and O-
methylation of pyrazoles 1b-d, containing longer polyfluoroalkyl substituents, with products
2b-d and 3b-d formation (Scheme 1, Table 1, and Entries 21-26). Similarly to pyrazole 1a, its
nonafluorobutyl-containing analog 1d treated DMF-DMA gave 4-dimethylaminomethylidene-
substituted product 4d (Entry 27).
The identification of isomeric structure of compounds 2a-d and 3a-d was made based
on IR and 1H, 13C NMR spectroscopy data. The IR spectra of pyrazolones 2a-d in contrast to
pyrazoles 3a-d contain the absorption bands of carbonyl groups at 1660-1680 cm-1. The 1H and
13C NMR spectra (CDCl3) of compounds 3a-d exhibit more low-field signals of OMe group
(δH 3.97-3.98, δC 59.24 ppm) in comparison with the analogous signals of NMe fragment in
pyrazolones 2a-d (δH 3.22, δC 36.7-37.6 ppm). The exact structure of compound 2a as 1-methyl-
2-phenyl-5-(trifluoromethyl)-1,2-dihydro-3H-pyrazol-3-one was confirmed by X-Ray analysis
(Fig. 3, CCDC 1553334). The crystal packing are characterized by the short contacts between
two molecules with distances F3…H—C4’ 2.59(4) Å, O1…H—C12’ 2.509 Å, O1…H—C8’
2.448 Å. Unfortunately, we could not obtain crystals for O-isomers 3a-d which were obtained
as oils.
The reasons of the observed regioselectivity of methylation of pyrazoles 1 deserve a
particular consideration. Firstly, the structure of initial pyrazoles 1, which can exist as three
tautomers I : II : III (Scheme 2), should be determined. Earlier H. Gallardo and co-authors [29]
have concluded that crystals of compound 1a exist in form of NH-pyrazolone II. However, this
conclusion causes a number of justified objections. Firstly, our IR spectrum of 1a in solid state
did not have an absorption band of carbonyl group in characteristic field. Secondly, the
geometrical parameters of pyrazole cycle in reference [29] indicate a significant shortening of
the N2—C3 and C4—C5 bond lengths. It does not agree with the valence scheme of NH-
pyrazolone II. These arguments prompted us to reinvestigate the crystal structure of compound
1a. We carried out the X-Ray analysis of compound 1a and it has a structure of 5-
hydroxypyrazole I (Fig. 4, CCDC 1553335) which is stabilized by intermolecular hydrogen
bonds between OH and N= groups of two molecules with distance 1.68(3) Å (Fig. 5). The
6

calculations for equilibrium tautomeric structures I–III of pyrazole 1 were carried out using
TPSSTPSS/6 311G+(d,p) approximation. These results clearly demonstrate that the best
correspondence between the experimental and calculated geometric parameters of 1a is
observed for the tautomeric form I (see Supplementary material section).
It should be noted that non-fluorinated analog of pyrazole 1a exists in crystals in two
tautomeric forms of 5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (NH-form) and 3-
methyl-1-phenyl-1H-pyrazol-5-ol (OH-form) linked through intermolecular O—H…O and
N—H…N hydrogen bonds [30,31].
The1H, 19F NMR spectra of pyrazole 1a in CD3CN and (CD3)2SO had one set of signals
and its IR spectrum in MeCN did not contain an absorption band of carbonyl group. Hence,
heterocycle 1a exists as tautomer I in these solutions. We note that the preference was also
1
13
15
given to tautomer I in investigation of the pyrazole 1a structure with the H, C, N NMR
spectroscopy in (CD3)2SO [32]. However, the 1H, 19F NMR spectra in CD3Cl contain the set of
signals of all tautomers I : II : III in ratio 43 : 21: 36 (see Experimental section). These
differences in tautomeric composition of compound 1a seems to be due to different properties
of used solvents [33]. In contrast to trifluoromethylpyrazole 1a, the methyl-containing analog
exists in aprotic polar solvent (CD3CN and (CD3)2SO) as a mixture of all three tautomers while
in non-polar and low-polar solvents as OH-tautomer [31].
Figure 4. The ORTEP view of
molecule 1a
Figure 5. Dimer packing of molecule 1a
We have calculated the Gibbs free energies in gas phase and three solvents (MeCN,
Me2SO and CHCl3) for the estimation of tautomers I–III content using TPSSTPSS/6-311G(d,p)
+ IEFPCM approximation (see Scheme 2).
According to quantum chemical calculations, a structure III is more stable form in gas
phase. However, this is in contrast with the experimental data where the tautomer I is preferred.
7

The stability of tautomer I in crystals seems to be connected with ability to dimerize with
enthalpy 32.4 kJ/mol (Scheme 2). X-Ray data also point out at binding of pyrazole 1a molecules
in chains owing to the intermolecular hydrogen bonds formation (Fig. 6).
Choosing a solvate model for calculations, we considered that MeCN and Me2SO are
hydrogen bond acceptor (HBA) solvents capable to form strong hydrogen bonding, while
CHCl3 contains an acidic H proton capable to shift the equilibrium in favour of free or less
associated species ([33], see p. 22). To account for the specific interaction of 1a with the
solvent, we used a monosolvate complex with HBA solvents and 1a:CHCl3 complexes in 1:1
and 1:2 ratios. The details of these calculations are presented in Supplementary material section.
Scheme 2. The plausible tautomeric structures of pyrazole 1a (inset: double fukui descriptors
of reaction centers of the molecule were shown).
The tautomer III was found to be a more thermodynamically stable form of 1a without
solvent. However, an inversion of tautomers I and III stability was observed in HBA solvents
(Scheme 2). There are two factors favoring the extra-stabilization of tautomer I. Firstly, the
presence of hydroxyl group, which is capable for effective interaction with HBA solvent
(MeCN…HO- и Me2S=O…HO-), while hydrogen bonds -NHSolv (tautomer II) and -
CHSolv (tautomer III) stabilize the corresponding tautomer to a less extent. Secondly, a
greater polarity of tautomer I which can be quantitatively characterized by the value of molecule
8

dipole moment. In polar MeCN ( = 35.7) and Me2SO ( = 46.8) solvents non-specific
electrostatic stabilization of tautomer I ( = 4.98 D) is significantly more effective compared
with the low-polar tautomer III ( = 0.71 D). The combined effect of these factors causes the
predominant existence of 1a in HBA solvents in the tautomeric form of the pyrazolol I.
In contrast, CHCl3 ( = 4.71) is less polar and favors the shift of tautomeric equilibrium
toward the non-polar tautomer III. The specific coordination of CHCl3 can occur on several
centers of 1a including electronegative atoms F, N, O and –system of phenyl. This fact
complicates the choice of solvate model and, therefore, the simplest mono- and bi-solvate
complexes were considered with the coordination of solvent at oxygen atom and N-C-CF3
binding field. The tautomer III was found to be thermodynamically more stable in solvate
model with 1:1 composition. An addition of second molecule of CHCl3 led to convergence of
the Gibbs free energies of tautomers (Scheme 2). Obviously, the refinement of solvation model
by increasing of the number of CHCl3 molecules in the solvate complex will result in
equalization of tautomers energies as follows from the analysis of 1H and 19F NMR spectra (see
above).
For our investigation the most valuable result of the theoretical modeling of tautomeric
equilibrium is that pyrazolol I is more stable tautomer in polar solvents. The experiments
showed that the most selective syntheses of products 2a-d, 3a-d and 4a,d from pyrazoles 1a-d
were realized in polar aprotic solvents (MeCN and Me2SO4). It can be assumed that the form
1,I reacts. The negative values of double descriptor of Fukui indexes (f) of all three N-, O-
and C-centers of tautomer I of pyrazole 1a point out to their nucleophilic character (Scheme 2).
It allows us to consider them as competitive centers for electrophilic attack.
Earlier, we have proposed a mechanism of selective methylation of polyfluoroalkyl-
substituted 1H-pyrazoles [34], containing two endo-cyclic reaction N-centers of pyridine- and
pyrrole-like types. It was shown that under basic conditions the reaction occurred via
intermediate anionic salts formation, but without base – through cationic intermediates, which
were generated during, upon addition of the methyl group to pyridine-like type nitrogen.
Analogously, the attack of methylating reagent without base is carried out on the
pyridine-like nitrogen atom of pyrazole 1,I to form an intermediate salt N. This intermediate
was treated with an aqueous solution of NaHCO3 and resulted in isolation of the N-methyl
substituted product 2 (Scheme 3). According to the data of theoretical investigations for CF3
derivatives, the salts C and O, which could be formed during the attack of the methylating agent
on the nucleophilic C and O centers, are thermodynamically less stable than the cation N both
9

in the gas phase and in polar solvents (MeCN and DMSO). This fact confirms the selective
product 2a formation in the absence of a base (Entry 13, Table 1).
Scheme 3. The proposed mechanism of pyrazololes 1a-d methylation
Under basic conditions, other transformations take place, during which a metal cation
blocks the nucleophilic centers of pyrazole with the possible formation of two cationic salts K1
and K2 (Scheme 3). According to the calculations for compound 1a in the experimental
conditions, the formation of salt K2 with participation of pyridine-like nitrogen is a
thermodynamically more preferable process in comparison with the salt K1 formation (an
addition of K+ to a lone pair of oxygen atom). The difference in the Gibbs free energies is 5.6
kJ/mol (Scheme 3). The subsequent attack of the methylating agent occurs on either the free
nitrogen atom of the salt K1 with intermediate K3 formation or the free oxygen atom of salt
K2 with the intermediate K4 formation. A stabilization of the intermediates K3 and K4 via KX
elimination completes the competitive formation of the products 2a and 3a correspondingly,
which we observed experimentally in methylation under basic conditions. The prevalence of
the product 3a under these conditions is due to the energy preference of the formation of the
intermediate K2 on the first stage of the reaction.
10

Special attention deserves the aminomethylidation reaction. It is known that DMF-DMA
dissociates in solution to form an iminium cation and methoxide which can act as a base [35].
Under its action, the proton of the hydroxyl group of pyrazolol 1a,d is cleaved to form the
intermediate C1. Meanwhile, the iminium cation isomerizes to the carbenium cation, which
attacks the anion C1 to give the intermediate C2. The latter is stabilized by the elimination of
methanol to yield products 4a,d (Scheme 4).
Scheme 4. The possible interaction mechanism of pyrazolol 1a,d with DMF-DMA
The obtained pyrazoles, especially polyfluorinated antipyrines, are very promising
objects for the biological testing. The initial investigations on the analgesic activity of
trifluoromethyl-containing antipyrine 2a proved to be high perspective. The action of the
pyrazole 2a was evaluated in vivo in “hot plate” test in rats at the dose of 15 mg/kg compared
to known active analgesic metamizole. The compound 2а revealed the higher analgesic activity
(latent period prolongation 128%) than metamizole (59.8 - 93.8%) at the same dose. These data
demonstrate the prospects of the further extended research of biological properties of
synthesized compounds. Details on biological activity will be submitted somewhere else.
3. Conclusion
Thus, we have found that the presence of polyfluoroalkyl substituent in pyrazolones
influences on their structure and reactivity in methylation process. In contrast to 3-methyl-1-
phenylpyrazol-5-one, their fluorinated analogs exist as 3-polyfluoroalkyl-1-phenylpyrazol-5-
ols in the solid state and the aprotic polar solvents. It was shown that the different conditions
are required for the chemoselective O-methylation of non-fluorinated and polyfluoroalkylated
pyrazoles. As a result of this investigation the highly chemoselective methods of N-, O- and C-
methylation of 3-polyfluoroalkyl-1-phenylpyrazol-5-ols were suggested, which allowed us to
obtain the O- and N-isomers as well as C-aminomethylated derivatives with good yields. The
synthesis of N-methylated derivatives - fluorinated analogs of the known anti-inflammatory
11

drug antipyrine - was successfully realized. The initial biological testing revealed a significant
analgesic activity of trifluromethyl-containing antipyrine.
4. Experimental section
Melting points were measured in open capillaries on “Stuart SMP30” melting point apparatus
and uncorrected. The IR spectra were recorded on “Perkin Elmer Spectrum One FT-IR” by diffuse
reflection accessory (DRA) and “Thermo Nicolet 6700 FT-IR” spectrometers at 4000-400 cm-1 using the
1
“Frustrated total internal reflection” method (FTIR). The H (13C) NMR spectra were registered on
“Bruker Avance DRX-500” spectrometer, 500 MHz (125 MHz) relative to SiMe4. The 19F NMR spectra
were obtained on “Bruker Avance DRX-500” spectrometer (470 MHz) using C6F6 as an internal
standard. The chemical shifts were converted from C6F6 to CCl3F. The microanalyses (C, H, N) were
carried out on “Perkin Elmer PE 2400” series II elemental analyzer.
A single crystal of compound 4a was obtained by crystallization from the methanol. The X-ray
studies were performed on “Xcalibur 3 CCD” diffractometer with graphite monochromator, 
scanning, λCuK 1.54184 Å radiation, T 295 K. The registration of absorption was carried out analytically
by the model of multi-facet crystal using a program “CrysAlis RED 1.171.29.9”.
Main crystallographic data for 4a: C13H12F3N3O, M = 283.26, space group C2/c, monoclinic, a =
15.282(14), b = 12.955(12), c = 14.021(13) Å,  = 114.74(9)°, V = 2521(4) Å3, Z = 8, Dcalc = 1.492 g∙cm-3,
(Cu-K) = 1.109 mm-1, 188 refinement parameters, 2242 reflections measured, 1341 unique
reflections which were used in all calculations. The final R is 0.053. CCDC 1553333 contains the
supplementary crystallographic data for this compound.
A single crystal of compound 2a was obtained by crystallization from chloroform:hexane – 4:1.
The X-ray studies were performed on “Xcalibur Eos CCD” diffractometer with graphite
monochromator, \w scanning, λMoK 0.7107 Å radiation, T 295 K. The registration of absorption was
carried out analytically by the model of multi-facet crystal using a program “CrysAlisPro 1.171.36.32”.
Main crystallographic data for 2a: C11H9F3N2O, M = 242.20, space group P21/c, monoclinic, a =
11.184(3), b = 8.4936(19), c = 12.323(3) Å,  = 109.91(3)°, V = 1100.6(5) Å3, Z = 4, Dcalc = 1.462 g∙cm-3,
(Mo-K) = 0.130 mm-1, 187 refinement parameters, 2399 reflections measured, 1187 unique
reflections which were used in all calculations. The final R is 0.059. CCDC 1553334 contains the
supplementary crystallographic data for this compound.
A single crystal of compound 1a was obtained by crystallization from the acetonitrile. The X-
ray studies were performed on “Xcalibur 3 CCD” diffractometer with graphite monochromator, 
scanning, λCuK 1.54184 Å radiation, T 295 K. The registration of absorption was carried out analytically
by the model of multi-facet crystal using a program “CrysAlis RED 1.171.29.9”.
12

Main crystallographic data for 1a: C10H7F3N2O, M = 228.18, space group P21/c, monoclinic, a =
5.798(4), b = 15.150(10), c = 11.086(11) Å,  = 92.27(7) °, V = 973.1(13) Å3, Z = 4, Dcalc = 1.557 g∙cm-3,
(Cu-K) = 1.253 mm-1, 200 refinement parameters, 1703 reflections measured, 1265 unique
reflections which were used in all calculations. The final R is 0.047. CCDC 1553335 contains the
supplementary crystallographic data for this compound.
The all crystal structures were solved by direct methods followed by Fourier synthesis with
SHELXS-97 [36] and refined with full-matrix least-squares methods for all non-hydrogen atoms with
SHELXL-97 software packages [36].
Typical procedure for pyrazololes 1a-d synthesis [37].
A 3.9 g, 27 mmol of phenylhydrazine hydrochloride was added to 27 mmol of the
corresponding ethyl 4-polyfluoroalkyl-3-oxo ester and 3.9 g, 30 mmol of K2CO3. The mixture was
refluxed in 50 ml of ethanol for 3-4 h. The solvent was removed in vacuo. The precipitate was isolated
and washed with water and hexane.
1-Phenyl-3-trifluoromethyl-1H-pyrazol-5-ol (1a). 4.99 g, 81% yield, off-white powder, mp
1
193–194 ºС. (lit. [38], mp 191–192 ºС). Н NMR (DMSO-d6):  5.93 (s, 1Н, CH), 7.37-7.40, 7.49-7.53,
7.70-7.72 (all m, 5H, Ph), 12.44 (s, 1H, OH). 19F NMR (DMSO-d6):  -62.1 (CF3). 1Н NMR (CD3CN):  5.96
(s, 1Н, CH), 7.39-7.41, 7.48-7.52, 7.69-7.72 (all m, 5H, Ph), OH is not observed. 19F NMR (CD3CN):  -
62.2 (CF3). 1Н NMR (CDCl3): mixture of tautomers I : II : III – 43 : 21 : 36;  7.29-7.32, 7.37-7.49, 7.66-
7.70, 7.79-7.81 (all m, 5H, Ph), I, 5.91 (s, 1Н, CH), 6.65 (br.s, 1H, OH); II, 4.68 (s, 1Н, CH), 8.09 (s, 1H,
NH), III, 3.71 (s, 2Н, CH2). 19F NMR (CDCl3):  I, -64.5 (CF3); II, -64.6 (CF3); III, -68.8 (CF3).
3-Pentafluoroethyl-1-phenyl-1H-pyrazol-5-ol (1b). 5.25 g, 70% yield, off-white powder, mp
210–211 ºС. (lit. [39] in Supplementary, mp 209–210 ºС).
3-Heptafluoropropyl-1-phenyl-1H-pyrazol-5-ol (1c). 5.31 g, 60% yield, off-white powder, mp
155–156 ºС. (lit. [37], mp 150–152 ºС).
3-Nonafluorobutyl-1-phenyl-1H-pyrazol-5-ol (1d). 6.32 g, 62% yield, off-white powder, mp
160–161 ºС. (lit. [37], mp 157–159 ºС).
Typical procedure for methylation of pyrazoles 1a–d (regioselective conditions).
Method for 2a-d preparation. A 3.15 g, 25 mmol of dimethyl sulfate was added to 5 mmol of
pyrazoles 1a-d. The flask was immersed in the oil bath and heated at 120-130 ºС for 6-7 h. After cooling,
30 ml of ether was added and the resulting precipitate was isolated and washed by 10% sodium
hydroxide. The residue was purified by column chromatography (eluent – CHCl3).
13

1-Methyl-2-phenyl-5-trifluoromethyl-1,2-dihydro-3H-pyrazol-3-one (2a). 0.99 g, 82% yield,
colorless crystals, mp 138-139 ºС. (lit. [22], mp 139.2-140.2 ºС). IR (DRA): ν 1662 (C=O), 1590, 1582,
1500 (С=С), 1175-1129 (С–F) cm-1. 1Н NMR (CDCl3):  3.22 (unresolved q, 3Н, Me, J 0.3 Hz), 6.04 (s, 1H,
CH), 7.40-7.42, 7.50-7.53 (both m, 5H, Ph). 13C NMR (CDCl3):  36.69 (q, Me, J 1.5 Hz), 101.92 (q, CH, J
5.4 Hz), 119.07 (q, CF3, J 271.0 Hz), 125.25, 128.19, 129.54, 132.95 (Ph), 145.18 (q, C—CF3, J 39.2 Hz),
163.14 (C=O). 19F NMR (CDCl3):  -64.2 (CF3). Anal. calcd. for C11H9F3N2O. С, 54.55; Н, 3.75; N, 11.57.
Found: С, 54.62; Н, 3.65, N, 11.42.
1-Methyl-5-pentafluoroethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (2b). 1.15 g, 79% yield,
orange crystals, mp 82-83 ºС. IR (DRA): ν 1680 (C=O), 1640, 1590, 1577 (С=С), 1196-1155 (С–F) cm-1.
1Н NMR (CDCl3):  3.22 (s, 3Н, Me), 6.09 (s, 1H, CH), 7.39-7.42, 7.50-7.54 (both m, 5H, Ph). 13C NMR
(CDCl3):  37.40 (Me), 104.52 (CH), 109.81 (tq, CF2, J 254.7, 40.2 Hz), 118.16 (qt, CF3, J 286.4, 36.2 Hz),
125.36, 128.31, 129.56, 132.90 (Ph), 143.78 (t, C—C2F5, J 28.1 Hz), 162.91 (C=O). 19F NMR (CDCl3):  -
114.0 (m, 2F, CF2), -84.7 (t, 3F, CF3, J 2.6 Hz). Anal. calcd. for C12H9F5N2O. С, 49.32; Н, 3.10; N, 9.59.
Found: С, 49.16; Н, 2.90, N, 9.49.
5-Heptafluoropropyl-1-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (2c). 1.32 g, 77%
yield, light-yellow crystals, mp 71-73 ºС. IR (DRA): ν 1683 (C=O), 1645, 1595, 1579 (С=С), 1243-1150
(С–F) cm-1. 1Н NMR (CDCl3):  3.23 (s, 3Н, Me), 6.13 (s, 1H, CH), 7.39-7.42, 7.51-7.55 (both m, 5H, Ph).
19F NMR (CDCl3):  -127.2 (m, β-2F, CF2), -111.6 (q, 2F, α-CF2, J 9.7 Hz), -81.2 (t, 3F, CF3, J 9.7 Hz), Anal.
calcd. for C13H9F7N2O. С, 45.63; Н, 2.65; N, 8.19. Found: С, 45.72; Н, 2.63, N, 8.12.
1-Methyl-5-nonafluorobuthyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (2d). 1.57 g, 80% yield,
light-yellow crystals, mp 62-63 ºС. IR (DRA): ν 1681 (C=O), 1594, 1572 (С=С), 1229-1131 (С–F) cm-1. 1Н
NMR (CDCl3):  3.21 (s, 3Н, Me), 6.10 (s, 1H, CH), 7.39-7.42, 7.50-7.54 (both m, 5H, Ph). 19F NMR (CDCl3):
 -126.8 (m, 2F, -CF2), -123.8 (m, 2F, β-CF2), -110.9 (m, 2F, α-CF2), -82.0 (tt, 3F, CF3, J 9.7, 2.3 Hz). Anal.
calcd. for C14H9F9N2O. С, 42.87; Н, 2.31; N, 7.14. Found: С, 42.88; Н, 2.33, N, 7.12.
Method for 3a-d preparation. A mixture of 5 mmol of pyrazoles 1a-d, 0.63 g, 5 mmol of
dimethyl sulfate and 1.04 g, 7.5 mmol of K2CO3 in 10 ml of acetonitrile was refluxed for 6-7 h. After
cooling, 30 ml of water was added and the solution was extracted with 2x30ml ether. The ether was
removed and the residue was purified by column chromatography (eluent – CHCl3).
5-Methoxy-1-phenyl-3-trifluoromethyl-1H-pyrazole (3a). 0.88 g, 73% yield, yellow oil. IR
(FTIR): ν 1599, 1571, 1511, 1496 (С=С, C=N), 1250-1153 (С–F) cm-1. 1Н NMR (CDCl3):  3.97 (s, 3Н, Me
5.95 (s, 1H, CH), 7.32-7.36, 7.42-7.45, 7.67-7.69 (all m, 5H, Ph). 13C NMR (CDCl3):  59.24 (Me), 84.12
(q, CH, J 1.9 Hz), 121.01 (q, CF3, J 268.9 Hz), 122.80, 127.53, 128.96, 137.66 (Ph), 141.79 (q, C—CF3, J
14

38.5 Hz), 155.64 (C—OMe). 19F NMR (CDCl3):  -64.4 (CF3). Anal. calcd. for C10H9F3N2O. С, 54.55; Н, 3.75;
N, 11.57. Found: С, 54.74; Н, 3.59, N, 11.43.
5-Methoxy-3-pentafluoroethyl-1-phenyl-1H-pyrazole (3b). 1.10 g, 75% yield, yellow oil. IR
(FTIR): ν 1597, 1569, 1510, 1484 (С=С, C=N), 1214-1137 (С–F) cm-1. 1Н NMR (CDCl3):  3.97 (s, 3Н, Me),
5.95 (s, 1H, CH), 7.31-7.35, 7.42-7.46, 7.67-7.69 (all m, 5H, Ph). 13C NMR (CDCl3):  59.24 (Me), 85.23
(CH), 110.59 (tq, CF2, J 251.0, 39.1 Hz), 118.85 (qt, CF3, J 286.0, 38.0 Hz), 122.80, 127.54, 128.96, 137.70
(Ph), 140.39 (t, C—C2F5, J 28.7 Hz), 155.82 (C—OMe). 19F NMR (CDCl3):  -115.1 (q, 2F, CF2, J 2.5 Hz), -
85.4 (t, 3F, CF3, J 2.5 Hz). Anal. calcd. for C12H9F5N2O. С, 49.32; Н, 3.10; N, 9.59. Found: С, 49.10; Н, 2.98,
N, 9.52.
3-Heptafluoropropyl-5-methoxy-1-phenyl-1H-pyrazole (3c). 1.32g, 77% yield, yellow oil. IR
(FTIR): ν 1598, 1569, 1510, 1482 (С=С, C=N), 1234-1117 (С–F) cm-1. 1Н NMR (CDCl3):  3.98 (s, 3Н, Me),
5.95 (s, 1H, CH), 7.32-7.36, 7.42-7.46, 7.67-7.70 (all m, 5H, Ph). 19F NMR (CDCl3):  -128.0 (m, 2F, β-CF2),
-113.0 (m, 2F, α-CF2), -81.3 (t, 3F, CF3, J 9.5 Hz). Anal. calcd. for C13H9F7N2O. С, 45.63; Н, 2.65; N, 8.19.
Found: С, 45.70; Н, 2.84, N, 8.09.
5-Methoxy-3-nonafluorobuthyl-1-phenyl-1H-pyrazole (3d). 1.59 g, 81% yield, yellow oil. IR
(FTIR): ν 1597, 1569, 1510, 1481 (С=С, C=N), 1240-1137 (С–F) cm-1. 1Н NMR (CDCl3):  3.97 (s, 3Н, Me),
5.95 (s, 1H, CH), 7.34-7.42, 7.42-7.45, 7.67-7.70 (all m, 5H, Ph). 19F NMR (CDCl3):  -126.8 (m, 2F, -CF2),
-124.4 (m, 2F, β-CF2), -112.2 (m, 2F, α-CF2), -82.11 (tt, 3F, CF3, J 9.7, 2.8 Hz). Anal. calcd. for C14H9F9N2O.
С, 42.87; Н, 2.31; N, 7.14. Found: С, 42.74; Н, 2.25, N, 7.02.
Synthesis of compounds 4a,d. A mixture of 5 mmol of pyrazoles 1a,d and 1.19 g, 10 mmol of
DMF-DMA in 10 ml of acetonitrile was refluxed for 6-7 h. After cooling, 20 ml of water was added and
a precipitate was filtered off. Recrystallization from methanol or ethanol gave the pure heterocycles
4a,d.
(4Z)-4-[(Dimethylamino)methylidene]-2-phenyl-5-trifluoromethyl-2,4-dihydro-3H-pyrazol-
3-one (4a). 1.21 g, 86% yield, yellow powder, mp 119-120 ºС. IR (DRA): ν 1691 (C=O), 1619, 1595, 1544,
1500 (С=С), 1178-1124 (С–F) cm-1. 1Н NMR (CDCl3):  3.41, 3.86 (both , 6Н, 2Me), 7.41 (s, 1H, CH), 7.20-
7.22, 7.38-7.40, 7.90-7.92 (all m, 5H, Ph). 13C NMR (CDCl3):  43.86, 48.66 (2Me), 94.73 (=CH), 120.65
(q, CF3, J 270.5 Hz), 120.36, 125.37, 128.64, 138.65 (Ph), 140.37 (q, C—CF3, J 36.2 Hz), 153.19 (C=CH),
161.16 (C=O). 19F NMR (CDCl3):  -63.6 (CF3). Anal. calcd. for C13H12F3N3O. С, 55.12; Н, 4.27; N, 14.84.
Found: С, 55.05; Н, 4.15, N, 14.75.
(4Z)-4-[(Dimethylamino)methylidene]-2-phenyl-5-nonafluorobuthyl-2,4-dihydro-3H-
pyrazol-3-one (4d). 1.80 g, 83% yield, light-yellow powder, mp 82-83 ºС. IR (DRA): ν 1695 (C=O), 1621,
15

1597, 1545, 1500 (С=С), 1230-1120 (С–F) cm-1. 1Н NMR (CDCl3):  3.41, 3.86 (both , 6Н, 2Me), 7.41 (s,
1H, CH), 7.20-7.22, 7.38-7.40, 7.90-7.92 (all m, 5H, Ph). 19F NMR (CDCl3):  -126.8 (m, 2F, -CF2), -124.4
(m, 2F, β-CF2), -112.2 (m, 2F, α-CF2), -82.1 (tt, 3F, CF3, J 9.7, 2.8 Hz). Anal. calcd. for C16H12F9N3O. С,
44.35; Н, 2.79; N, 9.70. Found: С, 44.25; Н, 2.65, N, 9.77.
Computational details
Theoretical calculations were performed using the GAUSSIAN 09 program [40]. The TPSSTPSS
[41] density functional with the 6–311+G(d,p) basic sets [42,43] was used throughout the work for
geometry optimization, frequency calculation and electron population analysis [44,45]. The type of
stationary points of the potential energy surface (PES) was characterized by the Hessian matrix. If the
Hessian matrix was positive definite at the total energy, then the stationary point attained a local
minimum of the PES (reagent or product of reaction). Thermodynamic parameters were calculated by
simulating the solvent effect of acetonitrile, DMSO or chloroform (IEF polarized continuum model
[46]). Solvation model includes specific solute-solvent interactions in a form of 1 : 1 or 1 : 2 (CHCl3)
complex. The basis set superposition error (BSSE, in milliHartree) was shown to be rather small ( 1 for
CH3CN,  1.5 for CHCl3, and  2 for DMSO complexes) at the level of theory used. The Gibbs free
energies of complexes were BSSE corrected.
Definition of Fukui function [47] for an atom A (in our case – atoms C, O, N), can be shown as:
fA+=qAN-qAN+1 for nucleophilic attack,
fA- =qAN-1-qAN for electrophilic attack,
when qAN is the atomic charge.
Summarily, dual descriptors of Fukui function can be written as:
ΔfA=fA+-fA- =(qAN-qAN-1)-(qAN-1-qAN)=2qAN-qAN+1-qAN-1
Biological testing
The hot plate test was conducted according to established guidelines [48,49] on Hot plate
60200 series (TSE-systems, Germany). Rats were administered with substances suspension 15 mg/kg
in 1% starch mucilage intraperitoneally. Baseline controls were animals that received vehicle only.
Metamizole sodium (15 mg/kg) was used as a reference drug. Rats were placed on an electrically
heated plate at 50ºC in a plexiglass cylindric restrainer (19 cm diameter x 30 cm). The nociceptive
response time was measured by observing movements consisting of jumping, licking, or shaking their
hind paws. Maximal cutoff time was 30 s regardless of response. Data are expressed as a percentage
change in withdrawal response time from baseline.
16

Supplementary materials
Supplementary data associated with this article can be found, in the online version, at http://
Acknowledgements
This work was financially supported by the Russian Scientific Foundation (Grant No. 16-
13-10255).
The authors are grateful for G.A. Triandafilova and Dr. O.P Krasnykh for the biological
experiments (Perm National Research Polytechnic University, Russia). The authors thank Dr.
Yu.S. Kudyakova (Postovsky Institute of Organic Synthesis UB RAS, Russia) for assistance in
manuscript preparation. All calculations were carried out on a cluster computer in the region
center for share computer equipment at the Ufa Institute of Chemistry RAS, Russia.
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21

Table 1. Conditions of pyrazoles 1a-d methylation and ratio of 1 : 2 : 3a
Entry Compound RF
Reaction conditions
Ratio of 1 : 2 : 3, %
1
2
3
4
5
6
7
8
9
10
CF3 MeI (2 equiv), MeCN
100 : 0 : 0 (No
reaction)
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
CF3 MeI (1 equiv), K2CO3 (1 equiv),
MeCN
11 : 3 : 86
CF3 MeI (1.5 equiv),
0 : 22 : 78
1 : 27 : 72
0 : 3 : 97
0 : 0 : 100
0 : 7 : 93
0 : 9 : 91
4 : 12 : 84
1 : 47 : 52
K2CO3 (1.5 equiv), MeCN
CF3 MeI (1 equiv), K2CO3 (1 equiv),
MeOH
CF3 MeI (5 equiv), K2CO3 (1,5 equiv),
MeCN
CF3 Me2SO4 (1 equiv),
K2CO3 (1.5 equiv), MeCN
CF3 Me2SO4 (1 equiv),
K2CO3 (1 equiv), MeOH
CF3 Me2SO4 (1 equiv),
NaOH (1 equiv), MeOH
CF3 Me2SO4 (1 equiv),
Cs2CO3 (1 equiv), MeOH
CF3 Me2SO4 (5 equiv),
K2CO3 (1.5 equiv), MeCN
CF3 Me2SO4 (1 equiv), MeCN
CF3 Me2SO4 (2 equiv), MeCN
CF3 Me2SO4 (5 equiv), 120-130 ºC
CF3 Me2SO4 (2 equiv), toluene
CF3 Me2SO4 (2 equiv), MeOH
CF3 (MeO)2CO (2 equiv), MeCN
11
12
13
14
15
16
21 : 72 : 6
4 : 96 : 0
1a
1a
1a
1a
1a
1a
0 : 100 : 0
44 : 53 : 3
27 : 50 : 23
100 : 0 : 0 (No
reaction)
17
CF3 (MeO)2CO (1 equiv),
K2CO3 (1.5 equiv), MeCN
23 : 0 : 77
1a
22

18
19
CF3 (MeO)2CO (1 equiv),
NaOH (1.5 equiv), MeCN
20 : 0 : 80
1a
1a
CF3 DMF-DMA (1 equiv),
K2CO3 (1.5 equiv), MeCN
Complex mixture
20
21
CF3 DMF-DMA (2 equiv), MeCN
C2F5 Me2SO4 (1 equiv),
1a
1b
4a
0 : 0 : 100
K2CO3 (1.5 equiv), MeCN
22
23
C2F5 Me2SO4 (5 equiv), 120-130 ºC
C3F7 Me2SO4 (1 equiv),
0 : 100 : 0
0 : 0 : 100
1b
1c
K2CO3 (1.5 equiv), MeCN
24
25
C3F7 Me2SO4 (5 equiv), 120-130 ºC
C4F9 Me2SO4 (1 equiv),
0 : 100 : 0
0 : 0 : 100
1c
1d
K2CO3 (1.5 equiv), MeCN
26
27
C4F9 Me2SO4 (5 equiv), 120-130 ºC
C4F9 DMF-DMA (2 equiv), MeCN
0 : 100 : 0
1d
1d
4d
23