One-pot synthesis of 5-fluoroalkyl-5-hydroxy-4-hydroxyimino-1- isonicotinoyl-4,5-dihydro-1H-pyrazoles and their tuberculostatic activity

Article abstract of DOI:10.1134/S1070428011060121

5-Fluoroalkyl-5-hydroxy-4-hydroxyimino-1-isonicotinoyl-4, 5-dihydro-1H-pyrazoles were synthesized via a one-pot procedure from polyfluoroalkyl-containing 1,3-diketones, sodium nitrite in acetic acid, and isoniazid. Acetylacetone gave rise to 3-hydroxyimin

Full text of DOI:10.1134/S1070428011060121

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 6, pp. 904–909. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © O.G. Khudina, Ya.V. Burgart, V.I. Saloutin, M.A. Kravchenko, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47,
No. 6, pp. 887–892.
One-Pot Synthesis of 5-Fluoroalkyl-5-hydroxy-4-hydroxy-
imino-1-isonicotinoyl-4,5-dihydro-1H-pyrazoles
and Their Tuberculostatic Activity
O. G. Khudinaa, Ya. V. Burgartb, V. I. Saloutina, and M. A. Kravchenkob
a Postovskii Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences,
ul. Akademicheskaya/S. Kovalevskoi 22/20, Yekaterinburg, 620990 Russia
e-mail: saloutin@ios.uran.ru
b Federal State Enterprise “Ural Research Institute of Phthisiopulmonology, Russian Medical Technologies,”
Yekaterinburg, Russia
Received August 30, 2010
Abstract—5-Fluoroalkyl-5-hydroxy-4-hydroxyimino-1-isonicotinoyl-4,5-dihydro-1H-pyrazoles were synthe-
sized via a one-pot procedure from polyfluoroalkyl-containing 1,3-diketones, sodium nitrite in acetic acid, and
isoniazid. Acetylacetone gave rise to 3-hydroxyiminopentane-2,4-dione monoisonicotinoylhydrazone which
underwent intramolecular cyclization to 5-hydroxy-4-hydroxyimino-1-isonicotinoyl-3,5-dimethyl-4,5-dihydro-
1H-pyrazole on heating in ethanol. The synthesized compounds exhibited moderate tuberculostatic activity.
DOI: 10.1134/S1070428011060121
Clinical efficiency of antitubercular agents is esti-
mated by their bacteriostatic activity, compatibility
with other medicines, the ability to penetrate into af-
fected organ and selectively act against mycobacteria,
and tolerance. Isoniazid is the most efficient antituber-
cular drug which is active against rapidly replicating
M. tuberculosis. Other drugs of this group, such as
ftivazide, metazide, and opiniazide, are derivatives of
isonicotinic acid hydrazide. The mechanism of action
of these compounds is based on inhibition of synthesis
of mycolic acids that are components of cell walls of
bacteria. Other microorganisms and macroorganism
cells contain no mycolic acids, which explains high
selectivity of isonicotinic acid derivatives. However,
these antitubercular drugs are characterized by a num-
ber of side effects. They affect liver and central nerv-
ous, cardiovascular, and endocrinous systems and
induce local allergic reactions [1, 2]. Taking the above
stated into account, an important problem is search for
new efficient and low-toxic tuberculostatic drugs struc-
turally and pharmacologically similar to those used in
medical practice.
4-nitroso-5-phenyl-3-trifluoromethyl-1H-pyrazole
which inhibited growth of a laboratory strain of
M. tuberculosis at a concentration of 0.36 μg/ml [3].
With a view to obtain new antitubercular agents, in
the present work we synthesized isonicotinic acid
hydrazide derivatives containing a 4-hydroxyimino-
4,5-dihydro-1H-pyrazole fragment. For this purpose,
polyfluoroalkyl-containing 1,3-diketones Ia–If were
treated with sodium nitrite in acetic acid, and interme-
diate hydroxyimino derivatives without isolation re-
acted with isoniazid (II) to give compounds IIIa–IIIf
(Scheme 1). The products may be assigned the struc-
ture of isomeric open-chain hydroxyimino hydrazones
HH and HH′ or cyclic dihydropyrazoles P and P′.
Apart from structural isomerism, compounds IIIa–IIIf
could give rise to nitroso–hydroxyimino tautomerism,
and the presence of exocyclic C=N bond in hydroxy-
imino tautomers makes Z,E isomerism possible as
well. Therefore, it was necessary to determine the
structure of the isolated compounds.
The molecular and crystalline structures of com-
pound IIIf were determined by X-ray analysis. Mole-
cule IIIf in crystal has cyclic structure P (5-hydroxy-4-
hydroxyimino-1-isonicotinoyl-3-methyl-5-nonafluoro-
We previously synthesized 4-nitroso-3-trifluoro-
methylpyrazoles which showed a fairly high tuberculo-
static activity. Among these, the most efficient was
904

ONE-POT SYNTHESIS OF 5-FLUOROALKYL-5-HYDROXY-4-HYDROXYIMINO-...
905
Scheme 1.
H
N
O
O
R1
NOH
O
R1 = AlkF
N
N
NH2
N
R2
H
N
IIIa–IIIg
NOH
O
II
O
O
NaNO2, AcOH, 10°C
H2O
R1
R2
EtOH, 78°C
O
R1
R2
O
Ia–Ig
O
H
H
O
N
N
N
R1 = Me
N
Me
Me
IV
I, III, R1 = CF3, R2 = Me (a), CF3 (b), Ph (c), t-Bu (d); R1 = C3F7, R2 = Ph (e); R1 = C4F9, R2 = Me (f); R1 = R2 = Me (g).
butyl-4,5-dihydro-1H-pyrazole, see figure). The car-
bonyl group in the isonicotinoyl fragment and hydroxy
group attached to the sp3-carbon atom are rigidly
fixed by intramolecular hydrogen bond [O3···H2O2
2.16(2) Å, ∠O2H2O3 131(1)°]. According to the X-ray
diffraction data, compound IIIf in crystal exists as
a mixture of E and Z isomers with respect to the exo-
cyclic C=N bond at a ratio of 75:25. Molecules IIIf
are linked to chains along the crystallographic a axis
via strong intermolecular hydrogen bonds between
protons in the hydroxyimino groups and nitrogen
atoms in the pyridine rings [N4···H1O1 1.92(1) and
1.69(1) Å for the E and Z isomers, respectively].
NMR spectra of compound IIIf in DMSO-d6 all
signals were doubled, indicating the presence of E and
Z isomers at a ratio of 87:13. The largest difference in
1
the H chemical shifts was observed for the methyl
protons, δ 2.30 and 2.04 ppm for the E and Z isomers,
respectively. Signals from proton in the hydroxyimino
group appeared at δ 8.75 and 8.89 ppm, and proton
in the 5-hydroxy group resonated at δ 13.15 and
13.25 ppm due to intramolecular hydrogen bonding.
19
In the F NMR spectrum, almost all signals from
fluorine atoms in the nonafluorobutyl group (which is
linked to asymmetric carbon atom) appear as AB spin
systems due to their nonequivalence.
The IR spectrum of a crystalline sample of com-
pound IIIf contains an absorption band at 1650 cm–1
due to stretching vibrations of the carbonyl group and
two absorption bands at 2655 and 3350 cm–1 due to
The IR spectra of crystalline samples of compounds
IIIa–IIIe were similar to that of IIIf. Characteristic
absorption bands are those belonging to stretching
vibrations of two hydroxy groups (3395–3330 and
2665–2530 cm–1), one carbonyl group (1695–
1
vibrations of two hydroxy groups. In the H and 19F
O
O
H
H
O
O
O
O
R1
R2
O
H
O
H
H
O
N
N
N
H
O
N
N
N
NOH
NOH
N
N
N
N
O
N
N
N
N
R1
R2
R2
R1
R2
R1
HH
HH'
P, IIIa–IIIg
P'
H
N
H
N
H
O
O
O
O
O
R1
R1
R1
OH
N
N
N
N
OH
O
N
N
HN
N
N
N
R2
R2
R2
E-HI-P
Z-HI-P
N-P
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 6 2011

KHUDINA et al.
F8
906
F6
substituted compound IIIa protons in the methyl group
F9
C4
F2
resonated in the same region (δ 2.29 ppm) as those
in the E isomer of nonafluorobutyl derivative IIIf
(δ 2.3 ppm). Taking into account these findings, as
well as similarity of the chemical shifts of fluorine
nuclei in the CF3 groups of compounds IIIa–IIId, we
concluded that trifluoromethyl-substituted dihydropyr-
azoles IIIa–IIId in DMSO-d6 exist as E isomer. On
the other hand, the chemical shifts of the α-fluorine
nuclei in the 19F NMR spectrum of heptaftluoropropyl-
substituted derivative IIIe were similar to those found
for the Z isomer of nonafluorobutyl-substituted analog
IIIf. Thus the formation of Z isomer is favored by the
presence of bulky phenyl and polyfluoroalkyl substit-
uents (compound IIIe), whereas a combination of
methyl and polyfluoroalkyl groups in dihydropyrazole
IIIf provides the possibility for formation of both
E and Z isomers. Dihydropyrazoles having a “short”
trifluoromethyl group exist preferentially as E isomers,
regardless of the nature of the R2 substituent.
F5
F1
F3
C3
C2
C1
F7
F4A
O3
O2
F3A
F4
N3
C13
O1A
C8
C5
C6
N1
C14
C7
N4
C10
N3A
C12
C11
C9
O1
N2
Structure of the molecule of (5-hydroxy-4-hydroxyimino-3-
methyl-5-nonafluorobutyl-4,5-dihydro-1H-pyrazol-1-yl)(pyr-
idin-4-yl)methanone (IIIf) according to the X-ray diffraction
data. Population of the N3, O1, F3, and F4 atoms in the E
isomer is 0.75; population of the N3A, O1A, F3A, and F4A atoms
in the Z isomer is 0.25.
For comparison, we performed one-pot reaction of
nonfluorinated acetylacetone (Ig) with sodium nitrite
in acetic acid and isoniazid (II) (Scheme 1). As
a result, we isolated compound IV which displayed in
the IR spectrum two strong absorption bands at 1715
and 1670 cm–1. These bands are likely to belong to two
carbonyl groups in the acetyl and isonicotinoyl frag-
ments. The 1H NMR spectrum of IV in DMSO-d6 con-
tained two sets of signals due to the presence of two
isomers of 3-hydroxyiminopentane-2,4-dione mono-
isonicotinoylhydrazone (IV) at a ratio of 64:36. How-
ever, we failed to reliably determine the isomer com-
position of compound IV on the basis of the above
data because of the presence of two C=N bonds in its
molecule.
1650 cm–1), and C=N, C=C, and C–F bonds (see Ex-
perimental). These data suggest that all compounds
IIIa–IIIf in crystal have cyclic structure P. Com-
pounds IIIa–IIIf in solution were studied by NMR
spectroscopy. The cyclic structure of IIIa (P) was
confirmed by the 13C NMR spectrum in DMSO-d6,
which contained a quartet at δC 88 ppm due to carbon
atom linked to the trifluoromethyl substituent; such
signal is typical of sp3-hybridized quaternary carbon
atom [4]. The 19F NMR spectra of IIIa–IIIf in
DMSO-d6 are also indicative of their cyclic structure
P. The chemical shifts of fluorine nuclei (δF ~84.24–
84.92 ppm) in the trifluoromethyl groups of IIIa–IIId
are typical of CF3 group linked to a quaternary carbon
atom [3]. Diastereotopic fluorine atoms in the α-posi-
tion of the heptafluoropropyl substituent in compound
IIIe gave rise to an AB system due to the presence of
neighboring asymmetric carbon atom (see Experi-
mental).
Hydrazone IV underwent intramolecular cycliza-
tion to dihydropyrazole IIIg without elimination of
water molecule on heating in boiling ethanol over
a period of 1 h (Scheme 1). The cyclic structure of
compound IIIg was confirmed by the IR spectrum
which contained only one carbonyl absorption band at
Thus all dihydropyrazoles IIIa–IIIg exist as hy-
droxyimino tautomer HI-P, as follows from similarity
of their spectral parameters. Only compound IIIf
having a nonafluorobutyl substituent was found to
exist as a mixture of Z and E isomers with respect to
the exocyclic C=N bond.
13
1
1655 cm–1. In the C and H NMR spectra of IIIg in
DMSO-d6 we observed two sets of signals corre-
sponding to E and Z isomers at a ratio of 62 :38.
Compound IIIg displayed in the 13C NMR spectrum
signals at δC 88.26 and 87.59 ppm due to sp3-carbon
atom, which is consistent with cyclic structure of both
isomers. The E and Z isomers of IIIg are characterized
by the largest differences in the chemical shifts of
protons and carbon nuclei in the methyl groups, as well
Dihydropyrazoles IIIa–IIIf were assigned the
structure of Z or E isomer on the basis of the NMR
1
data. In the H NMR spectrum of trifluoromethyl-
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ONE-POT SYNTHESIS OF 5-FLUOROALKYL-5-HYDROXY-4-HYDROXYIMINO-...
907
1
as in the chemical shifts of C3 and C4. The observed
signals were assigned to the E and Z isomers, taking
into account that signals of the 3-methyl group in the
NMR spectra of the Z isomer of IIIf are located in
a stronger field relative to the corresponding signals of
the E isomer.
376 MHz for H, 13C, and 19F, respectively; the
chemical shifts were determined relative to SiMe4
(1H, 13C) or C6F6 (19F). The elemental compositions
were determined using a Perkin–Elmer 2400 Series II
analyzer.
A single crystal of compound IIIf suitable for
X-ray analysis was grown from a solution in ethanol.
The X-ray diffraction data were acquired at 150(2) Κ
on an Xcalibur 3 CCD diffractometer [λ(MoΚα)
0.71073 Å, graphite monochromator, ω-scanning]. The
structure was solved by the direct method with subse-
quent Fourier syntheses using SHELXS-97 software
[5] and was refined by the least-squares procedure in
full-matrix anisotropic approximation for all non-hy-
drogen atoms (SHELXL-97) [5]. The O2H hydrogen
atom was localized by the direct method, and its posi-
tion was refined independently in isotropic approxima-
tion. The other hydrogen atoms were placed into
positions calculated on the basis of geometry consider-
ations and were refined according to the riding model
in isotropic approximation with dependent thermal
parameters.
Analysis of the experimental data obtained in the
present work allowed us to presume that polyfluoro-
alkyl-substituted dihydropyrazoles IIIa–IIIf are also
formed through intermediate hydroxyimino hydra-
zones HH and that the presence in the latter of elec-
tron-withdrawing polyfluoroalkyl groups facilitates
their cyclization to dihydropyrazoles as compared to
fluorine-free analog IV.
We also made an attempt to effect dehydration of
compound IIIg by heating in anhydrous ethanol or
benzene. However, we failed to isolate the expected
pyrazole due to formation of a large amount of decom-
position products. Trifluoromethyl-substituted deriva-
tive IIIc remained unchanged under analogous condi-
tions. The observed stability of dihydropyrazole IIIc
toward dehydration may be explained by the presence
of electron-withdrawing polyfluoroalkyl group which
hampers elimination of water molecule.
Crystallographic data for compound IIIf.
C14H9F9N4O3, M 452.25; triclinic crystal system, space
group P-1; unit cell parameters; a = 7.1378(5), b =
10.3990(7), c = 12.6243(11) Å; α = 81.692(7), β =
82.860(7), γ = 81.408(6)°; V = 911.75(12) Å3; Z = 2;
dcalc = 1.647 g/cm3; μ = 0.177 mm–1. Total of 5215 re-
flection intensities were measured, 4460 of which were
independent, and 3112 reflections were characterized
by I > 2σ(I). Number of refined parameters 312, scan
range θ 2.74–28.28°, spherical segment –8 ≤ h ≤ 9,
–10 ≤ k ≤ 13, –16 ≤ l ≤ 16; R1 = 0.0550 for reflections
with I > 2σ(I). The complete set of crystallographic
data for compound IIIf was deposited to the Cam-
bridge Crystallographic Data Centre (entry no. CCDC
782879) and is available at www.ccdc.cam.ac.uk/conts/
retrieving.html (CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; e-mail: deposit@ccdc.cam.ac.uk).
Tuberculostatic activity of compounds IIIa, IIIc,
and IV was evaluated in vitro against H37Rv labora-
tory strain of M. tuberculosis using isoniazid as refer-
ence. The minimal inhibitory concentration (MIC) of
the latter is 0.15 μg/ml. Trifluoromethyl-substituted
dihydropyrazole IIIa and fluorine-free hydrazone IV
showed a moderate antitubercular activity, the minimal
inhibitory concentration being 1.56 μg/ml. Replace-
ment of methyl group in position 3 of the pyrazole ring
by phenyl reduces tuberculostatic activity: dihydropyr-
azole IIIc inhibited growth of M. tuberculosis at
a concentration of 3.12 μg/ml. Previously synthesized
4-hydroxyimino-3-methyl-1-phenyl-5-trifluoromethyl-
4,5-dihydro-1H-pyrazol-5-ol [3] showed an MIC value
of 3.12 μg/ml, i.e., it is twice as weak as dihydropyr-
azole IIIa having an isonicotinoyl substituent in
position 1 instead of phenyl.
The newly synthesized compounds were tested for
tuberculostatic activity using the vertical diffusion
technique on a Novaya solid nutrient medium.
An H37Rv laboratory strain was inoculated. The culture
was weighed using a torsion balance, and a 10-mg
sample was placed into a porcelain mortar, thoroughly
ground, and dispersed to achieve a concentration of
108 bacteria per milliliter using a turbidity standard.
A 0.2-ml portion of the resulting suspension was
inoculated onto a nutrient in a test tube containing
5.0 ml of a solution of a compound to be tested with a
required concentration. Solutions of compounds with
EXPERIMENTAL
The metling points were determined in open capil-
laries using a Stuart SMP30 melting point apparatus.
The IR spectra were recorded in the range from 400 to
4000 cm–1 on a Perkin–Elmer Spectrum One spectrom-
eter with Fourier transform, equipped with a diffuse
reflectance probe. The NMR spectra were measured on
a Bruker DRX-400 spectrometer at 400, 125, and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 6 2011

KHUDINA et al.
908
concentrations of 5.0, 2.5, 1.25, 0.6, 0.3, and
0.15 μg/ml were prepared by successive dilution. The
test tube was incubated for 7–10 days at 37°C [6].
Three parallel runs were performed with each con-
centration.
mp 180–181°C (decomp.). IR spectrum, ν, cm–1: 3330,
2645 (OH); 1680 (C=O); 1645, 1610, 1560, 1520,
1
1500 (C=N, C=C); 1180–1200 (C–F). H NMR spec-
trum (DMSO-d6), δ, ppm: 7.38–7.56 m (5H, Ph), 7.60–
7.61 m (2H, 2-H, 6-H), 8.73–8.74 m (2H, 3-H, 5-H),
8.98 s (1H, OH), 13.33 s (1H, OH). 19F NMR spectrum
(DMSO-d6): δF 84.87 ppm, s (CF3). Found, %: C 52.6;
H 3.14; F 15.20; N 15.26. C16H11F3N4O3. Calculated,
%: C 52.75; H 3.04; F 15.65; N 15.38.
Compounds IIIa–IIIf and IV (general procedure).
A solution of 1 g of sodium nitrite in 5 ml of water was
added dropwise under stirring at 8–12°C to a mixture
of 12.5 mmol of 1,3-diketone Ia–Ig and 4 ml of glacial
acetic acid. The mixture was stirred for 20 min, and
a solution of 12.5 mmol of pyridine-4-carbohydrazide
in 5 ml of water was added at room temperature (in the
synthesis of compound IIIb, on cooling to 8–10°C). If
intermediate hydroxyimino derivative separated from
the solution, ethanol was added to dissolve it. The
mixture was stirred until the reaction was complete,
and the precipitate was filtered off and recrystallized
from ethanol.
(3-tert-Butyl-5-hydroxy-4-hydroxyimino-5-tri-
fluoromethyl-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-
4-yl)methanone (IIId). Yield 47% (reprecipitation
from ethanol with water), white powder, mp 186–
187°C (decomp.). IR spectrum, ν, cm–1: 2635, 3390
(OH); 1675 (C=O); 1500, 1510, 1560, 1610 (C=N,
1
C=C); 1160–1200 (C–F). H NMR spectrum
(DMSO-d6), δ, ppm: 1.22 s (9H, t-Bu), 7.54–7.55 m
(2H, 2-H, 6-H), 8.71–8.72 m (3H, 3-H, 5-H, OH),
13.55 s (1H, OH). 19F NMR spectrum (DMSO-d6):
δF 84.24 ppm, s (CF3). Found, %: C 48.94; H 4.28;
F 16.05; N 16.09. C14H15F3N4O3. Calculated, %:
C 48.84; H 4.39; F 16.55; N 16.27.
(5-Hydroxy-4-hydroxyimino-3-methyl-5-tri-
fluoromethyl-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-
4-yl)methanone (IIIa). Yield 82%, white powder,
mp 190–191°C (decomp.). IR spectrum, ν, cm–1: 3355,
2665 (OH); 1650 (C=O); 1600, 1580, 1550, 1515
(5-Heptafluoropropyl-5-hydroxy-4-hydroxy-
imino-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(pyri-
din-4-yl)methanone (IIIe). Yield 58%, white powder,
mp 177–178°C (decomp.). IR spectrum, ν, cm–1: 2655,
3350 (OH); 1695 (C=O); 1490, 1550, 1610, 1655
1
(C=N, C=C); 1165–1185 (C–F). H NMR spectrum
(DMSO-d6), δ, ppm: 2.29 s (3H, Me), 7.50–7.51 d (2H,
2-H, 6-H), 8.72 br.s (2H, 3-H, 5-H), 8.80 s (1H, OH),
13.23 s (1H, OH). 13C NMR spectrum (DMSO-d6), δC,
ppm: 16.66 (Me), 88.03 q (C5′, J = 35 Hz), 121.9 q
(CF3, J = 287 Hz), 122.42 m (C2, C6), 142.32 (C4),
144.29 (C3′), 149.53 (C4′), 149.74 (C3, C5), 164.24
(C=O). 19F NMR spectrum (DMSO-d6): δF 84.92 ppm,
s (CF3). Found, %: C 43.74; H 3.17; F 18.70; N 18.38.
C11H9F3N4O3. Calculated, %: C 43.72; H 3.00;
F 18.86; N 18.54.
1
(C=N, C=C); 1175–1220 (C–F). H NMR spectrum
(DMSO-d6), δ, ppm: 7.45–7.57 m (5H, Ph), 7.81–
7.83 m (2H, 2-H, 6-H), 8.75–8.76 m (2H, 3-H, 5-H),
8.97 br.s (1H, OH), 13.38 br.s (1H, OH). 19F NMR
spectrum (DMSO-d6), δF, ppm: 36.81–36.83 m (2F,
β-CF2), 50.74 m (2F, α-CF2, AB system, Δν = 2.04,
2J = 279 Hz), 82.61 t (3F, CF3, 3J = 11 Hz). Found, %:
C 46.64; H 2.20; F 28.97; N 12.01. C18H11F7N4O3.
Calculated, %: C 46.56; H 2.39; F 28.64; N 12.07.
[5-Hydroxy-4-hydroxyimino-3,5-bis(trifluoro-
methyl)-4,5-dihydro-1H-pyrazol-1-yl](pyridin-4-yl)-
methanone (IIIb). Yield 51% (reprecipitation from
ethanol with water), white powder, mp 161–162°C
(decomp.). IR spectrum, ν, cm–1: 3395, 2530 (OH);
1690 (C=O); 1500, 1530, 1560, 1575, 1605, 1645
(5-Hydroxy-4-hydroxyimino-3-methyl-5-nona-
fluorobutyl-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-
4-yl)methanone (IIIf) (a mixture of E and Z isomers
at a ratio of ~87:13). Yield 60%, white powder,
mp 183–184°C (decomp.). IR spectrum, ν, cm–1: 3360,
3045, 2645 (OH); 1650 (C=O); 1610, 1560, 1500
1
(C=N, C=C); 1165–1200 (C–F). H NMR spectrum
(DMSO-d6), δ, ppm: 7.56–7.58 m (2H, 2-H, 6-H),
8.76–8.78 m (2H, 3-H, 5-H), 9.43 s (1H, OH), 14.01 s
(1H, OH). 19F NMR spectrum (DMSO-d6), δF, ppm:
84.56 s (3F, CF3), 98.25 s (3F, CF3). Found, %:
C 37.06; H 1.81; F 31.67; N 15.44. C11H6F6N4O3. Cal-
culated, %: C 37.09; H 1.7; F 32.0; N 15.73.
1
(C=N, C=C); 1150–1215 (C–F). H NMR spectrum
(DMSO-d6), δ, ppm: E isomer: 2.30 s (3H, Me), 7.45–
7.47 m (2H, 2-H, 6-H), 8.71–8.72 m (2H, 3-H, 5-H),
8.89 s (1H, OH), 13.25 s (1H, OH); Z isomer: 2.04 s
(3H, Me), 7.44–7.45 m (2H, 2-H, 6-H), 8.70–8.71 m
(2H, 3-H, 5-H), 8.75 s (1H, OH), 13.15 s (1H, OH).
(5-Hydroxy-4-hydroxyimino-3-phenyl-5-tri-
fluoromethyl-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-
4-yl)methanone (IIIc). Yield 54%, white powder,
19F NMR spectrum (DMSO-d6), δ, ppm: E isomer:
2
36.97 m (2F, γ-CF2, AB system, Δν = 2.06, JFF
=
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ONE-POT SYNTHESIS OF 5-FLUOROALKYL-5-HYDROXY-4-HYDROXYIMINO-...
909
291 Hz), 40.72 m (2F, β-CF2, AB system, Δν = 0.86,
2JFF = 297 Hz), 45.69 m (2F, α-CF2, AB system, Δν =
OH). 13C NMR spectrum (DMSO-d6), δC, ppm:
E isomer: 16.93 and 24.44 (Me), 88.26 (C5′), 122.54
(C2, C6), 142.82 (C4), 144.13 (C3′), 149.52 (C3, C5),
154.6 (C4′), 163.76 (C=O); Z isomer: 11.57 and 19.95
(Me), 87.59 (C5′), 122.46 (C2, C6), 143.11 (C4), 148.96
(C3′), 149.49 (C3, C5), 156.33 (C4′), 163.14 (C=O).
Found, %: C 53.07; H 4.62; N 22.33. C11H12N4O3. Cal-
culated, %: C 53.22; H 4.87; N 22.57.
2
3
6.39, JFF = 280 Hz), 82.34 t (3F, CF3, J = 9 Hz);
Z isomer: 37.25 m (2F, γ-CF2, AB system, Δν = 1.16,
2JFF = 289 Hz), 39.86–39.98 m (2F, β-CF2), 51.18 m
2
(2F, α-CF2, AB system, Δν = 1.89, JFF = 281 Hz),
3
82.34 t (3F, CF3, J = 9 Hz). Found, %: C 37.17;
H 2.14; F 37.74; N 12.45. C14H9F9N4O3. Calculated,
%: C 37.18; H 2.01; F 37.81; N 12.39.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 09-03-00 274a), by the state contract
no. 02.740.11.0260, by the Integration Project for
Basic Research at the Ural Division of the Russian
Academy of Sciences “Scientific Principles of the
Design and Development of Medicines of Natural and
Synthetic Origin” (project no. 09-I-3-2004), and by the
Program for State Support of Leading Scientific
Schools (project no. NSh-65261.2010.3).
N′-(3-Hydroxyimino-4-oxopentan-2-ylidene)pyr-
idine-4-carbohydrazide (IV) (a mixture of isomers at
a ratio of ~64:36). Yield 62%, white powder, mp 173–
174°C (decomp.). IR spectrum, ν, cm–1: 3190, 2715,
1555 (NH, OH); 1715 (C4′=O); 1670 (4-C=O); 1605,
1
1500, 1480 (C=N, C=C). H NMR spectrum
(DMSO-d6), δ, ppm: E isomer: 2.17 s and 2.30 s
(3H each, Me), 7.75 br.s (2H, 2-H, 6-H), 8.76 br.s (2H,
3-H, 5-H), 11.16 s and 12.10 s (1H each, NH, OH);
Z isomer: 1.93 s and 2.10 s (3H each, Me), 7.45 br.s
(2H, 2-H, 6-H), 8.64 br.s (2H, 3-H, 5-H), 11.5 br.s
(2H, NH, OH). Found, %: C 53.13; H 4.68; N 22.48.
C11H12N4O3. Calculated, %: C 53.22; H 4.87; N 22.57.
REFERENCES
1. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
Moscow: Meditsina, 1993, vol. 2, p. 367.
(5-Hydroxy-4-hydroxyimino-3,5-dimethyl-4,5-di-
hydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanone
(IIIg) (a mixture of E and Z isomers at a ratio of
~62:38). A mixture of 100 mg of compound IV and
10 ml of ethanol was heated for 1 h under reflux. The
precipitate was filtered off and washed with hot
chloroform. Yield 83%, white powder, mp 166–167°C
(decomp.). IR spectrum, ν, cm–1: 3260, 2785 (OH);
1655 (C=O); 1620, 1605, 1555, 1500 (C=N, C=C).
1H NMR spectrum (DMSO-d6), δ, ppm: E isomer:
1.86 s and 2.28 s (3H each, Me), 7.18 s (1H, OH),
7.51–7.53 m (2H, 2-H, 6-H), 8.68–8.69 m (2H, 3-H,
5-H), 12.29 s (1H, OH); Z isomer: 1.97 s and 2.07 s
(3H each, Me), 7.17 s (1H, OH), 7.50–7.51 m (2H,
2-H, 6-H), 8.67–8.68 m (2H, 3-H, 5-H), 12.25 s (1H,
2. Khomenko, A.G., Averbakh, M.M., and Aleksandro-
va, A.V., Tuberkulez organov dykhaniya (Tuberculosis of
Respiratory Apparatus), Khomenko, A.G., Ed., Moscow:
Meditsina, 1988.
3. Khudina, O.G., Burgart, Ya.V., Saloutin, V.I., and Krav-
chenko, M.A., Izv. Ross. Akad. Nauk, Ser. Khim., 2010,
p. 1917.
4. Khudina, O.G., Shchegol’kov, E.V., Burgart, Y.V., Ko-
dess, M.I., Saloutin, V.I., and Chupakhin, O.N., Hetero-
cycles, 2006, vol. 68, p. 2515.
5. Scheldrik, G.M., SHELXS 97, SHELXL 97, Göttingen,
Germany: University of Göttingen, 1997.
6. Vasilev, V.N., Mikobakteriozy i mikozy legkikh (Pul-
monary Mycobacteriosis and Mycosis), Sofia: Meditsina
i Fizkul’tura, 1971, p. 377.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 6 2011