Synthesis of 1-[4-(1,3-diaryl-4,5-dihydro-1H-pyrazol-5-yl)-2,3,5,6-tetrafluorophenyl]piperidin-4-ols and their acrylates

Article abstract of DOI:10.1134/S1070428017030149

(4-Hydroxypiperidin-1-yl)tetra- and -octafluorochalcones reacted with phenylhydrazine in acetic acid to give mixtures of polyfluoro-1,3,5-triaryl-4,5-dihydro-1H-pyrazoles and their O-acetyl derivatives. Analogous reactions in ethanol afforded in satisfact

Full text of DOI:10.1134/S1070428017030149

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 3, pp. 398–406. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © E.A. Soboleva, N.A. Orlova, V.V. Shelkovnikov, 2017, published in Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 3,
pp. 400–407.
Synthesis of 1-[4-(1,3-Diaryl-4,5-dihydro-1H-pyrazol-5-yl)-
2,3,5,6-tetrafluorophenyl]piperidin-4-ols
and Their Acrylates
E. A. Sobolevaa, N. A. Orlovaa,* V. V. Shelkovnikova, b
a Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
*e-mail: ona@nioch.nsc.ru
b Novosibirsk State Technical University, pr. Karla Marksa 20, Novosibirsk, 630073 Russia
Received October 12, 2016
Abstract—(4-Hydroxypiperidin-1-yl)tetra- and -octafluorochalcones reacted with phenylhydrazine in acetic
acid to give mixtures of polyfluoro-1,3,5-triaryl-4,5-dihydro-1H-pyrazoles and their O-acetyl derivatives.
Analogous reactions in ethanol afforded in satisfactory yields 1-[4-(1,3-diaryl-4,5-dihydro-1H-pyrazol-5-yl)-
2,3,5,6-tetrafluorophenyl]piperidin-4-ols which were treated with acryloyl chloride to obtain the corresponding
acrylates that are promising as monomers for the preparation of fluorescent films.
DOI: 10.1134/S1070428017030149
1,3,5-Triaryldihydropyrazoles and their derivatives
are the most widely known heterocyclic organic
fluorophores [1] which attract persistent attention due
to their possible application as fluorescent probes [2],
organic light-emitting diodes [3], organic one-dimen-
sional nanomaterials [4], nonlinear optical materials
[5], and biologically active compounds [6–9]. Some
pyrazoline-based fluorescent monomers give rise to
thin transparent polymer films with strong fluores-
cence [10].
We have synthesized acryloyl-substituted 1,3,5-tris-
(polyfluoroaryl)-4,5-dihydro-1H-pyrazoles exhibiting
a combination of fluorophore and monomer properties,
which makes them promising starting materials for the
preparation of fluorescent polymer films.
of polyfluorinated chalcones makes it possible to
introduce various substituents, such as dialkylamino,
phenoxy, and azido groups, via reactions with nucleo-
philes [14]. Substituents containing hydroxy or amino
groups can be subjected to further functionalization
[15, 16]. Our choice of piperidin-4-ol as nucleophile
was based on the following considerations: the secon-
dary amino group of piperidine is capable of replacing
aromatic fluorine atoms under mild conditions [14];
free hydroxy group can be involved in further trans-
formations, e.g., esterification; alicyclic skeleton
acts as a linker connecting the heterocycle and func-
tional group.
Reactions of chalcones with phenylhydrazine are
usually carried out in acid medium, mostly in acetic
acid. Pereyaslova et al. [17] were the first to report on
reactions of polyfluorinated chalcones with phenyl-
hydrazine [17]. Later on, we revealed some peculiar
features of this reaction [13]. For example, 3-(penta-
One of the main methods for the synthesis of
1,3,5-triaryl-4,5-dihydro-1H-pyrazoles is based on the
reaction of chalcones with phenylhydrazine [11–13].
The presence of labile fluorine atoms in the molecules
O
F
O
F
F
O
F
F
F
F
F
Ph
Ph
F
N
F
N
N
F
F
N
F
F
F
F
OH
OH HO
OH
1a
1b
1c
398

SYNTHESIS OF 1-[4-(1,3-DIARYL-4,5-DIHYDRO-1H-PYRAZOL-5-YL)-...
399
Scheme 1.
Ph
Ph
N
N
N
F
F
N
F
F
PhNHNH2
AcOH, ∆, 6 h
Ar
Ar
F
F
+
1a, 1c
N
N
F
F
OH
OAc
2a, 4
3a, 3c
2a, 3a, Ar = Ph; 3c, 4, Ar = 4-(4-acetoxypiperidin-1-yl)-2,3,5,6-tetrafluorophenyl; 2a:3a = 69:31, 3c:4 = 48:52.
Scheme 2.
Ph
Ph
N
N
N
F
F
N
F
F
PhNHNH2
AcOH, ∆, 6 h
Ph
Ph
F
F
+ +
3a
+
1b
2a
N
N
F
F
OH
OAc
2b
3b
2a:3a:2b:3b = 14:9:48:29
fluorophenyl)-1-phenylprop-2-en-1-one and its para-
substituted derivatives reacted with phenylhydrazine to
give a mixture of isomeric dihydropyrazoles differing
by the substituents in positions 3 and 5.
with phenylhydrazine in acetic acid we obtained mix-
tures of (4-hydroxypiperidin-1-yl)-substituted triaryldi-
hydropyrazoles and O-acetyl derivatives (Scheme 1;
the product ratios were determined on the basis of the
19F NMR spectra). Chalcone 1a was converted to
hydroxy and O-acetyl derivatives 2a and 3a, and
chalcone 1c, to di- and monoacetyl derivatives 3c and
4. In the latter case, preferential acetylation of hydroxy
group in the substituent on C3 of the pyrazole ring
was observed.
We used as starting compunds (4-hydroxypiperidin-
1-yl)tetra- and -octafluorochalcones 1a–1c which were
prepared as described in [15] from the corresponding
fluorinated chalcones, 1-(pentafluorophenyl)-3-phenyl-
prop-2-en-1-one (1d), 3-(pentafluorophenyl)-1-phenyl-
prop-2-en-1-one (1e), and 1,3-bis(pentafluorophenyl)-
prop-2-en-1-one (1f). We have optimized the proce-
dure for the synthesis of chalcone 1b from 1e: the use
of DMF instead of ethanol made it possible to avoid
formation of ortho-substituted isomer and improve the
yield of 1b to 94% against 60% in [15].
Chalcone 1b reacted with phenylhydrazine under
analogous conditions to give a mixture of two pairs of
isomeric dihydropyrazoles 2a/3a and 2b/3b differing
by the substituents on C3 and C5 (cf. [13]; Scheme 2).
We failed to isolate pure compounds 2b and 3b.
Preparative thin-layer chromatography afforded two
fractions which were mixtures of regioisomers 2a and
2b and their acetyl derivatives 3a and 3b. The structure
of 3b (in a mixture with 3a) was determined by NMR
The presence of a hydroxy group in molecules 1a–
1c led us to expect that their reaction with phenyl-
hydrazine in acetic acid could be accompanied by
O-acetylation. In fact, by heating chalcones 1a and 1c
Scheme 3.
Ph
N
O
F
N
F
F
PhNHNH2
EtOH, ∆, 6 h
Ph
F
F
F
F
Ph
F
F
F
1d
5
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

SOBOLEVA et al.
400
Scheme 4.
Ph
F
F
F
N
N
F
F
PhNHNH2
EtOH, ∆, 6 h
1c
N
N
F
HO
OH
F
F
2c
Scheme 5.
Ph
N
N
F
F
F
Ph
F
N
O
CH2
O
H2C=CHC(O)Cl
K2CO3, CH2Cl2, ~20°C
6a
2a
Ph
N
N
F
Ph
F
F
N
F
OH
7
spectroscopy and was confirmed by gas chromatog-
raphy/mass spectrometry.
no acylation of 7 occurred under these conditions. In
keeping with published data, we presumed that the
instability of dihydropyrazoles is determined by the
presence of methylene chloride [17, 20]. When
methylene chloride was replaced by benzene, and
potassium carbonate, by triethylamine, target acrylates
6a–6c were obtained with moderate yields (Scheme 6).
Triarylpyrazolines are strong fluorophores emitting
in the blue and green regions of the spectrum. Fluo-
rescence properties of compound 2b depend on the
solvent polarity. The electronic absorption and fluores-
cence spectra of triaryldihydropyrazoles 2a–2c, 3a, 3c,
and 4 and pyrazole 7 were recorded in toluene and
ethanol (see table). The spectra of acrylates 6a–6c
were recorded only in toluene because of their poor
solubility in ethanol.
The long-wave fluorescence maximum of 1,3,5-tri-
aryldihydropyrazoles 2a, 3a, and 6a with the fluorinat-
ed aromatic substituent on C5 is located at λ ~450 nm
in ethanol and λ 425–427 nm in toluene. The fluor-
escence maxima of isomers 2b and 6b are observed at
longer wavelengths (Δ λ = 22‒27 nm) due to the
presence of fluorinated aromatic substituent in the
3-position conjugated with the N-phenyl ring [1, 21].
Dihydropyrazoles 2c, 3c, 4, and 6c with polyfluorinat-
To avoid acetylation, reactions of polyfluorinated
chalcones with phenylhydrazine were carried out in
ethanol which was used as solvent in some reactions of
chalcones with hydrazine hydrate [18, 19]. By reaction
of 1-(pentafluorophenyl)-3-phenylprop-2-en-1-one
(1d) with phenylhydrazine in boiling ethanol we
obtained dihydropyrazole 5 (Scheme 3).
Polyfluorochalcones 1a–1c reacted with phenyl-
hydrazine in ethanol in a similar way. Chalcone 1a was
thus converted to dihydropyrazole 2a in 50% yield.
The reaction of 1b with phenylhydrazine in ethanol
was most efficient. Instead of a mixture of four com-
pounds (2a, 2b, 3a, 3b) formed in acetic acid, the
reaction in ethanol gave 78% of 2b as the only prod-
uct. Under analogous conditions, octafluorochalcone
1c was converted with high yield to dihydropyrazole
2c which was not formed in acetic acid (Scheme 4).
Compounds 2a–2c were then used to synthesize the
corresponding acrylates. However, the reaction of 2a
with acryloyl chloride in methylene chloride in the
presence of potassium carbonate produced pyrazole 7
rather than expected acrylate 6a (Scheme 5), whereas
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

SYNTHESIS OF 1-[4-(1,3-DIARYL-4,5-DIHYDRO-1H-PYRAZOL-5-YL)-...
401
Scheme 6.
Ph
Ph
H2C=CHC(O)Cl
PhH, Et3N, ~60°C
N
N
N
N
Ar
Ar'
Ar
Ar'
2a–2c
6a–6c
F
F
F
F
F
F
F
2, Ar = Ph, Ar′ =
(a); Ar =
, Ar′ = Ph (b); Ar = Ar′ =
(c);
N
F
N
F
N
F
F
F
HO
HO
F
HO
F
F
F
6, Ar = Ph, Ar′ =
(a); Ar =
, Ar′ = Ph (b);
O
N
F
O
N
F
H2C
H2C
F
F
O
O
F
F
F
F
Ar = Ar′ =
(c).
O
N
H2C
O
ed aromatic substituents on both C3 and C5 are
characterized by intermediate position of the long-
wave maximum in the absorption and fluorescence
spectra. A small blue shift (Δλ = 6‒7 nm) of the
absorption maxima is observed in going from toluene
to ethanol, whereas the fluorescence maxima shift red
by 16‒23 nm, which is consistent with published data
on the solvent effect on the fluorescence properties of
fluorophores [21]. The Stokes shift in ethanol is larger
by 22‒30 nm than in toluene and is 100 nm. Pyrazole 7
showed fluorescence in the same region as dihydro-
pyrazoles, but the intensity of the long-wave maximum
was considerably lower.
Figure 1 shows fluorescence spectra of 2a–2c in
ethanol and toluene, and the fluorescence spectra of
acrylates 6a–6c are given in Fig. 2. It is seen that
compound 2 b fluoresces green in ethanol
(λmax 473 nm) and blue in toluene (λmax 454 nm). The
lowest fluorescence intensity is observed for dihydro-
pyrazoles with the fluorinated aromatic ring on C5,
Long-wave absorption and fluorescence maxima of compounds 2a–2c, 3a, 3c, 4, 6a–6c, and 7
Ethanol
Toluene
Compound no.
λmax, nm (logε)
λmax, nm (Ifl)a
λmax, nm (logε)
λmax, nm (Ifl.)a
2a
2b
2c
3a
3c
4
352 (4.32)
367 (4.42)
361 (4.43)
352 (4.21)
362 (4.44)
363 (4.47)
–
451 (650)
473 (648)
460 (605)
452 (594)
462 (553)
463 (675)
–
358 (4.32)
373 (4.42)
368 (4.43)
358 (4.29)
368 (4.45)
369 (4.36)
358 (4.30)
373 (4.41)
368 (4.38)
427 (621)
454 (654)
444 (461)
425 (528)
442 (533)
442 (657)
427 (521)
459 (663)
443 (684)
6a
6b
6c
–
–
–
–
7
276 (4.53)
450 (404)
283 (4.38)
459 (140)
a
λexcit ≈ 350 nm.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

SOBOLEVA et al.
402
Ifl (rel. units)
(a)
Ifl (rel. units)
(b)
700
700
600
500
400
300
200
100
0
454 nm, 2b
444 nm, 2c
451 nm, 2a
473 nm, 2b
427 nm, 2a
600
460 nm, 2c
500
400
300
200
100
0
350
400
450
500
550
λ, nm
350
400
450
500
550
λ, nm
Fig. 1. Fluorescence spectra of compounds 2a–2c in (a) ethanol and (b) toluene.
which is consistent with the data of [13]. Acrylates 6a–
6c are characterized by strong fluorescence with
an intensity comparable with the emission intensity of
the corresponding hydroxy and acetyl derivatives.
Therefore, it may be presumed that polymerization of
6a–6c would lead to formation of polymer films with
bright blue fluorescence.
EXPERIMENTAL
Chalcones 1a and 1c were synthesized according to
the procedure described in [15]. The spectral and
analytical data were obtained at the Joint Chemical
Service Center, Siberian Branch, Russian Academy of
Sciences. The H and 19F NMR spectra were recorded
1
on a Bruker AV-300 spectrometer at 300.13 and
282.37 MHz, respectively, using CDCl3 as solvent and
reference for 1H (CHCl3, δ 7.24 ppm); the 19F chemical
shifts were measured relative to hexafluorobenzene.
Gas chromatographic–mass spectrometric analysis was
performed on an Agilent Technologies instrument
consisting of an Agilent 6890N gas chromatograph and
an Agilent 5973N mass-selective detector [electron
impact, 70 eV; HP-5MS capillary column, 30 m×
0.25 mm, film thickness 0.25 μm; carrier gas helium,
flow rate 1 mL/min; oven temperature programming
from 50°C (2 min) to 280°C at a rate of 10 deg/min;
30 min at 280°C; injector temperature 280°C, ion
source temperature 230°C; scan rate 1.2 scan/s; a.m.u.
range 30–800]. The melting points were determined on
a Kofler hot stage (Carl Zeiss Jena).
Thus, the use of ethanol instead of acetic acid as
solvent in the reactions of (4-hydroxypiperidin-1-yl)-
substituted polyfluorochalcones 1a–1c with phenylhy-
drazine makes it possible to avoid side formation of
O-acetyl derivatives, as well as the formation of
regioisomer mixture in the reaction with chalcone 1b,
and to improve the yield of dihydropyrazoles 2a–2c
with a free hydroxy group which can be subjected to
further functionalization.
Ifl (rel. units)
700
600
500
400
300
200
100
0
443 nm, 6c
459 nm, 6b
427 nm, 6a
1-[4-(4-Hydroxypiperidin-1-yl)-2,3,5,6-tetra-
fluorophenyl]-3-phenylprop-2-en-1-one (1b). Piperi-
din-4-ol, 1.36 g (13.4 mmol), was added to a solution
of 2.0 g (6.7 mmol) of chalcone 1e in 20 mL of DMF,
and the mixture was stirred for 5 h at room tempera-
ture. The mixture was then poured onto ice and left
overnight at room temperature, and the precipitate was
filtered off, washed with water and hexane, and dried
in air. Yield 2.40 g (94%). Compound 1b was identical
to that described in [15] in the melting point and
1H and 19F NMR spectra.
350
400
450
500
550
λ, nm
Fig. 2. Fluorescence spectra of compounds 6a–6c in toluene.
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SYNTHESIS OF 1-[4-(1,3-DIARYL-4,5-DIHYDRO-1H-PYRAZOL-5-YL)-...
403
1,3-Diphenyl-5-(pentafluorophenyl)-4,5-dihydro-
1H-pyrazole (5). Chalcone 1d, 0.1 g (0.34 mmol), was
added to a solution of 0.17 mL (1.7 mmol) of phenyl-
hydrazine in 4 mL of ethanol, and the mixture was
refluxed for 6 h with stirring and left overnight at room
temperature. The precipitate was filtered off, washed
with water, and dried in air. Yield 0.05 g (38%).
Compound 5 was identical to that described in [13] in
the melting point and 1H and 19F NMR spectra.
in 2 mL of ethanol, and the mixture was refluxed for
6 h with stirring and left overnight at room tempera-
ture. The precipitate was filtered off, washed with
water, and dried in air. The filtrate was extracted with
ethyl acetate, the extract was washed with water and
dried over CaCl2, and the solvent was removed under
reduced pressure. The products were analyzed by
1H and 19F NMR, combined (overall weight 0.16 g),
and subjected to preparative thin-layer chromatog-
raphy on Al2O3 plates using hexane–ethyl acetate (4:1)
as eluent to isolate 0.06 g (50%) of compound 2a
which was identical to a sample obtained as described
Reaction of chalcone 1a with phenylhydrazine.
a. Chalcone 1a, 3.26 g (8.6 mmol), was added to
a solution of 4.26 mL (43.0 mmol) of phenylhydrazine
in 10 mL of glacial acetic acid, and the mixture was
refluxed for 6 h with stirring and left overnight at room
temperature. The precipitate was filtered off, washed
with water, and dried in air. The product (5.55 g) was
analyzed by 1H and 19F NMR and subjected to column
chromatography on aluminum oxide to isolate two
fractions. The first fraction (hexane–methylene
chloride, 4:1) contained compound 3a, and the second
(methylene chloride), compound 2a.
1
above in a in the melting point and H and 19F NMR
spectra.
Reaction of chalcone 1b with phenylhydrazine.
a. Chalcone 1b, 1.0 g (2.6 mmol), was added to
a solution of 1.31 mL (13.2 mmol) of phenylhydrazine
in 5 mL of glacial acetic acid, and the mixture was
refluxed for 6 h with stirring and left overnight at room
temperature. A viscous material separated and was
extracted with ethyl acetate, the extract was washed
with water and dried over CaCl2, and the solvent was
removed under reduced pressure. The residue (1.53 g)
was analyzed by 1H and 19F NMR and was subjected to
preparative thin-layer chromatography on Al2O3 plates
using hexane–ethyl acetate (25:3) as eluent. The first
fraction was a mixture of compounds 3a and 3b at
a ratio of 23:77, and the second was a mixture of 2a
and 2b (23:77).
1-[4-(1,3-Diphenyl-4,5-dihydro-1H-pyrazol-5-yl)-
2,3,5,6-tetrafluorophenyl]piperidin-4-ol (2a). Yield
1.59 g (39%), colorless crystals, mp 142‒145°C (from
1
75% aq. EtOH). H NMR spectrum, δ, ppm: 1.57‒
1.71 m (3H, CH2, OH), 1.89‒2.00 m (2H, CH2), 3.00‒
3.16 m (2H, CH2), 3.22‒3.42 m (3H, CH2, 4-H), 3.71‒
3.90 m (2H, CHOH, 4-H), 5.66 d.d (1H, 5-H, J = 13.2,
6.5 Hz), 6.76‒6.83 m (1H, Harom), 7.03‒7.12 m (2H,
H
H
arom), 7.15‒7.23 m (2H, Harom), 7.29‒7.42 m (3H,
1-[4-(1,5-Diphenyl-4,5-dihydro-1H-pyrazol-3-yl)-
2,3,5,6-tetrafluorophenyl]piperidin-4-yl acetate
(3b). Yield 29% (according to the NMR data).
1H NMR spectrum, δ, ppm: 1.73‒1.85 m (2H, CH2),
1.94‒2.01 m (2H, CH2), 2.07 s (3H, COCH3), 3.15‒
3.25 m (2H, CH2), 3.36‒3.48 m (3H, CH2, 4-H),
3.88 d.d (1H, 4-H, J = 17.6, 12.6 Hz), 4.94 m [1H,
CHOC(O)], 5.24 d.d (1H, 5-H, J = 12.6, 7.3 Hz), 6.76–
6.84 m (1H, Harom), 7.00‒7.06 m (2H, Harom), 7.11–
7.17 m (2H, Harom), 7.24‒7.32 m (5H, Harom). 19F NMR
spectrum, δF, ppm: 9.96 m (2F), 20.36 m (2F).
arom), 7.66‒7.78 m (2H, Harom). 19F NMR spectrum,
δF, ppm: 11.14 m (2F), 16.80 br.s (2F). Found: m/z
469.1772 [M]+. C26H23F4N3O. Calculated: M 469.1774.
1-[4-(1,3-Diphenyl-4,5-dihydro-1H-pyrazol-5-
yl)-2,3,5,6-tetrafluorophenyl]piperidin-4-yl acetate
(3a). Yield 0.82 g (19%), colorless crystals, mp 185‒
1
188°C (from EtOAc–hexane, 2:3). H NMR spectrum,
δ, ppm: 1.68‒1.81 m (2H, CH2), 1.90‒1.99 m (2H,
CH2), 2.05 s (3H, COCH3), 3.08‒3.19 m (2H, CH2),
3.23‒3.39 m (3H, CH2, 4-H), 3.81 d.d (1H, 4-H, J =
17.3, 13.2 Hz), 4.89 m [1H, CHOC(O)], 5.66 d.d (1H,
5-H, J = 13.2, 6.5 Hz), 6.76‒6.83 m (1H, Harom), 7.04‒
7.11 m (2H, Harom), 7.16‒7.23 m (2H, Harom), 7.31‒
7.42 m (3H, Harom), 7.68‒7.76 m (2H, Harom). 19F NMR
spectrum, δF, ppm: 11.17 m (2F), 16.94 br.s (2F).
Found, %: C 65.75; H 4.93; F 14.86; N 8.21.
C28H25F4N3O2. Calculated, %: C 65.34; H 5.13;
F 14.86; N 8.18.
b. Chalcone 1b, 1.0 g (2.6 mmol), was added to
a solution of 1.3 mL (13.2 mmol) of phenylhydrazine
in 10 mL of ethanol, and the mixture was refluxed for
6 h with stirring and left overnight in a refrigerator.
The precipitate of 2b was filtered off, washed with
water, and dried in air (0.93 g). An additional amount
of compound 2b (0.04 g) was isolated from the filtrate
by extraction with ethyl acetate, followed by column
chromatography on Al2O3 (ethyl acetate–hexane, 1:3).
Yield 0.97 g (78%).
b. Chalcone 1a, 0.1 g (0.26 mmol), was added to
a solution of 0.13 mL (1.3 mmol) of phenylhydrazine
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

SOBOLEVA et al.
404
6.87 m (1H, Harom), 7.02‒7.10 m (2H, Harom), 7.16‒
1-[4-(1,5-Diphenyl-4,5-dihydro-1H-pyrazol-3-yl)-
7.24 m (2H, Harom). 19F NMR spectrum, δF, ppm:
10.03 m (2F), 11.21 m (2F), 16.84 br.s (2F), 20.39 m
(2F). Found, %: C 58.06; H 4.43; F 22.27; N 8.21.
C33H30F8N4O3. Calculated, %: C 58.13; H 4.49;
F 22.38; N 8.17.
2,3,5,6-tetrafluorophenyl]piperidin-4-ol (2b). Yield
0.97 g (78%), light yellow crystals, mp 142‒145°C
1
(from 75% aq. EtOH). H NMR spectrum, δ, ppm:
1.51 br.s (1H, OH), 1.61‒1.75 m (2H, CH2), 1.92‒
2.05 m (2H, CH2), 3.08‒3.27 m (3H, CH2, 4-H), 3.36–
3.51 m (2H, CH2), 3.79–3.96 m (2H, CHOH, 4-H),
5.24 d.d (1H, 5-H, J = 12.7, 7.2 Hz), 6.74‒6.83 m (1H,
Harom), 6.99‒7.06 m (2H, Harom), 7.11‒7.20 m (2H,
Harom), 7.24‒7.38 m (5H, Harom). 19F NMR spectrum,
δF, ppm: 9.95 m (2F), 20.25 m (2F). Found, %:
C 66.52; H 4.94; F 16.19; N 8.95. C26H23F4N3O. Cal-
culated, %: C 66.44; H 4.94; F 16.24; N 8.94.
b. Chalcone 1c, 1.0 g (1.8 mmol), was added to
a solution of 0.9 mL (9.1 mmol) of phenylhydrazine in
10 mL of ethanol. The mixture was refluxed for 6 h
with stirring, cooled to room temperature, and poured
into water. The precipitate was filtered off, washed
with water, and dried in air.
1,1′-[(1-Phenyl-4,5-dihydro-1H-pyrazole-3,5-di-
yl)bis(2,3,5,6-tetrafluoro-1,4-phenylene)]dipiperi-
din-4-ol (2c). Yield 1.07 g (92%), light yellow powder,
Reaction of chalcone 1c with phenylhydrazine.
a. Chalcone 1c, 1.0 g (1.8 mmol), was added to
a solution of 0.90 mL (9.1 mmol) of phenylhydrazine
in 5 mL of glacial acetic acid, and the mixture was
refluxed for 6 h with stirring and left overnight at room
temperature. The precipitate was filtered off, washed
with water, and dried in air. The product (0.75 g) was
1
mp 170‒173°C (from 75% aq. EtOH). H NMR spec-
trum, δ, ppm: 1.56‒1.76 m (6H, OH, CH2), 1.90‒
2.05 m (4H, CH2), 3.01‒3.24 m (5H, CH2, 4-H), 3.30‒
3.51 m (4H, CH2), 3.78‒3.92 m (3H, CHOH, 4-H),
5.67 d.d (1H, 5-H, J = 13.3, 6.2 Hz), 6.79‒6.86 m (1H,
Harom), 7.03‒7.09 m (2H, Harom), 7.17‒7.24 m (2H,
Harom). 19F NMR spectrum, δF, ppm: 10.01 m (2F),
11.20 m (2F), 16.84 br.s (2F), 20.28 m (2F). Found, %:
C 58.13; H 4.41; F 23.73; N 8.75. C31H28F8N4O2.
Calculated, %: C 57.74; H 4.38; F 23.74; N 8.75.
1
analyzed by H and 19F NMR and subjected to pre-
parative thin-layer chromatography on Al2O3 (hexane–
ethyl acetate, 3:1). The first fraction contained com-
pound 3c, and the second, compound 4.
(1-Phenyl-4,5-dihydro-1H-pyrazole-3,5-diyl)bis-
[(2,3,5,6-tetrafluoro-1,4-phenylene)piperidine-1,4-
diyl] diacetate (3c). Yield 0.18 g (14%), light yellow
crystals, mp 155‒157°C (from EtOAc–hexane, 2:3).
1H NMR spectrum, δ, ppm: 1.68‒1.86 m (4H, CH2),
1.90–2.03 m (4H, CH2), 2.05 s (3H, CH3), 2.07 s (3H,
COCH3), 3.08‒3.27 m (4H, CH2), 3.29‒3.48 m (5H,
CH2, 4-H), 3.86 d.d (1H, 4-H, J = 17.7, 13.3 Hz),
4.84–5.00 m [2H, CHOC(O)], 5.67 d.d (1H, 5-H, J =
13.3, 6.2 Hz), 6.76‒6.89 m (1H, Harom), 7.02‒7.11 m
(2H, Harom), 7.15‒7.23 m (2H, Harom). 19F NMR spec-
trum, δF, ppm: 10.03 m (2F), 11.24 m (2F), 16.97 br.s
(2F), 20.39 m (2F). Found, %: C 58.01; H 4.45;
F 20.97; N 7.73. C35H32F8N4O4. Calculated, %:
C 57.90; H 4.53; F 21.34; N 7.90.
1-[4-(1,3-Diphenyl-4,5-dihydro-1H-pyrazol-5-yl)-
2,3,5,6-tetrafluorophenyl]piperidin-4-yl acrylate
(6a). A solution of 0.16 mL (1.92 mmol) of acryloyl
chloride in 5 mL of benzene was added dropwise at
room temperature to a solution of 0.3 g (0.64 mmol) of
compound 2a and 0.18 mL (1.28 mmol) of triethyl-
amine in 10 mL of benzene. The mixture was stirred
for 5 h at 55°C and left overnight in a refrigerator. The
mixture was then diluted with 20 mL of benzene,
washed with ~5% aqueous HCl, and the acidic
aqueous phase was extracted with ethyl acetate. The
organic fractions were combined, washed with water,
and dried over CaCl2, and the solvent was removed
under reduced pressure with slight heating. The residue
(0.25 g) was subjected to column chromatography on
Al2O3 using ethyl acetate–hexane (1:4) as eluent, the
eluate was evaporated, and the residue was washed
with hexane. Yield 0.11 g (33%), colorless powder,
1-(2,3,5,6-Tetrafluoro-4-{5-[4-(4-hydroxypiperi-
din-1-yl)-2,3,5,6-tetrafluorophenyl]-1-phenyl-4,5-
dihydro-1H-pyrazol-3-yl}phenyl)piperidin-4-yl
acetate (4). Yield 0.48 g (39%), light yellow crystals,
1
mp 154‒156°C (from benzene–hexane, 1:1). H NMR
1
mp 200‒203°C (from EtOAc–hexane, 2:3). H NMR
spectrum, δ, ppm: 1.74‒1.89 m (2H, CH2), 1.95‒
2.05 m (2H, CH2), 3.11‒3.22 m (2H, CH2), 3.24‒
3.42 m (3H, CH2, 4-H), 3.81 d.d (1H, 4-H, J = 17.7,
13.1 Hz), 5.00 m [1H, CHOC(O)], 5.67 d.d (1H, 5-H,
J = 13.1, 6.6 Hz), 5.82 d.d (1H, CH2=CH, J = 10.4,
1.5 Hz), 6.12 d.d (1H, CH2=CH, J = 17.4, 10.4 Hz),
6.41 d.d (1H, CH2=CH, J = 17.4, 1.5 Hz), 6.80 m (1H,
spectrum, δ, ppm: 1.52 br.s (1H, OH), 1.56‒1.71 m
(2H, CH2), 1.74‒1.86 m (2H, CH2), 1.90‒2.04 m (4H,
CH2), 2.07 s (3H, COCH3), 3.02‒3.15 m (2H, CH2),
3.16‒3.27 m (2H, CH2), 3.29‒3.48 m (5H, CH2, 4-H),
3.76‒3.95 m [2H, CHOH, 4-H], 4.94 m [1H,
CHOC(O)], 5.67 d.d (1H, 5-H, J = 13.3, 6.3 Hz), 6.77‒
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

SYNTHESIS OF 1-[4-(1,3-DIARYL-4,5-DIHYDRO-1H-PYRAZOL-5-YL)-...
405
H
H
arom), 7.04‒7.12 m (2H, Harom), 7.17‒7.24 m (2H,
arom), 7.29‒7.43 m (5H, Harom), 7.68‒7.76 m (2H,
1-[4-(1,3-Diphenyl-1H-pyrazol-5-yl)-2,3,5,6-
tetrafluorophenyl]piperidin-4-ol (7). Compound 2a,
0.3 g (0.64 mmol), was dissolved in 6 mL of methyl-
ene chloride, 0.13 g (0.96 mmol) of potassium car-
bonate was added, the mixture was cooled to 2‒4°C,
and a solution of 0.08 mL (0.96 mmol) of acryloyl
chloride in 4 mL of methylene chloride was added. The
mixture was stirred for 2 h at 2‒4°C and for 3 h at
room temperature. When the reaction was complete,
the mixture was diluted with 20 mL of methylene
chloride, washed with distilled water, dried over
CaCl2, and left overnight in a refrigerator. The solvent
was removed under reduced pressure with slight
heating, and the residue (0.26 g) was purified by
column chromatography on Al2O3 (ethyl acetate–
hexane, 1:3). Yield 0.1 g (27%), colorless powder,
Harom). 19F NMR spectrum, δF, ppm: 11.20 m (2F),
16.96 br.s (2F). Found: m/z 523.1877 [M]+.
C29H25F4N3O2. Calculated: M 523.1869.
1-[4-(1,5-Diphenyl-4,5-dihydro-1H-pyrazol-3-yl)-
2,3,5,6-tetrafluorophenyl]piperidin-4-yl acrylate
(6b) was synthesized in a similar way. The product
(0.30 g) was purified by column chromatography on
Al2O3 (EtOAc–hexane, 1:3) and was additionally
precipitated from benzene with hexane. Yield 0.14 g
(42%), light yellow powder, mp 130‒133°C (from
1
benzene–hexane, 1:1). H NMR spectrum, δ, ppm:
1.78‒1.91 m (2H, CH2), 1.97‒2.09 m (2H, CH2), 3.14‒
3.30 m (3H, CH2, 4-H), 3.37–3.52 m (2H, CH2),
3.88 d.d (1H, 4-H, J = 12.5, 18.0 Hz), 5.03 m [1H,
CHOC(O)], 5.24 d.d (1H, 5-H, J = 12.5, 7.3 Hz),
5.84 d.d (1H, CH2=CH, J = 10.5, 1.4 Hz), 6.13 d.d
(1H, CH2=CH, J = 17.2, 10.5 Hz), 6.42 d.d (1H,
CH2=CH, J = 17.2, 1.4 Hz), 6.79 m (1H, Harom), 6.99‒
7.08 m (2H, Harom), 7.11‒7.19 m (2H, Harom), 7.25‒
7.37 m (5H, Harom). 19F NMR spectrum, δF, ppm:
10.01 m (2F), 20.40 m (2F). Found: m/z 523.1877
[M]+. C29H25F4N3O2. Calculated: M 523.1869.
1
mp 162‒164°C (from EtOAc–hexane, 2:3). H NMR
spectrum, δ, ppm: 1.52 br.s (1H, OH), 1.61‒1.75 m
(2H, CH2), 1.93‒2.04 m (2H, CH2), 3.08‒3.22 m (2H,
CH2), 3.38‒3.52 m (2H, CH2), 6.85 s (1H, 4-H), 7.28–
7.39 m (3H, Harom), 7.39‒7.46 m (2H, Harom), 7.85‒
7.92 m (2H, Harom). 19F NMR spectrum, δF, ppm:
10.99 m (2F), 20.92 m (2F). Found, %: C 66.80;
H 4.53; F 16.26; N 8.99. Found: m/z 467.1615 [M]+.
C26H21F4N3O. Calculated, %: C 66.38; H 4.61;
F 16.20; N 9.10. M 467.1619.
(1-Phenyl-4,5-dihydro-1H-pyrazole-3,5-diyl)bis-
[(2,3,5,6-tetrafluoro-4,1-phenylene)piperidine-1,4-
diyl] bisacrylate (6c). A solution of 0.15 mL
(1.9 mmol) of acryloyl chloride in 5 mL of benzene
was added dropwise at room temperature to a solution
of 0.3 g (0.47 mmol) of dihydropyrazole 2c and
0.26 mL (1.9 mmol) of triethylamine in 10 mL of ben-
zene. The procedure was the same as that described
above for compound 6a. The product isolated by
chromatography was dissolved in benzene, and the
solvent was slowly evaporated at room temperature
(from an open vessel). Yield 0.09 g (26%), yellow
powder, mp 87‒90°C (from benzene–hexane, 1:1).
1H NMR spectrum, δ, ppm: 1.75‒1.91 m (4H, CH2),
1.95‒2.09 m (4H, CH2), 3.11‒3.30 m (4H, CH2), 3.30‒
3.51 m (5H, CH2, 4-H), 3.87 d.d (1H, 4-H, J = 17.6,
13.6 Hz), 5.02 m (2H, 4-H), 5.67 d.d (1H, 5-H, J =
13.5, 6.0 Hz), 5.82 d.d (1H, CH2=CH, J = 10.4,
1.5 Hz), 5.84 d.d (1H, CH2=CH, J = 10.4, 1.5 Hz),
6.10 d.d (1H, CH2=CH, J = 17.3, 10.4 Hz), 6.15 d.d
(1H, CH2=CH, J = 17.3, 10.4 Hz), 6.40 d.d (1H,
CH2=CH, J = 17.3, 1.5 Hz), 6.43 d.d (1H, CH2=CH,
J = 17.3, 1.5 Hz), 6.82 m (1H, Harom), 7.02‒7.10 m
(2H, Harom), 7.15‒7.23 m (2H, Harom). 19F NMR spec-
trum, δF, ppm: 10.06 m (2F), 11.27 m (2F), 16.98 br.s
(2F), 20.42 m (2F). Found: m/z 748.2290 [M]+.
C37H32F8N4O4. Calculated: M 748.2304.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. OFI_M 14-29-08134).
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