Synthesis of polyfluoroalkyl-containing 1-(4-acetoxybutyl)- and 1-(4-hydroxybutyl)pyrazoles and their tuberculostatic activity

Article abstract of DOI:10.1007/s11172-011-0368-4

Alkylation of polyfluoroalkyl-containing pyrazoles with 4-bromobutyl acetate in acetone in the presence of potassium carbonate leads to a mixture of isomeric 1-(4-acetoxybutyl)-3-fluoroalkyl- and 1-(4-acetoxybutyl)-5- fluoroalkylpyrazoles, which in a number of cases were successfully separated by HPLC. Deacylation in acidic medium with gaseous hydrogen chloride and in basic medium with gaseous ammonia leads to 1-(4-hydroxybutyl)pyrazoles, which manifest moderate tuberculostatic activity.

Full text of DOI:10.1007/s11172-011-0368-4

Russian Chemical Bulletin, International Edition, Vol. 60, No. 11, pp. 2396—2400, November, 2011
2396
Synthesis of polyfluoroalkylꢀcontaining 1ꢀ(4ꢀacetoxybutyl)ꢀ
and 1ꢀ(4ꢀhydroxybutyl)pyrazoles and their tuberculostatic activity*
A. E. Ivanova,a O. G. Khudina,a Ya. V. Burgart,a V. I. Saloutin,a and M. A. Kravchenkob
aI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 ul. S. Kovalevskoi, 620041 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 5954. Eꢀmail: saloutin@ios.uran.ru
bUral Research Institute of Phthisiopulmonology, Ministry of Healthcare and Social Development of the Russian Federation,
50 ul. 22 Parts´ezda, 620039 Ekaterinburg, Russian Federation.
Fax: +7 (343) 333 4463. Eꢀmail: kravchenko@nexcom.ru
Alkylation of polyfluoroalkylꢀcontaining pyrazoles with 4ꢀbromobutyl acetate in acetone in
the presence of potassium carbonate leads to a mixture of isomeric 1ꢀ(4ꢀacetoxybutyl)ꢀ3ꢀ
fluoroalkylꢀ and 1ꢀ(4ꢀacetoxybutyl)ꢀ5ꢀfluoroalkylpyrazoles, which in a number of cases were
successfully separated by HPLC. Deacylation in acidic medium with gaseous hydrogen chloride
and in basic medium with gaseous ammonia leads to 1ꢀ(4ꢀhydroxybutyl)pyrazoles, which manꢀ
ifest moderate tuberculostatic activity.
Key words: pyrazoles, alkylation, deacylation, tuberculostatic activity.
Scheme 1
Pyrazoles are known for their various biological activity.
They give rise to febrifugal and antiinflammatory drugs,
such as analgin, antipyrin, butadion,1 and celebrex,2 which
are widely used in practical medicine.
Recently, it has been found3 that 4ꢀnitrosoꢀsubstituted
fluoroalkylpyrazoles possess high tuberculostatic activity.
In continuation of works on the search for tuberculostatꢀ
ics among fluoroalkylꢀcontaining pyrazoles, in the present
work we synthesized their Nꢀalkylated derivatives.
4ꢀBromobutyl acetate has been chosen as the alkylatꢀ
ing agent. The butyl acetate moiety incorporated into the
heterocycle can be deacylated to 4ꢀhydroxybutyl substituꢀ
ent. The presence of the hydroxyalkyl fragment in the
heterocycle increases the lipophilicity of the molecule,
and it can acquire new, including biological, properties,
for example, antiviral activity.4
Heating in acetone in the presence of potassium carꢀ
bonate has proved the most appropriate conditions for the
alkylation of pyrazoles 1a—d (Scheme 1). As a result,
monofluoroalkylꢀsubstituted pyrazoles 1a—c were convertꢀ
ed to the mixtures of isomeric pyrazoles 2a—c and 3a—c.
Isomers 2c and 3c were successfully separated by HPLC.
Alkylation of symmetric bis(tetrafluoroethyl) substituted
pyrazole 1d led to the only product 2d. To assign isomers 2
and 3, we used the NMR spectroscopic data.
1—3: R = Ph, RF = CF3 (a); R = Me, RF = (CF2)2H (b);
R = Ph, RF = (CF2)2H (c); R = RF = (CF2)2H (d)
butyl substituent. Earlier,5 it has been found that the CF3
group at position 3 in 4ꢀ(het)arylazoꢀ1ꢀmethylꢀ3,5ꢀbisꢀ
(trifluoromethyl)pyrazoles has more highꢀfield chemical
shift in the 19F NMR spectrum (in the region δ 99.1—100.2)
as compared to the CF3 group at position 5, whose chemꢀ
ical shift is observed in the region δ 102.1—104.1. For the
same reason, the signal for the fluorine nuclei observed in
the 19F NMR spectrum of the reaction products of pyrꢀ
azole 1a at δ 99.96 was assigned to 3ꢀCF3ꢀpyrazole 2a,
whereas the signal at δ 102.46, to 5ꢀCF3ꢀpyrazole 3a. It is
obvious that 3ꢀCF3ꢀpyrazole 2a was formed by the alkylation
of pyrazole 1a at the nitrogen atom neighboring to the
phenyl substituent, whereas 5ꢀCF3ꢀpyrazole 3a, by the alkylaꢀ
tion at the other nitrogen atom, adjacent to the CF3 group.
Isomeric pyrazoles 2a and 3a differ in the position of
the trifluoromethyl group with respect to the 4ꢀacetoxyꢀ
* Dedicated to Academician of the Russian Academy of Sciences
O. M. Nefedov on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2349—2353, November, 2011.
1066ꢀ5285/11/6011ꢀ2396 © 2011 Springer Science+Business Media, Inc.

1ꢀ(4ꢀHydroxybutyl)ꢀ3(5)ꢀpolyfluoroalkylpyrazoles
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011 2397
In the work,6 the fluorine nuclei of the αꢀCF2 group in
the 3ꢀpolyfluoroalkyl substituent of pyrazoles were found
to resonate in more high field with respect to the δ value of
53.9 (C6F6 internal standard). Therefore, the signals at δ
48 observed in the 19F NMR spectra for the αꢀCF2 group
should correspond to 3ꢀtetrafluoroethylpyrazoles 2b,c,
whereas more lowꢀfield signals at δ ~54, to 5ꢀtetrafluoroꢀ
ethylpyrazoles 3b,c. The fluorine nuclei signals in comꢀ
pounds 2a and 3a also confirm this assignment. Thus, the
signal for the 3ꢀCF3 group is observed more upꢀfield
(δ 99.96) as compared to the signal for the 5ꢀCF3 substꢀ
ituent (δ 102.46).
Scheme 2
In the mixtures, isomers 2a,b were found to be preꢀ
dominant over isomers 3a,b (the ratio for regioisomers 2a
and 3a is 62 : 38, for 2b and 3b, 9 : 1), whereas isomers 2c
and 3c are present in the equal amounts. Comparison of
the selectivity of alkylation of tetrafluoroethylꢀsubstituted
pyrazoles containing methyl (1b) and phenyl (1c) substitꢀ
uents led us to a conclusion that the presence of the methꢀ
yl group increases regioselectivity of the alkylation, giving
predominantly one of the isomers, which is formed at the
nitrogen atom adjacent to the methyl substituent. When
bulky phenyl substituent is present (pyrazoles 1a,c), the
alkylation can take both directions with almost equal probꢀ
ability, though an additive negative inductive effect of the
CF3 group leads to some predominance of isomer 2a over
isomer 3a.
Bubbling ammonia through the methanol solution of
symmetric bis(1,1,2,2ꢀtetrafluoroethyl)ꢀsubstituted pyrꢀ
azole 2d has proved more efficient for the removal of the
acetyl group from this compound (Scheme 3). The reacꢀ
tion takes place at room temperature in 99.8% yield
(GLC data).
Scheme 3
The position of 4ꢀacetoxybutyl substituent affects
chemical shifts of the adjacent phenyl and tetrafluoroethyl
substituents in isomers 2 and 3. Thus, the vicinal protons
of the 4ꢀacetoxybutyl fragment in compounds 2a,c shield
the orthoꢀprotons of the phenyl substituent (δ 7.37—7.38)
and deshield the proton in the (CF2)2H fragment (δ 6.16).
The situation is reverse for compounds 3a,c: the orthoꢀ
protons are deshielded (δ 7.78), whereas the proton of the
(CF2)2H group, which is vicinal with respect to the 4ꢀacetꢀ
oxybutyl substituent, is shielded (δ 6.03).
The structures of compounds 2 and 3 were confirmed
by GLCꢀMS. As it was expected, isomers 2a,c and 3a,c
containing phenyl substituents have longer retention time
(23.8—25.3 min) as compared to pyrazoles 2b,d and 3b
containing alkyl and fluoroalkyl substituents (retention
time of 18.8—20.7 min). The following pattern is observed
in the mass spectra: the molecules of 3ꢀRFꢀisomers are
cleaved with the formation of more stable fragment ions,
since the intensities of the [M – C4H7OC=OCH3]+,
[M – C4H6OC=OCH3]+, [M – OC=OCH3]+, and
[M – C=OCH3]+ peaks in the spectra are higher than
those for 5ꢀRFꢀisomers.
The IR spectra of compounds 4—6 exhibit an absorpꢀ
tion band of the OH group at 3375—3380 cm–1, while no
absorption band of the acetate carbonyl group is observed.
In the 1H NMR spectra, the signal for the hydroxyl proton
is observed in the high field at δ 1.94—2.45.
We studied the tuberculostatic activity of obtained
(4ꢀhydroxybutyl)pyrazoles 4—6 in the in vitro experiments
toward a laboratory strain of tuberculosis mycobacteria
(TMB) H37Rv. Isoniazide was used as a comparison agent,
whose minimum concentration necessary for the retardaꢀ
tion of the TMB growth is 0.15 μg mL–1
.
Our studies showed that introduction of 4ꢀhydroxyꢀ
butyl substituent does not significantly affect antitubercuꢀ
losis properties. Thus, the starting 5ꢀphenylꢀ3ꢀtrifluoroꢀ
methylpyrazole (1a) possess moderate tuberculostatic activꢀ
ity (the minimum inhibition concentration (MIC) is
6.25 μg mL–1). Introduction of 4ꢀhydroxybutyl substituꢀ
ent at the position adjacent to the phenyl group does not
affect tuberculostatic activity, since 1ꢀ(4ꢀhydroxybutyl)ꢀ
3ꢀtrifluoromethylpyrazole 4 manifests comparable activiꢀ
For the mixture of pyrazoles 2a and 3a taken as an examꢀ
ple, it was shown that the 4ꢀacetoxybutyl moiety can be
deacylated under acidic conditions by bubbling gaseous
hydrogen chloride through their solution in anhydrous ethanol
to obtain a mixture of compounds 4 and 5 in quantitative yield
(Scheme 2). Isomers 4 and 5 were separated by HPLC.

2398
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011
Ivanova et al.
liquor was concentrated. The products were purified by column
chromatography (the eluent was chloroform—ethyl acetate, 7 : 1
(2b,d, 3b) or hexane—ethyl acetate, 1 : 1 (2a, 3a)). Isomers 2a,b
and 3a,b were not separated. Compounds 2a and 3a were obꢀ
tained as a mixture in the ratio of 62 : 38 and in 52% yield,
colorless oil; compounds 2b and 3b were obtained as a mixture in
the ratio of 9 : 1 and in 54% yield, colorless oil. Isomers 2c and 3c
were separated by HPLC.
ty. The presence of 4ꢀhydroxybutyl substituent at the posiꢀ
tion adjacent to the CF3 group in regioisomer 5 decreases
tuberculostatic activity (the MIC is 12.5 μg mL–1). Reꢀ
placement of the phenyl substituent in pyrazole 4 with the
fluoroalkyl fragment does not affect antituberculous propꢀ
erties either. Thus, the MIC for the Nꢀalkylated 3,5ꢀbisꢀ
(tetrafluoroethyl)ꢀsubstituted pyrazole 6 is 6.25 μg mL–1
.
Further, we are planning to synthesize Nꢀalkylated and
Nꢀglycosilated pyrazoles modified at position 4 with
(het)arylhydrazone substituents, in particular, with antiꢀ
pyrinehydrazone fragment, which imposes antiinflammaꢀ
tory activity on compounds.
1ꢀ(4ꢀAcetoxybutyl)ꢀ5ꢀphenylꢀ3ꢀtrifluoromethylpyrazole (2a).
1H NMR, δ: 1.54 (m, 2 H, CH2, 3J = 6.5 Hz); 1.89 (m, 2 H,
CH2); 1.98 (s, 3 H, MeCO2); 3.97 (t, 2 H, OCH2, 3J = 6.4 Hz);
4.17 (t, 2 H, NCH2, 3J = 7.3 Hz); 6.52 (s, 1 H, H(4)); 7.37 (dd, 2 H,
3
4
oꢀHPh, J = 6.9 Hz, J = 2.4 Hz); 7.47—7.48 (m, 3 H, mꢀHPh
,
pꢀHPh). 19F NMR, δ: 99.96 (s, CF3). MS, m/z (Irel (%)): 43
[C=OCH3]+ (42.7), 55 [C4H7]+ (22.8), 71 [C4H7O]+ (37.4), 77
[C6H5]+ (16.6), 164 [M – C6H5 – C4H5O2]+ (10.1), 193 [M –
– C4H7OC=OCH3 – F]+ (11.3), 205 [M – C6H6 – C=OCH3]+
(25.6), 212 [M – C4H7OC=OCH3]+ (88.8), 213 [M –
– C4H6OC=OCH3]+ (35.5), 225 [M – C3H6OC=OCH3]+
(99.9), 239 [M – C2H4OC=OCH3]+ (26.1), 265 [M – C2H5O2]+
(20.8), 266 [M – CH3COOH]+ (16.3), 267 [M – OC=OCH3]+
(87.9), 283 [M – C=OCH3]+ (49.9), 326 [M]+ (15.0).
Found (%): C, 59.02; H, 5.21; F, 17.66; N, 8.61. C16H17F3N2O2.
Calculated (%): C, 58.89; H, 5.25; F, 17.47; N, 8.58 (the eleꢀ
mental analysis data are given for the mixture of pyrazoles 2a
and 3a).
1ꢀ(4ꢀAcetoxybutyl)ꢀ5ꢀmethylꢀ3ꢀ(1,1,2,2ꢀtetrafluoroethyl)ꢀ
pyrazole (2b). 1H NMR, δ: 1.64 (m, 2 H, CH2, 3J = 6.4 Hz); 1.90
(m, 2 H, CH2, 3J = 7.4 Hz); 2.04 (s, 3 H, MeCO2); 2.28 (s, 3 H,
Me); 4.06—4.11 (m, 4 H, OCH2, NCH2); 6.09 (tt, 1 H, H(CF2)2,
2JH,F = 53.6 Hz, 3JH,F = 4.3 Hz); 6.28 (s, 1 H, H(4)). 19F NMR,
δ: 25.34 (dt, 2 F, HCF2, 2JF,H = 53.6 Hz, 3JF,F = 7.4 Hz); 48.52
(td, 2 F, CF2, 3JF,F = 7.4 Hz, 3JF,H = 4.3 Hz). MS, m/z (Irel (%)):
43 [C=OCH3]+ (22.2), 55 [C4H7]+ (13.0), 71 [C4H7O]+ (17.4),
131 [M – C4H7OC=OCH3 – HCF2]+ (24.0), 182 [M –
– C4H7OC=OCH3]+ (16.2), 183 [M – C4H6OC=OCH3]+
(23.1), 195 [M – H(CF2)2]+ (99.9), 209 [M – C2H4OC=OCH3]+
(12.8), 235 [M – C2H5O2]+ (14.4), 236 [M – CH3COOH]+
(9.9), 237 [M – OC=OCH3]+ (52.4), 253 [M – C=OCH3]+
(40.8), 296 [M]+ (14.6). Found (%): C, 48.8; H, 5.42; F, 25.51;
N, 9.31. C12H16F4N2O2. Calculated (%): C, 48.65; H, 5.44;
F, 25.65; N, 9.46 (the elemental analysis data are given for the
mixture of pyrazoles 2b and 3b).
Experimental
1
H and 19F NMR spectra were recorded on a Bruker DRXꢀ400
spectrometer (400 (1H) and 75 MHz (19F)) in CDCl3 relative
to SiMe4 and C6F6, respectively. IR spectra in the region of
4000—400 cm–1 were recorded on a Perkin—Elmer Spectrum
One Fourierꢀtransformed IR spectrometer equipped with a frusꢀ
trated total internal reflection (FTIR) accessory. Melting points
were measured in unsealed capillaries on a Stuart SMP30 appaꢀ
ratus. Column chromatography was performed on silica gel 60
(0.063—0.02 mm). Mass spectra were recorded on a Agilent GC
7890A MSD 5975C inert XL EI/CI GLCꢀMS spectrometer with
an HP5ꢀMS quartz capillary column (dimethylpolysiloxane with
5% of Ph groups, 30 m × 0.25 mm, 0.25 μm thick film) and
a quadrupole mass spectrometric detector in the mode of elecꢀ
tron ionization (70 eV); helium carrier gas, chloroform solvent.
An Agilent 1200 Series preparative liquid chromatograph was
used for HPLC, which was equipped with a diodeꢀmatrix deꢀ
tector, preparative autosampler (900 μL), ZORBAX Eclipse
XDBꢀC18 PrepHT column (21.2×150 mm, 5 μm particle size).
The acetonitrile—water mixtures in the ratios of 50 : 50 and
60 : 40 were used as eluents for the separation of (4ꢀacetꢀ
oxybutyl)pyrazoles 2c and 3c and (4ꢀhydroxybutyl)pyrazoles 4
and 5, respectively, at the rate of 20 mL min–1, 254 nm waveꢀ
length. Elemental analysis was performed on a Perkin—Elmer
PE 2400 series II analyzer.
Tuberculostatic activity of compounds 1a, 4—6 was deterꢀ
mined by the vertical diffusion using a Novaya solid culture
medium. The H37Rv laboratory strain was prepared for the seedꢀ
ing. The culture strain was weighed on a torsional scale, a weighed
amount (10 mg) was placed into a porcelain mortar, thoroughly
mulled, and the culture suspension was prepared using a bacteriꢀ
al turbidity standard of 100 million of microbial bodies in 1 mL.
A resulting suspension (0.2 mL) was seeded into the testꢀtubes
with the culture medium and the compound under study of the
corresponding dilution (5 mL). The agents of the following conꢀ
centrations were prepared by a successive dilution: 100, 50, 12.5,
6.25, 3.5, 1.5, 0.7, 0.3, and 0.15 μg mL–1. A testꢀtube was incuꢀ
bated for 7—10 days in a thermostat at 37 °C.7 Activity of the
compounds toward TMB was studied independently in three
testꢀtubes for each concentration.
1ꢀ(4ꢀAcetoxybutyl)ꢀ5ꢀphenylꢀ3ꢀ(1,1,2,2ꢀtetrafluoroethyl)ꢀ
1
pyrazole (2c). The yield was 36%, yellow oil. H NMR, δ: 1.53
3
3
(m, 2 H, CH2, J = 6.5 Hz); 1.88 (m, 2 H, CH2, J = 7.4 Hz);
3
1.99 (s, 3 H, MeCO2); 3.97 (t, 2 H, OCH2, J = 6.4 Hz); 4.18
(t, 2 H, NCH2, 3J = 7.4 Hz); 6.16 (tt, 1 H, H(CF2)2, JH,F
= 53.5 Hz, JH,F = 4.3 Hz); 6.54 (s, 1 H, H(4)); 7.38 (dd, 2 H,
2
=
3
3
4
oꢀHPh, J = 7.2 Hz, J = 2.2 Hz); 7.46—7.50 (m, 3 H, mꢀHPh
,
pꢀHPh). 19F NMR, δ: 25.43 (dt, 2 F, HCF2, JF,H = 53.5 Hz,
2
3JF,F = 7.4 Hz); 48.68 (td, 2 F, CF2, 3J = 7.4 Hz, J = 4.3 Hz).
3
MS, m/z (Irel (%)): 43 [C=OCH3]+ (30.1), 55 [C4H7]+ (18.1), 71
[C4H7O]+ (27.3), 77 [C6H5]+ (9.5), 193 [M – C4H7OC=OCH3 –
– HCF2]+ (25.5), 244 [M – C4H7OC=OCH3]+ (58.2), 245
[M – C4H6OC=OCH3]+ (36.7), 257 [M – H(CF2)2]+ (99.9),
271 [M – C2H4OC=OCH3]+ (23.4), 297 [M – C2H5O2]+ (13.2),
299 [M – OC=OCH3]+ (97.6), 315 [M – C=OCH3]+ (45.8),
358 [M]+ (13.0). Found (%): C, 57.19; H, 5.02; F, 21.50; N, 8.01.
C17H18F4N2O2. Calculated (%): C, 56.98; H, 5.06; F, 21.21;
N, 7.82.
Synthesis of 1ꢀ(4ꢀacetoxybutyl)ꢀsubstituted pyrazoles 2a—d
and 3a—c (general procedure). A mixture of pyrazole 1a—d
(2.5 mmol), acetone (10 mL), 4ꢀbromobutyl acetate (0.49 g,
2.5 mmol), and potassium carbonate (0.3 g, 3.0 mmol) was reꢀ
fluxed for 16—20 h. A precipitate was filtered off, the mother

1ꢀ(4ꢀHydroxybutyl)ꢀ3(5)ꢀpolyfluoroalkylpyrazoles
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011 2399
1ꢀ(4ꢀAcetoxybutyl)ꢀ3,5ꢀbis(1,1,2,2ꢀtetrafluoroethyl)pyrazole
(2d). The yield was 54%, colorless oil. IR, ν/cm–1: 1738 (MeCO2);
1470, 1550 (C=C, C=N); 1110—1239 (C—F). 1H NMR, δ: 1.68
(m, 2 H, CH2, J = 6.4 Hz); 2.02 (m, 2 H, CH2); 2.05 (s, 3 H,
MeCO2); 4.09 (t, 2 H, OCH2, 3J = 6.4 Hz); 4.33 (t, 2 H, NCH2,
Deacylation of the mixture of compounds 2a and 3a. A mixꢀ
ture of (4ꢀacetoxybutyl)ꢀsubstituted pyrazoles 2a and 3a (0.16 g,
0.5 mmol) was dissolved in ethanol (5 mL), then gaseous hydroꢀ
gen chloride was bubbled through the solution for 1 h. The reacꢀ
tion mixture was stirred for 30 min at room temperature and
neutralized with NaHCO3. The product was extracted with
chloroform and dried with Na2SO4. The solvent was evaporated.
Isomers 4 and 5 were separated by HPLC.
1ꢀ(4ꢀHydroxybutyl)ꢀ5ꢀphenylꢀ3ꢀtrifluoromethylpyrazole (4).
The yield was 82%, yellow oil. IR, ν/cm–1: 3375 (OH); 1475,
1505 (C=C, C=N); 1130—1210 (C—F). 1H NMR, δ: 1.48 (m, 2 H,
CH2, 3J = 6.3 Hz); 1.91 (m, 2 H, CH2, 3J = 7.4 Hz); 2.45 (br.s,
1 H, OH); 3.57 (t, 2 H, OCH2, 3J = 6.3 Hz); 4.18 (t, 2 H, NCH2,
3J = 7.4 Hz); 6.51 (s, 1 H, H(4)); 7.38 (dd, 2 H, oꢀHPh, 3J = 7.2 Hz,
4J = 2.5 Hz); 7.46—7.50 (m, 3 H, mꢀHPh, pꢀHPh). 19F NMR,
δ: 99.81 (s, CF3). Found (%): C, 59.37; H, 5.29; F, 20.34;
N, 9.77. C14H15F3N2O. Calculated (%): C, 59.15; H, 5.32;
F, 20.05; N, 9.85.
3
2
3
3J = 7.4 Hz); 6.05 (tt, 1 H, H(CF2)2, JH,F = 53.5 Hz, JH,F
=
= 2.4 Hz); 6.12 (tt, 1 H, H(CF2)2, 2JH,F = 53.4 Hz, 3JH,F = 4.1 Hz);
6.84 (s, 1 H, H(4)). 19F NMR, δ: 25.67 (dt, 2 F, HCF2, 2JF,H
=
= 53.4 Hz, 3JF,F = 6.7 Hz); 28.63 (dt, 2 F, HCF2, 2JF,H = 53.5 Hz,
3JF,F = 4.7 Hz); 48.72 (td, 2 F, CF2, 3J = 6.7 Hz, J = 4.1 Hz);
3
54.02 (m, 2 F, CF2). MS, m/z (Irel (%)): 43 [C=OCH3]+ (61.2),
54 [C4H6]+ (22.2), 55 [C4H7]+ (20.8), 71 [C4H7O]+ (21.2), 209
[M – H(CF2)2 – C3H4O2]+ (9.5), 217 [M – HCF2
–
– C4H7OC=OCH3]+ (15.6), 221 [M – H(CF2)2 – CH3COOH]+
(52.8), 243 [M – HCF2 – C2H5OC=OCH3]+ (19.2), 269
[M – C4H6OC=OCH3]+ (10.9), 281 [M – H(CF2)2]+ (99.9),
294 [M – C2H5OC=OCH3]+ (22.8), 321 [M — C2H5O2]+ (38.2),
322 [M – CH3COOH]+ (24.6), 382 [M]+ (0.3). Found (%):
C, 40.91; H, 3.59; F, 40.10; N, 7.48. C13H14F8N2O2. Calculatꢀ
ed (%): C, 40.85; H, 3.69; F, 39.76; N, 7.33.
1ꢀ(4ꢀHydroxybutyl)ꢀ3ꢀphenylꢀ5ꢀtrifluoromethylpyrazole (5).
The yield was 16%, yellow oil. IR, ν/cm–1: 3375 (OH); 1475,
1515, 1555 (C=C, C=N); 1125—1200 (C—F). 1H NMR, δ: 1.62
1ꢀ(4ꢀAcetoxybutyl)ꢀ3ꢀphenylꢀ5ꢀtrifluoromethylpyrazole (3a).
1H NMR, δ: 1.71 (m, 2 H, CH2, 3J = 6.5 Hz); 2.01—2.07 (m, 5 H,
(m, 2 H, CH2, J = 6.4 Hz); 2.02 (m, 2 H, CH2, J = 7.4 Hz);
3
3
3
CH2, MeCO2); 4.10 (t, 2 H, OCH2, J = 6.4 Hz); 4.28 (t, 2 H,
2.37 (br.s, 1 H, OH); 3.66 (t, 2 H, OCH2, 3J = 6.4 Hz); 4.28 (t, 2 H,
NCH2, J = 7.4 Hz); 6.86 (s, 1 H, H(4)); 7.33 (tt, 1 H, pꢀHPh
NCH2, 3J = 7.3 Hz); 6.88 (s, 1 H, H(4)); 7.33 (t, 1 H, pꢀHPh
,
,
3
3J = 7.3 Hz); 7.40 (t, 2 H, mꢀHPh, J = 7.3 Hz); 7.78 (dd, 2 H,
oꢀHPh, 3J = 7.3 Hz, 4J = 2.0 Hz). 19F NMR, δ: 102.46 (s, CF3).
MS, m/z (Irel (%)): 43 [C=OCH3]+ (27.2), 55 [C4H7]+ (19.1), 71
[C4H7O]+ (23.1), 77 [C6H5]+ (16.3), 205 [M – C6H6 – C=OCH3]+
3J = 7.3 Hz, 4J = 1.3 Hz); 7.40 (m, 2 H, mꢀHPh); 7.76 (dd, 2 H,
oꢀHPh, 3J = 8.3 Hz, 4J = 1.3 Hz). 19F NMR, δ: 102.27 (s, CF3).
Found (%): C, 59.01; H, 5.33; F, 20.37; N, 9.98. C14H15F3N2O.
Calculated (%): C, 59.15; H, 5.32; F, 20.05; N, 9.85.
3
(9.6), 212 [M
–
C4H7OC=OCH3]+ (38.4), 225 [M
–
Deacylation of 1ꢀ(4ꢀacetoxybutyl)pyrazole 2d. Compound 2d
(0.19 g, 0.5 mmol) was dissolved in methanol (5 mL), then gasꢀ
eous ammonia was bubbled through the solution for 1 h. The
reaction mixture was stirred for 30 min at room temperature and
neutralized with dilute HCl to pH 7. The product was extracted
with chloroform and dried with Na2SO4. The solvent was evapoꢀ
rated to obtain 1ꢀ(4ꢀhydroxybutyl)ꢀ3,5ꢀbis(1,1,2,2ꢀtetrafluoroꢀ
– C3H6OC=OCH3]+ (99.9), 257 [M – CF3]+ (27.2), 265
[M – C2H5O2]+ (17.0), 267 [M – OC=OCH3]+ (42.8), 283
[M – C=OCH3]+ (11.4), 326 [M]+ (15.2).
1ꢀ(4ꢀAcetoxybutyl)ꢀ3ꢀmethylꢀ5ꢀ(1,1,2,2ꢀtetrafluoroethyl)ꢀ
pyrazole (3b). 1H NMR, δ: 1.71, 1.97 (both m, 2 H each, 2 CH2);
2.05 (s, 3 H, MeCO2); 2.31 (s, 3 H, Me); 4.08 (t, 2 H, OCH2,
3J = 6.4 Hz); 4.19 (t, 2 H, NCH2, 3J = 7.4 Hz); 5.98 (tt, 1 H,
H(CF2)2, 2JH,F = 53.7 Hz, 3JH,F = 2.8 Hz); 6.31 (s, 1 H, H(4)).
19F NMR, δ: 28.25 (dt, 2 F, HCF2, 2JF,H = 53.7 Hz, 3JF,F = 5.6 Hz);
ethyl)pyrazole (6), the yield was 100%, yellow oil. IR, ν/cm–1
:
3380 (OH); 1475, 1550 (C=C, C=N); 1110—1225 (C—F).
1H NMR, δ: 1.60 (m, 2 H, CH2, 3J = 6.3 Hz); 1.94 (s, 1 H, OH);
2.02 (m, 2 H, CH2, 3J = 7.5 Hz); 3.67 (t, 2 H, OCH2, 3J = 6.3 Hz);
3
3
54.01 (td, 2 F, CF2, JF,F = 5.6 Hz, JF,H = 2.8 Hz). MS, m/z
(Irel (%)): 43 [C=OCH3]+ (14.5), 55 [C4H7]+ (8.7), 71 [C4H7O]+
(10.8), 131 [M – C4H7OC=OCH3 – HCF2]+ (16.0), 182
[M – C4H7OC=OCH3]+ (7.2), 183 [M – C4H6OC=OCH3]+
(14.0), 195 [M – H(CF2)2]+ (99.9), 237 [M – OC=OCH3]+
(18.8), 296 [M]+ (3.0).
4.34 (t, 2 H, NCH2, 3J = 7.5 Hz); 6.05 (tt, 1 H, H(CF2)2, 2JH,F
=
= 53.5 Hz, 3JH,F = 2.4 Hz); 6.11 (tt, 1 H, H(CF2)2, 2JH,F = 53.4 Hz,
3JH,F = 4.0 Hz); 6.82 (s, 1 H, H(4)). 19F NMR, δ: 25.68 (dt, 2 F,
HCF2, 2JF,H = 53.4 Hz, 3JF,F = 6.5 Hz); 28.57 (dt, 2 F, HCF2,
2JF,H = 53.5 Hz, 3JF,F = 4.6 Hz); 48.69 (td, 2 F, CF2, 3J = 6.5 Hz,
3J = 4.0 Hz); 53.9 (m, 2 F, CF2). MS, m/z (Irel (%)): 55 [C4H7]+
(9.6), 199 [M – HCF2 – F – C4H6OH]+ (10.3), 209 [M –
– H(CF2)2 – CH2O]+ (19.6), 217 [M – HCF2 – C4H7OH]+
(42.8), 239 [M – H(CF2)2]+ (52.6), 249 [M – F – C4H7OH]+
(10.5), 269 [M – C4H6OH]+ (14.9), 281 [M – C3F6OH]+ (99.9),
295 [M – C2H4OH]+ (10.9), 340 [M]+ (1.4). Found (%):
C, 38.67; H, 3.61; F, 44.43; N, 7.97. C11H12F8N2O. Calculatꢀ
ed (%): C, 38.83; H, 3.56; F, 44.67; N, 8.23.
1ꢀ(4ꢀAcetoxybutyl)ꢀ3ꢀphenylꢀ5ꢀ(1,1,2,2ꢀtetrafluoroethylꢀ
1
pyrazole (3c). The yield was 36%, yellow oil. H NMR, δ: 1.71
(m, 2 H, CH2, 3J = 6.5 Hz); 2.00—2.08 (m, 5 H, CH2, MeCO2);
4.10 (t, 2 H, OCH2, 3J = 6.5 Hz); 4.30 (t, 2 H, NCH2, 3J = 7.3 Hz);
2
3
6.03 (tt, 1 H, H(CF2)2, JH,F = 53.7 Hz, JH,F = 2.6 Hz); 6.82
3
(s, 1 H, H(4)); 7.33 (t, 1 H, pꢀHPh, J = 7.4 Hz); 7.41 (t, 2 H,
mꢀHPh, 3J = 7.4 Hz); 7.78 (dd, 2 H, oꢀHP2h, 3J = 7.4 Hz, 4J = 1.5 Hz).
19F NMR, δ: 28.44 (dt, 2 F, HCF2, JF,H = 53.7 Hz, JF,F
=
3
3
3
= 5.5 Hz); 54.0 (td, 2 F, CF2, JF,F = 5.5 Hz, JF,H = 2.6 Hz).
MS, m/z (Irel (%)): 43 [C=OCH3]+ (17.2), 55 [C4H7]+ (13.6), 71
[C4H7O]+ (15.9), 77 [C6H5]+ (8.3), 193 [M – C4H7OC=OCH3 –
– HCF2]+ (21.1), 244 [M – C4H7OC=OCH3]+ (17.2), 245
[M – C4H6OC=OCH3]+ (17.4), 257 [M – H(CF2)2]+ (99.9),
297 [M – C2H5O2]+ (10.8), 299 [M – OC=OCH3]+ (46), 315
[M – C=OCH3]+ (9.9), 358 [M]+ (10.1). Found (%): C, 56.76;
H, 4.98; F, 21.57; N, 7.63. C17H18F4N2O2. Calculated (%):
C, 56.98; H, 5.06; F, 21.21; N, 7.82.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 09ꢀ03ꢀ
00274a), the Ministry of Education and Science of the
Russian Federation (State Contract 02.740.11.0260), the
Ural Branch of the Russian Academy of Sciences (Inteꢀ
gration Project of Basic Research No. 09ꢀIꢀ3ꢀ2004), and
the Counsil on Grants at the President (Program of State

2400
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 11, November, 2011
Ivanova et al.
4. O. Moukhaꢀchafiq, M. L. Taha, A. Mouna, Nucleosides,
Nucleotides and Nucleic Acids, 2007, 26, 1107.
Support for Leading Scientific Schools of the Russian Fedꢀ
eration, Grant NShꢀ65261.2010.3).
5. O. G. Khudina, E. V. Shchegol´kov, Y. V. Burgart, M. I.
Kodess, O. N. Kazheva, A. N. Chekhlov, G. V. Shilov, O. A.
Dyachenko, V. I. Saloutin, O. N. Chupakhin, J. Fluor. Chem.,
2005, 126, 1230.
6. J. L. Peglion, R. E. Pastor, A. R. Cambon, Bull. Soc. Chim.
Fr., 1980, IIꢀ309; E. V. Shchegol´kov, Ya. V. Burgart, O. G.
Khudina, V. I. Saloutin, O. N. Chupakhin, Izv. Akad. Nauk,
Ser. Khim., 2004, 2478 [Russ. Chem. Bull., Int. Ed., 2004,
53, 2584].
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Received May 31, 2011;
in revised form October 19, 2011