Synthesis of 4-(1-Adamantyl)-3-polyfluoromethyl-1H-pyrazoles

Article abstract of DOI:10.1134/S1070428010080117

4-(1-Adamantyl)-3-polyfluoromethylpyrazoles were synthesized for the first time in high yields by condensation of fluorinated 2-(1-adamantyl)-1,3-diketones with hydrazine hydrate. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070428010080117

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 8, pp. 1178–1180. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © G.M. Butov, V.M. Mokhov, G.Yu. Parshin, S.A. Shevelev, I.L. Dalinger, I.A. Vatsadze, T.K. Shkineva, 2010, published in Zhurnal
Organicheskoi Khimii, 2010, Vol. 46, No. 8, pp. 1177–1179.
Synthesis of 4-(1-Adamantyl)-3-polyfluoromethyl-1H-pyrazoles
G. M. Butova, V. M. Mokhovb, G. Yu. Parshina, S. A. Shevelevc, I. L. Dalingerc,
I. A. Vatsadzec, and T. K. Shkinevac
a Volzhsk Polytechnic Institute (a Division of Volgograd State Technical University),
ul. Engel’sa 42a, g. Volzhskii, Volgogradskaya oblast, 404121 Russia
e-mail: butov@volpi.ru
b Volgograd State Technical University, Volgograd, Russia
c Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences,
Leninskii pr. 47, Moscow, 119991 Russia
Received July 10, 2009
Abstract—4-(1-Adamantyl)-3-polyfluoromethylpyrazoles were synthesized for the first time in high yields by
condensation of fluorinated 2-(1-adamantyl)-1,3-diketones with hydrazine hydrate.
DOI: 10.1134/S1070428010080117
Fluorinated 1,3-diketones and heterocyclic com-
pounds based thereon are known to exhibit a stronger
biological activity as compared to their nonfluorinated
analogs. Polyfluorinated pyrazole possess anti-inflam-
matory and analgesic activity; they are used for the
treatment of hyperglycemia and are heat-resistant heat-
transfer agents and surfactants [1]. Introduction of
an adamantane fragment into organic molecules
changes their properties and often enhances or modi-
fies their biological activity [2]. The chemistry of het-
aryl-substituted adamantanes was reviewed in [3, 4].
Some adamantyl-substituted pyrazoles were synthe-
sized from adamantyl-containing 1,3-diketones [4–7].
However, there are no published data on fluorinated
adamantyl-containing pyrazoles and methods for their
preparation.
electron-donor adamantyl group at the α-carbon atom
and an electron-withdrawing trifluoromethyl group at
one carbonyl carbon atom. Therefore, these com-
pounds may be regarded as novel synthons for various
heterocyclic compounds. It seemed important to
examine chemical properties of adamantyl-containing
fluorinated 1,3-diketones with a view to obtain hetero-
cyclic compounds based thereon.
Our results showed that, unlike 1,3-diketones hav-
ing no adamantyl fragment [1], compounds Ia–Ie do
not form chelates with copper(II) salts and, unlike
nonfluorinated analogs [4, 6], they do not react with
phenylhydrazine under standard conditions. By reac-
tions of 1,3-diketones Ia–Ih with hydrazine hydrate we
synthesized hitherto unknown 4-(1-adamantyl)-5-aryl-
(hetaryl)-3-tri(or di)fluoromethyl-1H-pyrazoles Ia–Ih
(Scheme 1). The reactions were carried out in boiling
ethanol using equimolar amounts of the reactants (or
slight excess of hydrazine hydrate), the reaction time
was 2–4 h, and target products IIa–IIh were isolated in
80–90% yield. The condensation was accompanied by
appreciable heat evolution. Pyrazoles IIa–IIh are
colorless high-melting crystalline substances. Their
structure was confirmed by mass and 1H NMR spectra.
We previously synthesized a series of adamantyl-
containing fluorinated 1,3-diketones Ia–Ie with high
yields under mild conditions [8, 9]. Structural speci-
ficity of such 1,3-diketones is the presence of a strong
Scheme 1.
O
R
RF
N2H4 ·H2O
RF
–2H2O
N
NH
EXPERIMENTAL
O
R
1
Ia–Ih
IIa–IIh
The H NMR spectra were recorded on a Bruker
DAX-500 spectrometer operating at 500.13 MHz using
CDCl3 (IIa–IIf, IIh) or DMSO-d6 (IIg) as solvent. The
mass spectra (electron impact, 70 eV) were obtained
RF = CF3, R = Ph (a), 4-ClC6H4 (b), 3,4-(MeO)2C6H3 (c),
1,3-benzodioxol-5-yl (d), 2-furyl (e), 2-thienyl (f),
4-(1H-pyrrol-1-yl)phenyl (g); RF = CF2H, R = Ph (h).
1178

SYNTHESIS OF 4-(1-ADAMANTYL)-3-POLYFLUOROMETHYL-1H-PYRAZOLES
1179
on a Kratos MS-30 instrument. Initial fluorinated
2-(1-adamantyl)-1,3-diketones Ia–Ih were synthesized
according to the procedures described in [3].
from 2 g (50 mmol) of 2-(1-adamantyl)-1-(1,3-benzo-
dioxol-5-yl)-4,4,4-trifluorobutane--1,3-dione and
0.33 ml (68 mmol) of hydrazine hydrate. Yield 1.8 g
1
(90%), colorless crystals, mp 207–209°C. H NMR
4-(1-Adamantyl)-5-aryl(hetaryl)-3-tri(di)fluoro-
methyl-1H-pyrazoles IIa–IIh (general procedure).
1,3-Diketone Ia–Ih, was dissolved in ethanol, 1.2–
1.5 equiv of hydrazine hydrate was added, and the
mixture was heated to the boiling point and kept for
6 h under reflux. When the reaction was complete, the
mixture was cooled to room temperature, and the
precipitate was filtered off, dried, and recrystallized
from isopropyl alcohol.
4-(1-Adamantyl)-5-phenyl-3-trifluoromethyl-1H-
pyrazole (IIa) was synthesized from 2 g (57 mmol) of
2-(1-adamantyl)-4,4,4-trifluoro-1-phenylbutane-1,3-
dione and 0.33 ml (68 mmol) of hydrazine hydrate.
Yield 1.7 g (86%), colorless crystals, mp 215–216°C.
1H NMR spectrum, δ, ppm: 1.61 s (12H, CH2, Ad),
1.9 s (3H, CH, Ad), 7.32–7.5 m (5H, Ph), 9.93 s (1H,
NH). Mass spectrum, m/z (Irel, %): 346 (100) [M]+, 135
(18) [Ad]+, 69 (27) [CF3]+. Found, %: C 69.54; H 6.31;
N 7.89. C20H21F3N2. Calculated, %: C 69.35; H 6.11;
N 8.08. M 346.39
spectrum, δ, ppm: 1.6 s (12H, CH2, Ad), 1.91 s (3H,
CH, Ad), 6.06 s (2H, CH2), 6.75 s (3H, Harom), 9.91 s
(1H, NH). Mass spectrum, m/z (Irel, %): 390 (100)
[M]+, 135 (19) [Ad]+, 69 (23) [CF3]+. Found, %:
C 64.65; H 5.51; N 7.15. C21H21F3N2O2. Calculated,
%: C 64.61; H 5.42; N 7.18. M 390.40.
4-(1-Adamantyl)-5-(2-furyl)-3-trifluoromethyl-
1H-pyrazole (IIIe) was synthesized from 2 g
(58 mmol) of 2-(1-adamantyl)-4,4,4-trifluoro-1-(2-
furyl)butane-1,3-dione and 0.35 ml (72 mmol) of hy-
drazine hydrate. Yield 1.67 g (85%), colorless crystals,
1
mp 139–141°C. H NMR spectrum, δ, ppm: 1.68 s
(12H, CH2, Ad), 1.98 s (3H, CH, Ad), 6.48–6.6 m (2H,
CH), 7.69 s (1H, CH), 10.18 s (1H, NH). Mass spec-
trum, m/z (Irel, %): 336 (100) [M]+, 135 (19) [Ad]+, 69
(46) [CF3]+. Found, %: C 64.52; H 5.74; N 8.29.
C18H19F3N2O. Calculated, %: C 64.28; H 5.69; N 8.33.
M 336.35.
4-(1-Adamantyl)-5-(2-thienyl)-3-trifluoromethyl-
1H-pyrazole (IIIf) was synthesized from 2 g
(56 mmol) of 2-(1-adamantyl)-4,4,4-trifluoro-1-(2-
thienyl)butane-1,3-dione and 0.35 ml (72 mmol) of
hydrazine hydrate. Yield 1.64 g (84%), colorless crys-
tals, mp 192–193°C. 1H NMR spectrum, δ, ppm: 1.66 s
(12H, CH2, Ad), 1.96 s (3H, CH, Ad), 7.09–7.18 m
(2H, CH), 7.51 s (1H, CH), 10.1 s (1H, NH). Mass
spectrum, m/z (Irel, %): 352 (100) [M]+, 135 (19) [Ad]+,
69 (42) [CF3]+. Found, %: C 61.50; H 5.51; N 7.91;
S 9.26. C18H19F3N2S. Calculated, %: C 61.35; H 5.43;
N 7.95; S 9.10. M 352.42.
4-(1-Adamantyl)-5-(4-chlorophenyl)-3-trifluoro-
methyl-1H-pyrazole (IIb) was synthesized from 2 g
(52 mmol) of 2-(1-adamantyl)-1-(4-chlorophenyl)-
4,4,4-trifluorobutane-1,3-dione and 0.33 ml (68 mmol)
of hydrazine hydrate. Yield 1.7 g (87%), colorless
1
crystals, mp 223–224°C. H NMR spectrum, δ, ppm:
1.63 s (12H, CH2, Ad), 1.91 s (3H, CH, Ad), 7.31 d
(2H, Harom), 7.43 d (2H, Harom), 12.5 s (1H, NH). Mass
spectrum, m/z (Irel, %): 380 (100) [M]+, 135 (17) [Ad]+,
69 (22) [CF3]+. Found, %: C 63.13; H 5.40; N 7.27.
C20H20ClF3N2. Calculated, %: C 63.08; H 5.29; N 7.36.
M 380.83.
4-(1-Adamantyl)-5-[4-(1H-pyrrol-1-yl)phenyl]-3-
trifluoromethyl-1H-pyrazole (IIIg) was synthesized
from 2 g (48 mmol) of 2-(1-adamantyl)-4,4,4-trifluoro-
1-[4-(1H-pyrrol-1-yl)phenyl]butane-1,3-dione and
0.28 ml (57 mmol) of hydrazine hydrate. Yield 1.75 g
4-(1-Adamantyl)-5-(3,4-dimethoxyphenyl)-3-tri-
fluoromethyl-1H-pyrazole (IIIc) was synthesized
from 2 g (48 mmol) of 2-(1-adamantyl)-1-(3,4-di-
methoxyphenyl-4,4,4-trifluorobutane-1,3-dione and
0.28 ml (57 mmol) of hydrazine hydrate. Yield 1.6 g
1
(88%), colorless crystals, mp 247–248°C. H NMR
spectrum, δ, ppm: 1.62 s (12H, CH2, Ad), 1.91 s (3H,
CH, Ad), 6.30 d (2H, CH), 7.31 s (2H, CH), 7.45 d
(2H, C6H4), 7.61 d (2H, C6H4), 13.18 s (1H, NH).
Mass spectrum, m/z (Irel, %): 411 (100) [M]+, 135 (20)
[Ad]+, 69 (34) [CF3]+. Found, %: C 70.29; H 5.95;
N 10.25. C24H24F3N3. Calculated, %: C 70.06; H 5.88;
N 10.21. M 411.46.
1
(80%), colorless crystals, mp 218–219°C. H NMR
spectrum, δ, ppm: 1.62 s (12H, CH2, Ad), 1.91 s (3H,
CH, Ad), 3.89 s (3H, OMe), 3.95 s (3H, OMe), 6.81–
6.95 m (3H, Harom), 11.2 s (1H, NH). Mass spectrum,
m/z (Irel, %): 406 (100) [M]+, 135 (19) [Ad]+, 69
(59) [CF3]+. Found, %: C 65.07; H 6.33; N 6.81.
C22H25F3N2O2. Calculated, %: C 65.01; H 6.20;
N 6.89. M 406.44.
4-(1-Adamantyl)-3-difluoromethyl-5-phenyl-1H-
pyrazole (IIIh) was synthesized from 2 g (60 mmol)
of 2-(1-adamantyl)-4,4-difluoro-1-phenylbutane-1,3-
dione and 0.35 ml (72 mmol) of hydrazine hydrate.
4-(1-Adamantyl)-5-(1,3-benzodioxol-5-yl)-3-
trifluoromethyl-1H-pyrazole (IIId) was synthesized
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 8 2010

BUTOV et al.
1180
3. Shvekhgeimer, G.A. and Litvinov, V.P., Russ. J. Org.
Chem., 1999, vol. 35, p. 165.
4. Shvekhgeimer, G.A., Usp. Khim., 1996, vol. 65, p. 606.
Yield 1.6 g (81%), colorless crystals, mp 184–185°C.
1H NMR spectrum, δ, ppm: 1.62 s (12H, CH2, Ad),
1.91 s (3H, CH, Ad), 6.94 t (1H, CF2H), 7.31–7.98 m
(5H, Ph), 9.1 s (1H, NH). Mass spectrum, m/z (Irel, %):
328 (100) [M]+, 135 (18) [Ad]+, 69 (25) [CF3]+. Found,
%: C 73.26; H 6.82; N 8.57. C20H22F2N2. Calculated,
%: C 73.15; H 6.75; N 8.53. M 328.40.
5. Makarova, N.V., Moiseev, I.K., and Zemtsova, M.N.,
Russ. J. Org. Chem., 2001, vol. 37, p. 269
6. Gonzalez, A., Marquet, J., and Moreno, M., Tetrahedron,
1986, vol. 42, p. 4253.
7. Klimochkin, Yu.I., Tili, T.S., and Moiseev, I.K., Zh. Org.
Khim., 1988, vol. 24, p. 1780.
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