3-Polyfluoroalkyl-1,5-diphenylpyrazoles in Suzuki Cross-Coupling Reactions

Article abstract of DOI:10.1134/S1070428018080250

Suzuki cross-coupling was used for modification of 3-polyfluoroalkyl-1-phenylpyrazoles at the position C⁴. The synthesized 4-bromo- and 4-phenyl derivatives showed antitubercular effect on pyrazinamide level.

Full text of DOI:10.1134/S1070428018080250

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 8, pp. 1265–1267. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © А.E. Ivanova, Ya.V. Burgart, V.I. Saloutin, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 8, pp. 1250–1252.
SHORT
COMMUNICATIONS
3-Polyfluoroalkyl-1,5-diphenylpyrazoles
in Suzuki Cross-Coupling Reactions
А. E. Ivanovaa, Ya. V. Burgarta, and V. I. Saloutina*
a Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences,
ul. Akademicheskaya/S. Kovalevskoi 20/22, Yekaterinburg, 620990 Russia
*e-mail: saloutin@ios.uran.ru
Received November 1, 2017
Abstract—Suzuki cross-coupling was used for modification of 3-polyfluoroalkyl-1-phenylpyrazoles at the
position C4. The synthesized 4-bromo- and 4-phenyl derivatives showed antitubercular effect on pyrazinamide level.
DOI: 10.1134/S1070428018080250
4-(Het)aryl-3-polyfluoroalkyl-1,5-diphenylpyra-
zoles were obtained from 3-polyfluoroalkyl-1,5-diphe-
nylpyrazoles by Suzuki cross-coupling. Recently increased
attention to pyrazoles chemistry is due to unique
properties of their derivatives. The high significance of
pyrazole ring was demonstrated in surveys [1–4]. Pyrazole
structural motif is present in molecules demonstrating
a wide spectrum of agrochemical and pharma-ceutical
actions [1]. Besides that pyrazoles are on demand in
supramolecular and polymer chemistry, and also as
cosmetic dyes and UV stabilizers, a series of pyrazoles
also possesses liquid-crystalline properties [5, 6].
pirad [10] and herbicide fluozolate [11] are applied.
The range of pyrazoles biological activity is determined
by the nature of peripheral surroundings of heterocyclic
ring. In this connection development of methods of
pyrazole scaffold modification is an actual task.
For modification of N-unsubstituted polyfluoro-
alkylpyrazoles reactions of alkylation [12–14] and
ribosylation [15, 16] are effectively utilized; therewith
the modulation of tuberculostatic [13], antibacterial [14],
or antiviral [16] properties of new derivatives is possible.
The alkylation and arylation of polyfluoroalkylpyrazoles,
particularly those containing a halogen atom in the position
4, occurs at competing atoms N1 and N2, while the
center С4 is not involved in these reactions [12–22].
In this study for modification in the position С4 of
polyfluoroalkyl containing pyrazoles 1a and 1b we
applied arylation by Suzuki cross-coupling reaction. To
this end from pyrazoles 1a and 1b first by reaction with
N-bromosuccinimide 4-bromoderivatives 2a and 2b
were prepared and further were brought into reactions with
(het)arylboronic acids 3a–3c in a microwave reactor at
In designing new drugs and agrochemicals good
prospects are expected for fluoro-containing pyrazoles
[7, 8]. In this series one of bestselling drugs may be
mentioned, antiphlogistic medicine celebrex (celecoxib),
veterinary antiarthritis drug mavacoxib (trocoxil), and
also compounds in the stage of clinical tests SC-560
(anticancer activity), AS-136A (antiviral effect),
razaxaban (anticoagulant activity) [9]. For preserving
and increasing harvest in agriculture fungicide penthio-
Br
N
RF
Br
RF
R
RF
O
O
RB(OH)2
3a_3c
N
N
N
Pd(PPh3)4, K2CO3, THF_H2O, MW
Ph
Ph
Ph
DMF
N
N
N
Ph
Ph
Ph
1a, 1b
2a, 2b
4a_4d
1, 2, RF = CF3 (а), HCF2 (b); 3, R = Ph (а), 4-MeSC6H6 (b), Th (c); 4, R = Ph, RF = CF3 (а), HCF2 (b); RF = CF3,
R = 4-MeSC6H4 (c), Th (d).
1265

IVANOVA et al.
1266
135–155°С (250 W) that led to the formation of 4-(het)-
aryl-substituted pyrazoles 4а–4d in good yields.
1.5 mL of THF was added a solution of 0.173 g
(0.6 mmol) of K2CO3 in 2 mL of water. Argon was
bubbled through obtained mixture and it was irradiated
in a microwave reactor at 155°С (250 W) for 20 min,
solvent was evaporated. The reaction product was
purified by column chromatography, eluent hexane–
ethyl acetate, 1 : 2 (4а), CH2Cl2 (4b and 4d), CH2Cl2–
hexane, 2 : 1 (4с).
1,4,5-Triphenyl-substituted pyrazole 4а was
obtained previously by Stille reaction [23] utilizing
more expensive ArSnR3 as arylating agent.
In tests in vitro on laboratory samples of H37Rv
tuberculosis microbacteria tuberculostatic activity of 4-
bromo- and 4-phenyl-substituted trifluormethylpyrazo-
les 2a and 4a was explored. As comparative prepara-
tion pyrazinamide was chosen, minimal inhibiting con-
centration (MIC) of which in the same experimental
conditions was 12.5 µg/mL. Compounds 2а and 4а show
moderate tuberculostatic activity at MIC 12.5 µg/mL.
3-(Trifluoromethyl)-1,4,5-triphenyl-1Н-pyrazole
(4а). Yield 85%, white powder, mp 162–164°С (159–
161°С [23]).
3-(1,1,2,2-Tetrafluoroethyl)-1,4,5-triphenyl-1Н-
pyrazole (4b). Yield 93%, white powder, mp 171–
173°С. IR spectrum, ν, cm–1: 1103–1052 s (С–F). 1Н NMR
spectrum [(CD3)2SO], δ, ppm: 6.92 t.t [1H, Н(СF2)2,
Hence with Suzuki cross-coupling a modification
of 3-polyfluoroalkyl-1-phenylpyrazoles at the position
С4 was performed. The synthesized 4-bromo- and 4-
phenyl derivatives showed antitubercular effect on
pyrazinamide level.
3
2JН–F 52.1, JН–F 5.2 Hz], 7.12–7.14 m (2Н, Ph), 7.22–
7.33 m (10Н, Ph), 7.39–7.41 m (3Н, Ph). 19F NMR spec-
2
trum [(CD3)2SO], δ, ppm: 25.61 t.d (2F, НCF2, JF–Н
3
3
3
52.1, JF–F 9.4 Hz), 53.66 d.t (2F, CF2, JF–Н 9.3, JF–F
9.2, 2JF–F 5.6 Hz). Found, %: С 69.68; Н 4.12; N 7.19.
С23Н16N2F4. Calculated, %: С 69.69; Н 4.07; N 7.07.
Pyrazoles 1а and 1b were synthesized by the
method [24].
4-[(4-Methylsulfanyl)phenyl]-3-(trifluorome-
thyl)-1,5-diphenyl-1Н-pyrazole (4c). Yield 86%,
white powder, mp 181–183°С. IR spectrum, ν, cm–1:
1179–1135 s (С–F). 1Н NMR spectrum (CDCl3), δ, ppm:
2.50 s (3Н, Me), 7.21–7.42 m (12Н, 2Ph, С6Н4), 7.48–
7.50 m (2Н, С6Н4). 19F NMR spectrum (CDCl3), δ, ppm:
102.28 s (CF3). Found, %: C 67.30; H 4.17; N 6.82.
С23Н17F3N2S. Calculated, %: C 67.18; H 4.13; N 6.75.
Pyrazoles (2а and 2b). A solution of 2.0 mmol of
pyrazole 1а and 1b and 0.71 g (4.0 mmol) of N-
bromosuccinimide in 10 ml of DMF was heated at
80°С for 10 h in an argon flow, then 50 mL of water
was added and the mixture was extracted with CH2Cl2
(2 × 20 mL), the extract was dried with MgSO4. The
solvent was evaporated, reaction products 2а and 2b
were purified by column chromatography, eluent
hexane–ethyl acetate, 9 : 1.
4-(Thiophen-2-yl)-3-(trifluoromethyl)-1,5-diphe-
nyl-1Н-pyrazole (4d). Yield 89%, white powder, mp
135–137°С. IR spectrum, ν, cm–1: 1183–1132 s (С–F).
1Н NMR spectrum (CDCl3), δ, ppm: 7.00 d.d (1H, Н4', J
5.1, 3.6 Hz), 7.04 d (1H, Н5', J 3.3 Hz), 7.11 m (1H, Н3'),
7.22–7.43 m (10Н, 2Ph). 19F NMR spectrum (CDCl3), δ,
ppm: 99.51 s (CF3). Found, %: C 64.73; H 3.52; N 7.51.
С20Н13F3N2S. Calculated, %: C 64.86; H 3.54; N 7.56.
4-Bromo-3-(trifluoromethyl)-1,4-diphenyl-1Н-
pyrazole (2а). Yield 79%, white powder, mp 100–
102°С (102–104°С [23]).
4-Bromo-3-(tetrafluoroethyl)-1,4-diphenyl-1Н-
pyrazole (2b). Yield 78%, white powder, mp 103–
1
105°С. IR spectrum, ν, cm–1: 1108–1079 s (С–F). Н
Method of biological experiment.1 Investigation
of tuberculostatic activity consisted in determining the
concentration inhibiting growth of the culture of labora-
tory strain MBT Н37Rv, while growing in liquid medium
Sotona and on dense yolky medium Novaya [25].
Culture of laboratory strain in an amount of 10 mg was
placed in porcelain mortar, ground, and prepared as
NMR spectrum (CDCl3), δ, ppm: 6.35 t.t [1H, Н(СF2)2,
3
2JН–F 53.1, JН–F 4.8 Hz], 7.20–7.23 m (2Н, Ho, Ph),
7.25–7.28 m (2Н, Ho, Ph), 7.31–7.33 m (3Н, Hm,p, Ph),
7.38–7.40 m (3Н, Hm,p, Ph). 19F NMR spectrum (CDCl3),
2
3
δ, ppm: 25.10 t.d (2F, НCF2, JF–Н 53.1, JF–F 8.4 Hz),
3
3
2
47.55 d.t (2F, CF2, JF–Н 4.8, JF–F 8.3, JF–F 8.4 Hz).
Found, %: С 51.03; Н 2.73; N 7.17. С17Н11N2F4Br.
Calculated, %: С 51.15; Н 2.78; N 7.02.
1
The antitubercular activity was tested in Ural Institute of
Compounds 4а–4d. To a mixture of 0.5 mmol of
bromopyrazol 2а or 2b, 0.6 mmol of arylboronic acid
3а, 3c or 3b, and 0.29 g (5 mol %) of Pd(PPh3)4 in
Phthisiopulmonology of the Ministry of Health of Russia
(Yekaterinburg) by the Candidate of biological sciences
M.A. Kravchenko
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 8 2018

3-POLYFLUOROALKYL-1,5-DIPHENYLPYRAZOLES IN SUZUKI CROSS-COUPLING
1267
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suspension of culture by bacterial standard of turbidity
100 millions of microbe bodies in 1 mL (10 digits).
The obtained suspension (0.2 mL) was seeded into test
tubes with 5 mL of nutritive medium and the tested
compound of an appropriate concentration. Test tubes
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NMR spectra were registered on a spectrometer
Bruker Avance-500 [500 МHz, internal reference SiMe4
(1Н), 470 МHz, reference С6F6 (19F)]. IR spectra were
recorded on a spectrometer Perkin Elmer Spectrum One
with ATR method or by DRA. Melting points were
measured in open capillaries on an apparatus for melting
points measurement Stuart SMP30. Column chromato-
graphy was performed on silica gel 60 (0.063–0.02 mm).
Elemental analysis (С, Н, N) was carried out on analyzer
Perkin Elmer PE 2400 series II. Microwave syntheses
were performed in hermetic vials (35 mL) in UHF
apparatus CEM Discover & Explorer with resulting power
in the range 0–300 W. Temperature was monitored
with IR detector. The content of the vial was mixed by
a magnet with regulated rotation speed positioned
under UHF cavity, and a Teflon magnetic stick inside
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registered with software controlled by a computer.
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ACKNOWLEDGMENTS
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This study was performed under the financial
support of the Russian Science Foundation (project
no. 16-13-10255).
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