One-pot synthesis of trifluoromethyl-and nitroso-substituted pyrazolines and pyrazoles and their tuberculostatic activity

Article abstract of DOI:10.1007/s11172-010-0341-7

3-Trifluoromethyl-substituted 4-nitrosopyrazolines and 4-nitrosopyrazoles were prepared by a one-pot synthesis from trifluoromethyl-containing 1,3-diketones, sodium nitrite in acetic acid, and hydrazines (hydrazine hydrate, methylhydrazine). 3-Trifluorome

Full text of DOI:10.1007/s11172-010-0341-7

Russian Chemical Bulletin, International Edition, Vol. 59, No. 10, pp. 1967—1973, October, 2010
1967
Oneꢀpot synthesis of trifluoromethylꢀ and nitrosoꢀsubstituted
pyrazolines and pyrazoles and their tuberculostatic activity
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,
50 ul. XXII Parts´ezda, 620039 Ekaterinburg, Russian Fedetation,
Fax: +7 (343) 333 4463. Eꢀmail: kravchenko@nexcom.ru
3ꢀTrifluoromethylꢀsubstituted 4ꢀnitrosopyrazolines and 4ꢀnitrosopyrazoles were prepared
by a oneꢀpot synthesis from trifluoromethylꢀcontaining 1,3ꢀdiketones, sodium nitrite in acetic
acid, and hydrazines (hydrazine hydrate, methylhydrazine). 3ꢀTrifluoromethylpyrazolines can
be converted to pyrazoles on heating. The use of phenylhydrazine in these reactions led to the
formation of regioisomeric 4ꢀhydroxyiminoꢀ5ꢀ(trifluoromethyl)pyrazoline. The structure of
heterocycles synthesized was established using Xꢀray diffraction study, 1H and 19F NMR specꢀ
troscopy. The obtained products exhibited considerable tuberculostatic activity.
Key words: 4ꢀnitrosopyrazoline, 4ꢀnitrosopyrazole, 1,3ꢀdiketone, hydrazine, tuberculoꢀ
static activity.
Intensive development of drug resistance in the tuberꢀ
Scheme 1
culosis micobacteria,1 as well as toxic and side effects of
known antituberculosis medicines,2 indicate a necessity to
develop new efficient antituberculosis drugs, differing from
the tuberculostatics used in practice in chemical structure
and mechanism of action. 4ꢀNitrosopyrazoles are known3
for their high fungicide and antibacterial activity, however,
there is no information on their tuberculostatic activity.
A possibility to synthesize nonfluorinated 4ꢀnitrosopyꢀ
razoles from acetylacetone, sodium nitrite, hydrochloric
acid, and hydrazines in one step without isolation of the
intermediate 3ꢀhydroxyiminoꢀsubstituted acetylacetone is
shown in Ref. 4. The present work is devoted to a oneꢀpot
synthesis of trifluoromethylꢀsubstituted derivatives of
4ꢀnitrosopyrazole from 1,3ꢀdiketones and the study of their
antituberculosis activity. Earlier,5 4ꢀnitrosoꢀ5ꢀphenylꢀ3ꢀ
trifluoromethylꢀ1Hꢀpyrazole has been obtained by us from
4,4,4ꢀtrifluoroꢀ2ꢀhydroxyiminoꢀ1ꢀphenylꢀ1,3ꢀbutanediꢀ
one by the reaction with hydrazine hydrate in ethanol.
However, it has not been determined whether it had niꢀ
trosoꢀ or hydroxyimine structure.
It was found that trifluoromethylꢀsubstituted 1,3ꢀdiꢀ
ketones 1a,b upon treatment with sodium nitrite in acetic
1, 2: R1 = Me (a), Ph (b)
3: R2 = H (a), Me (b)
acid without isolation of the intermediate oxime 2 form
with hydrazines 3a,b mixtures of pyrazolines 4a—c and
pyrazoles 5a—c (Scheme 1). The reaction of trifluoroꢀ
acetylacetone 1a with hydrazine hydrate 3a predominantꢀ
ly furnishes pyrazoline 4a, whereas in the reaction of
1,3ꢀdiketones 1a,b with methylhydrazine 3b, pyrazoles 5b,c
4, 5: R1 = Me, R2 = H (a), R1 = R2 = Me (b), R1 = Ph, R2 = Me (c),
R
1 = Ph, R2 = H (d)
are the predominant products. Trifluoromethylꢀsubstitutꢀ
ed diketone 1b reacts with sodium nitrite and hydrazine
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1917—1923, October, 2010.
1066ꢀ5285/10/5910ꢀ1967 © 2010 Springer Science+Business Media, Inc.

1968
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
Khudina et al.
hydrate 3a to give only pyrazoline 4d, which on heating at
90 °C virtually completely undergoes dehydration to form
pyrazole 5d in 98% yield (see Experimental). It turned out
that 5ꢀMeꢀsubstituted pyrazoline 4a on heating at 90 °C
undergoes dehydration with partial decomposition, thereꢀ
fore, pyrazole 5a was obtained in moderate yield (62%)
after additional purification by column chromatography.
Unlike convertions of trifluoromethylꢀcontaining 1,3ꢀdiꢀ
ketones, reactions of acetylacetone with sodium nitrite
and hydrazines led to the exclusive formation of pyrazoles.4
A possibility of isolation of pyrazolines 4 is due to the
presence of electronꢀwithdrawing trifluoromethyl group
in these compounds, which hinders easy elimination of
the water molecule.
Apparently, under conditions of the oneꢀpot synthesis
nitrosation of 1,3ꢀdiketone 1a,b takes place initially with
the intermediate formation of the corresponding 2ꢀhydroꢀ
xyiminoꢀ1,3ꢀdiketone 2 (see Scheme 1) followed by cycloꢀ
condensation of oximes 2a,b with hydrazines 3a,b to yield
pyrazole derivatives 4 and 5.
Cyclocondensation of unsymmetric trifluoromethylꢀ
containing 1,3ꢀdiketones with substituted hydrazines can
lead to the formation of 3ꢀCF3ꢀ and 5ꢀCF3ꢀregioisomeric
pyrazoles or their mixture.
Regioisomeric and tautomeric structure of pyrazoles
5c,d was established by Xꢀray diffraction study, according
to which the crystal of compound 5d is formed by two
crystallographically independent molecules of 4ꢀnitrosoꢀ
3ꢀtrifluoromethylpyrazole with close geometrical paꢀ
rameters (Fig. 1). The independent molecules differ
in the turning angle of the phenyl substituent with reꢀ
spect to the plane of heterocycle: the torsional angles
C(2)—C(1)—C(7)—C(8) and C(6A)—C(1A)—C(7A)—C(8A)
are –30.28° and 31.94°, respectively. The molecules
are bound with each other by the system of intermolecular
hydrogen bonds (IHB) between the nitroso group and
the NH group of the heterocycle forming polymeric
chains (Table 1).
The Xꢀray study also confirms 3ꢀCF3ꢀregioisomeric
structure of pyrazole 5c (Fig. 2). The N(3)—O(1) bond disꢀ
tance is 1.245(2) Å, that is considerably shorter than the
C(3)—N(3) bond (1.406(2) Å) and corresponds to the double
N=O bond, therefore, pyrazole 5c exists in the nitroso form.
The nitroso group N(3)O(1) deviates from the plane of the
pyrazole ring by only 7.26(2)°, whereas the turn of the
phenyl substituent with respect to the pyrazole ring is sigꢀ
nificant and equal to 44.24(2)°. In the packing, molecules
of 5c are bound between each other by shortened contacts,
which exist between the O(1) oxygen atom of the nitroso
group and the hydrogen atom at position 6 (H(6A)) of the
phenyl ring of neighboring molecule (see Table 1).
Pyrazoles 5a,b are oily substances, therefore, to estabꢀ
lish their regioisomeric structures we compared the 1H and
19F NMR spectroscopic data of these products and pyrꢀ
azoles 5c,d, whose structure was established by Xꢀray difꢀ
fraction study.
Chemical shift of the signal for the pyrazole CF3 group
in the 19F NMR spectrum is characteristic for determinꢀ
ing its regioisomeric structure. Thus, in the 19F NMR
spectra of pyrazoles, the signals for the CF3 substituents in
the case of 3ꢀCF3 isomer are found at δF ≈ 101, whereas
the 5ꢀCF3ꢀpyrazoles have them at δF ≈ 105 (see Refs 6
and 7). Therefore, chemical shifts of the signals for the
CF3 groups (δF 98.79—100.6) in the 19F NMR spectra of
pyrazoles 5a—d indicate the 3ꢀCF3 regioisomeric strucꢀ
ture of these heterocyclic compounds.
F(3)
F(2)
F(1)
C(4A)
C(10)
C(5A)
C(6A)
C(9)
C(8)
O(1)
N(3)
N(1)
N(2)
C(3A)
C(1A)
C(7A)
N(3A)
C(2A)
C(7)
C(1)
O(1A)
F(1A)
H(2)
C(8A)
C(9A)
H(2A)
N(2A)
C(6)
C(2)
C(3)
N(1A)
C(10A)
F(3A)
C(4)
C(5)
F(2A)
Fig. 1. Two crystallographically independent molecules in the structure of pyrazole 5d. The dashed line shows the hydrogen bond.

3ꢀTrifluoromethylꢀ4ꢀnitrosopyrazoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
1969
Table 1. Characteristics of intermolecular hydrogen bonds (D—H...A) and short contacts (D...A) in the
crystal structure of heterocyclic compounds 5c,d and 6
Compound
D—H...A
d(D—H)
d(H...A)
ω/deg
d(D...A)/Å
Å
5c
5d
C(6A)—H(6А)...O(1)a
N(2)—H(2)...O(1A)
N(2)—H(2)...N(3A)
N(2A)—H(2A)...O(1)b
O(1)—H(1)...N(3)c
N(3)—H(3)...O(1)c
N(3)—H(3)...N(3)c
O(2)—H(2)...N(2)d
0.93
2.574
134.33
178.5(9)
155.4(9)
170(1)
144.36
143.05
110.61
171(1)
3.293(2)
2.795(2)
3.521(2)
2.831(2)
2.816(2)
2.816(2)
2.999(2)
2.871(2)
0.934(15)
0.934(15)
0.842(14)
0.820
0.860
0.860
1.861(15)
2.651(15)
1.998(14)
2.109
2.081
2.586
6
0.86(2)
2.02(2)
Note. The following signs are used: d is the bond lengths or interatomic distances, ω is the corresponding angles
D—H...A. Operation of symmetry: a [x + 1/2, –y + 1/2, z + 1/2]; b [x + 1, y, z + 1]; c [–x + 1, –y, –z + 2];
d [–x + 3/2, y + 1/2, –z + 3/2].
1
In the H and 19F NMR spectra of 4ꢀ(het)arylazoꢀ1ꢀ
indicates the presence of the Me group at position 5 of the
heterocycle.
methylꢀ3,5ꢀbis(trifluoromethyl)pyrazoles, the spinꢀspin
coupling was observed between the fluorine atoms of the
5ꢀCF3 group and the protons of the NMe fragment with
the spinꢀspin coupling constant 0.9—1.3 Hz and the fluorine
atoms of the 3ꢀCF3 group with the protons of the NMe
group with the spinꢀspin coupling constant 0—0.5 Hz.8
The singlet signals of the NMe and CF3 groups are obꢀ
1
Thus, the H and 19F NMR spectroscopic data conꢀ
firm the structure of 3ꢀCF3ꢀpyrazole for heterocycles 5a—d.
The structures of 3ꢀhydroxyꢀ4ꢀnitrosopyrazoline A,
5ꢀhydroxyꢀ4ꢀhydroxyiminopyrazoline B, and 3ꢀhydrꢀ
azonoꢀsubstituted ketone C can be assigned to the precurꢀ
sors of pyrazoles 5a—d, i.e., pyrazolines 4a—d, depending
on how they were formed (Scheme 2).
served in the H and 19F NMR spectra of pyrazoles 5b,c
1
that testifies in favor of 3ꢀCF3 isomer.
Scheme 2
In addition, regioisomeric structure of pyrazoles can
be inferred from the chemical shifts for the protons of the
CꢀMe groups in the 1H NMR spectra, since in 3ꢀMeꢀ
pyrazoles they are observed more upfield (δH 2.3) as
compared to the analogous signals in 5ꢀMeꢀpyrazoles
1
(δH 2.7).9 In the H NMR spectra of CꢀMeꢀcontaining
pyrazoles 5a,b synthesized by us, the singlet signals for the
Me groups are found in the region δH 2.76—2.88, that
C(9)
C(8)
O(1)
N(3)
C(10)
C(7)
C(6)
C(3)
C(2)
C(5)
C(4)
F(2)
H(6)
N(1)
C(1)
F(1)
Fig. 2. Molecular structure of pyrazole 5c.
F(3)
N(2)
C(11)

1970
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
Khudina et al.
The absence of the absorption band for the carbonyl
group in the IR spectra of pyrazolines 4a—d allowed us to
exclude the structure of 3ꢀhydrazonoꢀsubstituted ketone
C from our consideration. The choice between pyrazolines
A and B has been made based on the 19F NMR spectroꢀ
scopic data. Thus, the singlet signals for the fluorine atꢀ
oms in the region δF 82.6—87.44 characteristic of the CF3
group at the sp3ꢀhybridized carbon atom unambiguously
confirm the structure A for pyrazolines 4a—d.
Note that the NMR spectra of pyrazoline 4d obtained
from the phenylꢀsubstituted 1,3ꢀdiketone 1b and hydrꢀ
azine hydrate 3a exhibits two sets of signals in the ratio
74 : 26 (see Experimental). However, based on the availꢀ
able data, it is impossible to unambiguously establish
whether 4d is a mixture of hydroxyiminoꢀimine E
and nitrosoꢀamine D tautomers or a mixture of Zꢀ and
Eꢀisomers of the hydroxyiminoꢀimine E tautomer.
C(11)
C(10)
O(1)
N(3)
N(2)
N(1)
C(6)
C(9)
C(5)
C(4)
C(8)
H(2)
C(1)
C(2)
F(1)
C(7)
O(2)
C(3)
F(3)
F(2)
Fig. 3. Molecular structure of pyrazoline 6.
of 3c reacts regiospecifically at the less electrophilic acetyl
group of 1a giving 5ꢀCF3ꢀpyrazoline 6 (see Scheme 3).
Pyrazoline 6 upon heating to 130 °C does not undergo
dehydration, heating to higher temperatures leads to its
decomposition. Therefore, 5ꢀCF3ꢀpyrazoline 6 is more
stable to dehydration as compared to its regioisomeric
analogs 4.
We compared the results obtained by us with the reacꢀ
tions of methylhydrazine and phenylhydrazine with 2ꢀunꢀ
substituted trifluoromethylꢀcontaining 1,3ꢀdiketones studꢀ
ied earlier.6,10 The latter in ethanol give regioisomeric mixꢀ
tures of Nꢀmethyl(phenyl)pyrazoles or mixtures of 3ꢀCF3ꢀ
pyrazole and 5ꢀCF3ꢀpyrazoline. To increase regioselectivꢀ
ity and purposefully obtain 3ꢀCF3ꢀpyrazoles the authors
in Ref. 10 used fluorinated alcohols. We found that the
reaction of trifluoromethylꢀsubstituted 1,3ꢀdiketones conꢀ
taining hydroxyimine or (het)arylhydrazone8 substituent
at position 2 with hydrazines proceeds regiospecifically.
These reactions with methylhydrazine exclusively afford
3ꢀCF3ꢀpyrazoles, whereas reactions with phenylhydrazine
give 5ꢀCF3ꢀpyrazoline. Regiospecificity of the reactions
of such 2ꢀsubstituted analogs of trifluoromethylꢀcontainꢀ
ing 1,3ꢀdiketones with hydrazines, on our opinion, is exꢀ
plained by greater isolation of their reaction centers (carꢀ
bonyl groups), for which the Pearson principle of hard and
soft acids and bases (HSAB) becomes more applicable.11
The HSAB principle states that the more stable bond is
formed when a hard acid reacts with a hard base or a soft
acid with a soft base. At present, there is no strict qualitaꢀ
tive evaluation of acid and base hardness and softness.
They can be only approximately arranged in orders. For
example, the hardness of bases decreases in the order:
NH3 > RNH2 >> PhNH2 (see Ref. 11). This fact can be
explained by the change in polarizability of bases. It is
obvious that the hardness of bases used by us decreases in
the order NH2NH2 > MeNHNH2 >> PhNHNH2. To use
the HSAB theory in the analysis of reactivity, an assumpꢀ
tion is made that properties of electrophiles are analogous
When phenylhydrazine 3c is involved into the reaction
with trifluoroacetylacetone 1a, direction of the reaction
changes (Scheme 3).
Scheme 3
The structure of product 6 obtained in this reaction
was established by Xꢀray diffraction study, which indiꢀ
cates that it is 5ꢀCF3ꢀpyrazoline existing in the hydroxyꢀ
imine tautomeric form unlike 4ꢀnitrosopyrazolines 4
(Fig. 3). In particular, the C(9)—N(3) bond (1.263(2) Å)
is considerably shorter than the N(3)—O(1) bond
(1.391(2) Å) and corresponds to the double C=N bond.
Molecular packing of pyrazoline 6 has a number of IHB
between hydroxyimine fragments, as well as between nitroꢀ
gen N(2) of the pyrazoline ring and hydrogen of the hydrꢀ
oxy group O(2)H(2) (see Table 1). Since the proton of the
hydroxyimine group cannot be unambiguously localized,
it was used in the refinement with delocalization on the
N(3) and O(1) atoms in the geometrically calculated poꢀ
sitions with the population coefficients 0.5 with depenꢀ
dent thermal parameters.
It is obvious that upon the reaction of phenylhydrazine
3c with trifluoroacetylacetone 1a, the primary amino group

3ꢀTrifluoromethylꢀ4ꢀnitrosopyrazoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
1971
to the properties of acids, whereas properties of nucleoꢀ
philes to the properties of bases. Therefore, it is possible to
talk about hard and soft electrophiles and nucleophiles.
The hardness of the nucleophile acceptor atom depends
on the nature of neighboring groups, for example, BF3 is
a hard electrophile, while ВH3 is a soft electrophile.11
Similarly, the carbon atom of a carbonyl group bonded to
a trifluoromethyl substituent is more hard electrophile as
compared to the acceptor carbon atom of an acetyl and
benzoyl groups. Therefore, hydrazine hydrate 3a and meꢀ
thylhydrazine 3b, as hard nucleophiles, attack a hard elecꢀ
trophile, viz., trifluoroacetyl group of oxime 2, giving rise
to 3ꢀCF3ꢀregioisomers 4 and 5. Softer nucleophile, pheꢀ
nylhydrazine 3c, reacts stronger with softer electrophile,
viz., the acetyl fragment leading to the formation of 5ꢀCF3ꢀ
regioisomer 6.
Experimental
1
H and 19F NMR spectra were recorded on a Bruker DRXꢀ
400 spectrometer (400 and 75 MHz, respectively) in DMSOꢀd6;
using SiMe4 (1H) and C6F6 (19F) as internal standards. Elemenꢀ
tal analysis was performed on a Perkin—Elmer PE 2400 series II
analyzer. IR spectra were recorded on a Perkin—Elmer Specꢀ
trum One FTIRꢀspectrometer in the region 4000—400 cm–1 in
Nujol, for neat samples on KBr plates, or using the diffuse reꢀ
flectance accessory (DRA). Melting points were measured in
open capillaries on a Stuart SMP3 apparatus. Column chromaꢀ
tography was performed using L 100—250 μm silica gel.
Reaction of 1,3ꢀdiketones 1a,b with hydrazines 2a—c (general
procedure). A solution of sodium nitrite (1 g) in water (5 mL) was
added dropwise to a mixture of trifluoromethylꢀsubstituted
1,3ꢀdiketone 1 (12.5 mmol) and glacial acetic acid (4 mL) at
8—12 °C with stirring. The reaction mixture was stirred for
20 min, cooled to 10 °C, followed by a slow dropwise addition of
hydrazine (12.5 mmol) in water (5 mL). The reaction mixture
was stirred for 3 h, extracted with diethyl ether. The extracts
were treated with aqueous NaHCO3 to pH 7, washed with water,
dried with MgSO4, the solvent was evaporated. For the isolation
of pyrazolines 4a—d and 6, the solid substance formed was
washed with hot chloroform (4a), reprecipitated with chloroꢀ
form from the solution in ethyl acetate (4b), recrystallized
from chloroform (4d, 6), purified by column chromatography
(4c, eluent: CHCl3—MeCN, 100 : 1). For the isolation of pyrꢀ
azoles 5a,b, the mother liquors obtained after isolation of pyrꢀ
azolines 4a,b were concentrated, the oily products 5a,b were
purified by column chromatography (eluent: CHCl3—Et2O,
10 : 1 (5a) or CHCl3 (5b)). In the reaction of 1,3ꢀdiketone 1b
with methylhydrazine 2b, pyrazole 5c precipitated from aqueous
alcoholic solution, it was filtered off and twice reprecipitated
with hexane from the solution in chloroform.
3ꢀHydroxyꢀ5ꢀmethylꢀ4ꢀnitrosoꢀ3ꢀtrifluoromethylꢀ2,3ꢀdiꢀ
hydroꢀ1Hꢀpyrazole (4a). The yield was 51%, m.p. 135—136 °C.
IR (Nujol), ν/cm–1: 3315, 3070, 2730, 1650 (2 NH, OH); 1650
(C=C); 1170—1200 (C—F). 1H NMR, δ: 2.21 (s, 3 H, Me);
7.72, 8.14 (both s, 1 H each, NH); 12.23 (s, 1 H, OH). 19F NMR,
δ: 82.6 (s, CF3). Found (%): C, 30.41; H, 3.05; F, 28.86; N, 21.39.
C5H6F3N3O2. Calculated (%): C, 30.47; H, 3.07; F, 28.91;
N, 21.32.
3ꢀHydroxyꢀ1,5ꢀdimethylꢀ4ꢀnitrosoꢀ3ꢀtrifluoromethylꢀ2,3ꢀdiꢀ
hydroꢀ1Hꢀpyrazole (4b). The yield was 36%, m.p. 138—139 °C.
IR (DRA), ν/cm–1: 3330, 3120 (NH, OH); 1160—1200 (C—F).
1H NMR, δ: 2.22 (s, 3 H, Me); 2.81 (s, 3 H, NMe); 8.01 (s, 1 H,
NH); 12.38 (s, 1 H, OH). 19F NMR, δ: 83.6 (s, CF3). Found (%):
C, 34.33; H, 3.66; F, 26.97; N, 20.06. C6H8F3N3O2. Calculatꢀ
ed (%): C, 34.13; H, 3.82; F, 26.99; N, 19.90.
We have studied tuberculostatic activity of heterocycles
4b, 5a,b,d, and 6 in vitro experiments for the laboratory
strain of tuberculosis micobacteria (TMB) H37Rv. Isoꢀ
niazide was used as a comparison sample, whose miniꢀ
mum concentration necessary for retarding the growth of
TMB, is 0.15 μg mL–1
.
4ꢀNitrosopyrazole 5d containing an NH group and
a phenyl substituent at position 5 of the pyrazole ring
possesses the highest tuberculostatic activity among comꢀ
pounds studied. This compound inhibits the growth of the
TMB laboratory strain in the concentration 0.36 μg mL–1
.
Replacement of the Ph group with the Me group in pyrꢀ
azole 5d leads to a decrease in tuberculostatic activity,
since the minimum inhibiting concentration (MIC) of
pyrazole 5a is 1.62 μg mL–1. Incorporation of the methyl
substituent to the nitrogen atom N(1) of the ring still deꢀ
creases antituberculosis activity, since the MIC of comꢀ
pound 5b is 6.15 μg mL–1
.
Pyrazolines 4b and 6 showed lower tuberculostatic acꢀ
tivity. However, 5ꢀCF3ꢀpyrazoline 6 are more active as
compared to the 3ꢀCF3ꢀpyrazoline 4b. The MIC for hetꢀ
erocycle 6 is 3.12 μg mL–1, whereas for compound 4b it is
the highest, viz., 12.5 μg mL–1
.
We additionally studied tuberculostatic properties for
the precursor of pyrazole 5d, 2ꢀhydroxyiminoꢀ4,4,4ꢀtriꢀ
fluoroꢀ1ꢀphenylbutaneꢀ1,3ꢀdione,4 which exhibited modꢀ
erate antituberculosis activity (the MIC of this compound
against the TMB laboratory strain is 1.25 μg mL–1).
In conclusion, the reaction of trifluoromethylꢀcontainꢀ
ing 1,3ꢀdiketones with sodium nitrite and hydrazines
(hydrazine hydrate, methylhydrazine) can be accomꢀ
plished as a oneꢀpot procedure giving 4ꢀnitrosoꢀ3ꢀtrifluoroꢀ
methylpyrazolines, which can be dehydrated to pyrazoles.
The use of phenylhydrazine leads to the formation of more
stable 4ꢀhydroxyiminoꢀ5ꢀ(trifluoromethyl)pyrazoline. The
study of tuberculostatic activity showed that it is promisꢀ
ing to search antituberculosis drugs in the series of trifluoꢀ
romethylꢀsubstituted 4ꢀnitrosopyrazoles and their precurꢀ
sors: pyrazolines and 2ꢀhydroxyiminoꢀ1,3ꢀdiketones.
3ꢀHydroxyꢀ1ꢀmethylꢀ4ꢀnitrosoꢀ5ꢀphenylꢀ3ꢀtrifluoromethylꢀ
2,3ꢀdihydroꢀ1Hꢀpyrazole (4c). The yield was 13%, m.p.
117—118 °C. IR (DRA), ν/cm–1: 3510, 3160, 3040, 1635 (NH,
OH); 1600, 1490 (C=C); 1175—1200 (C—F). 1H NMR, δ: 3.00
(s, 3 H, NMe); 7.34—7.55 (m, 5 H, Ph); 8.34, 12.50 (both s,
1 H each, NH, OH). 19F NMR, δ: 84.54 (s, CF3). Found (%):
C, 48.59; H, 3.72; F, 21.12; N, 15.44. C11H10F3N3O2. Calculatꢀ
ed (%): C, 48.36; H, 3.69; F, 20.86; N, 15.38.
3ꢀHydroxyꢀ4ꢀnitrosoꢀ5ꢀphenylꢀ3ꢀtrifluoromethylꢀ2,3ꢀdiꢀ
hydroꢀ1Hꢀpyrazole (4d). The yield was 66%, m.p. 134—135 °C.
IR (DRA), ν/cm–1: 3290, 3190, 3070, 1640 (2 NH, OH); 1600,
1530, 1495 (C=C); 1160—1200 (C—F). 1H NMR of major isoꢀ

1972
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
Khudina et al.
mer (74%), δ: 7.33—7.57 (m, 5 H, Ph); 8.06, 9.09, 12.40 (all s,
1 H each, NH, OH); of minor isomer (26%), δ: 7.35—7.94 (m, 5 H,
Ph); 7.88, 8.89, 12.41 (all s, 1 H each, NH, OH). 19F NMR of
major isomer, δ: 83.25 (s, CF3); of minor isomer, δ: 87.44 (s, CF3).
Found (%): C, 46.28; H, 3.15; F, 22.12; N, 16.28. C10H8F3N3O2.
Calculated (%): C, 46.34; H, 3.11; F, 21.99; N, 16.21.
5ꢀMethylꢀ4ꢀnitrosoꢀ3ꢀtrifluoromethylꢀ1Hꢀpyrazole (5a). The
yield was 23%. IR (KBr), ν/cm–1: 3190 (NH); 1575, 1490 (C=N,
C=C, N=O); 1130—1180 (C—F). 1H NMR, δ: 2.76 (s, 3 H,
Me); 14.53 (s, 1 H, NH). 19F NMR, δ: 100.6 (s, CF3). Found (%):
C, 33.67; H, 2.44; F, 31.59; N, 23.31. C5H4F3N3O. Calculatꢀ
ed (%): C, 33.53; H, 2.25; F, 31.82; N, 23.46.
1,5ꢀDimethylꢀ4ꢀnitrosoꢀ3ꢀtrifluoromethylpyrazole (5b). The
yield was 41%. IR (KBr), ν/cm–1: 1570, 1500 (C=N, C=C,
N=O); 1110—1180 (C—F). 1H NMR, δ: 2.88 (s, 3 H, Me); 3.94
(s, 3 H, NMe). 19F NMR, δ: 100.25 (s, CF3). Found (%):
C, 37.57; H, 3.43; F, 29.56; N, 22.08. C6H6F3N3O. Calculatꢀ
ed (%): C, 37.31; H, 3.13; F, 29.51; N, 21.76.
1ꢀMethylꢀ4ꢀnitrosoꢀ5ꢀphenylꢀ3ꢀtrifluoromethylpyrazole (5c).
The yield was 63%, m.p. 97—98 °C. IR (DRA), ν/cm–1: 1600, 1500
(C=N, C=C, N=O); 1140—1190 (C—F). 1H NMR, δ: 3.98 (s, 3 H,
Me); 7.66—7.96 (m, 5 H, Ph). 19F NMR, δ: 99.3 (s, CF3).
Found (%): C, 51.93; H, 3.17; F, 22.37; N, 16.50. C11H8F3N3O.
Calculated (%): C, 51.77; H, 3.16; F, 22.33; N, 16.47.
equipped with a reflux condenser and heated for 3 h in a water
bath at 90 °C.
5ꢀMethylꢀ4ꢀnitrosoꢀ3ꢀtrifluoromethylꢀ1Hꢀpyrazole (5a). The
yield was 62%, the product was isolated by column chromatogꢀ
raphy, eluent: CHCl3—Et2O, 10 : 1. Physicoꢀchemical characꢀ
teristics were identical to those for the product obtained by the
reaction of 1a with 3a (see above).
4ꢀNitrosoꢀ5ꢀphenylꢀ3ꢀtrifluoromethylꢀ1Hꢀpyrazole (5d). The
yield was 98%, m.p. 125—126 °C (cf. Ref. 5: 124—126 °C).
19F NMR, δ: 98.79 (s, CF3).
Xꢀray study. Monocrystals of heterocycles 5d and 6 were
obtained by crystallization from chloroform, crystals of pyrazole
5c were grown in dichloromethane. Xꢀray diffraction experiꢀ
ments were performed on a Xcalibur 3 CCD diffractomeꢀ
ter (λ(MoꢀКα) = 0.71073 Å, graphite monochromator, ωꢀscanꢀ
ning, temperature 295(2) К). No allowance for absorption
was made. Crystal structure was solved by the direct methods
and subsequent Fourierꢀsyntheses using the SHELXSꢀ97
program.12 The structure was refined by the least squares
method in anisotropic fullꢀmatrix approximation for all the
nonhydrogen atoms using the SHELXLꢀ97 program.13 The
hydrogen atoms were placed in the geometrically calculated poꢀ
sitions and included into the refinement using the riding model
in isotropic approximation with dependent thermal parameters.
The H(2) atom of the hydroxy group of compound 6 and atoms
of the NH groups of compound 5d were solved by the direct
method and included into the refinement independently in isoꢀ
tropic approximation. The principal crystallographic data of
compounds 5c,d and 6 and some experimental characteristics
are given in Table 2. Crystallographic data for compounds 5c,d
and 6 were deposited with the Cambridge Structural Database
(CCDC 752784, CCDC 759260, and CCDC 752785, respecꢀ
tively) and are available at www.ccdc.cam.ac.uk/conts/reꢀ
trieving.html.
5ꢀHydroxyꢀ4ꢀhydroxyiminoꢀ3ꢀmethylꢀ1ꢀphenylꢀ5ꢀtrifluoꢀ
romethylꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (6). The yield was 56%, m.p.
135—136 °C. IR (Nujol), ν/cm–1: 3260, 3100 (N=OH, OH);
1655, 1600, 1500 (C=N, C=C); 1180—1260 (C—F). 1H NMR,
δ: 2.36 (s, 3 H, Me); 6.97—7.41 (m, 5 H, Ph); 8.62, 12.69 (both s,
1 H each, OH). 19F NMR, δ: 83.74 (s, CF3). Found (%): C, 48.37;
H, 3.7; F, 20.48; N, 15.41. C11H10F3N3O2. Calculated (%):
C, 48.36; H, 3.69; F, 20.86; N, 15.38.
Dehydration of pyrazolines 4a,d to pyrazoles 5a,d (general
procedure). Pyrazoline 4 (5 mmol) was placed into a flask
Table 2. Principal crystallographic data and parameters of refinement for compounds 5c,d and 6
Parameter
5c
5d
6
Molecular formula
Molecular weight
C11H8F3N3O
255.2
C10H6F3N3O
241.18
C11H10F3N3O2
273.22
Crystal system
Space group
Monoclinic
P21/n
Triclinic
Pꢀ1
Monoclinic
P21/n
a/Å
b/Å
c/Å
α/deg
12.043(5)
7.8048(16)
12.596(3)
90.00
98.08(3)
90.00
1172.3(6)
4
1.446
7.8183(11)
11.8(2)
10.9449(12)
7.3731(6)
15.0971(13)
90.00
95.760(8)
90.00
1212.2(2)
4
1.497
12.239(18)
95.055(17)
94.993(12)
108.32(14)
1059.8(3)
4
β/deg
γ/deg
V/Å3
Z
dcalc/g cm–3
1.512
0.138
μ/mm–1
0.129
0.136
Angle of scanning θ/deg
Total number of reflections
Number of independent reflections
Number of reflections with I > 2σ(I)
Number of refined parameters
R1/wR2 (I > 2σ(I))
R1/wR2 ((on all the reflections)
3.08—26.5
5660
2.76—28.28
10517
3.08—26.37
5099
2390
1335
164
5041
2049
315
2370
1363
177
0.0421/0.1054
0.0771/0.1161
0.0357/0.0427
0.1255/0.0467
0.0445/0.1206
0.0842/0.1324

3ꢀTrifluoromethylꢀ4ꢀnitrosopyrazoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 10, October, 2010
1973
Study of tuberculostatic activity. Tuberculostatic activity was
determined by the method of serial dilutions with the use of the
Novaya dense yolk medium or the Levenshtein—Yensen egg
medium.14 The H37Rv tuberculosis micobacteria culture was used
as a laboratory strain.
4. S. F. Torf, N. I. Kudryashova, N. V. KhromovꢀBorisov, T. A.
Mikhailova, Zh. Obshch. Khim., 1962, 32, 1740 [Russ. J. Gen.
Chem. (Engl. Transl.), 1962, 32].
5. V. I. Saloutin, Y. V. Burgart, Z. E. Skryabina, O. G. Kuzueꢀ
va, J. Fluor. Chem., 1997, 84, 107.
The laboratory strain culture was weighted on a torsion balꢀ
ance, the sample (10 mg) was placed into a porselain mortar,
thoroughly mulled, and a suspension of the culture was prepared
using a bacterial standard turbidity 100 million of microbe bodies
per 1 mL. A suspended matter obtained (0.2 mL in amount) was
sown into the testꢀtubes containing a culture medium and a comꢀ
pound studied (5.0 mL) of each dilution, incubated for 7—10 days
in a thermostat at 37 °C. The action of the substance on the
tuberculosis micobacteria was studied simultaneously in three
testꢀtubes for each concentrations.
6. J. C. Sloop, C. L. Bumgardner, W. D. Loehle, J. Fluor. Chem.,
2002, 118, 135.
7. S. P. Singh, J. K. Kapoor, D. Kumar, M. D. Threadgill,
J. Fluor. Chem., 1997, 83, 73.
8. 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.
9. S. P. Singh, D. Kumar, M. D. Threadgill, Ind. J. Chem.,
Sec. B, 1992, 31, 233; S. P. Singh, L. S. Tarar, R. K. Vaid,
J. Elguero, A. Martinez, J. Heterocycl. Chem., 1989, 26, 733.
10. S. Fustero, R. Román, J. F. SanzꢀCervera, A. SimónꢀFuentꢀ
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 09ꢀ03ꢀ
00274a), the Ministry of Education and Science of Rusꢀ
sian Federation (State Contract No. 02.740.11.0260), and
the Ural Branch of the Russian Academy of Sciences
(Integration Project of Fundamental Studies "Scientific
Principles for Creation and Development of Pharmaceuꢀ
tical Drugs of Natural and Synthetic Origin").
∨
es, A. C. Cunat, S. Villanova, M. Murguía, J. Org. Chem.,
2008, 73, 3523.
11. R. D. Pearson, Usp. Khim., 1971, 40, 1259 [Russ. Chem. Rev.
(Engl. Transl.), 1971, 40, No. 7].
12. G. M. Sheldrick, SHELXSꢀ97, Program for the Solution of
Crystal Structure, University of Göttingen, Germany, 1997.
13. G. M. Sheldrick, SHELXLꢀ97, Program for the Refinement of
Crystal Structure, University of Göttingen, Germany, 1997.
14. T. N. Yashchenko, I. S. Mecheva, Rukovodstvo po laboraꢀ
tornym issledovaniyam pri tuberkuleze [Handbook on Tuberꢀ
culosis Laboratory Studies], Meditsina, Moscow, 1973, 260 pp.
(in Russian); V. N. Vasilyov, Mikobakteriozy i mikozy legkikh
[Lung Micobacteriose and Micose], Meditsina i Fizkul´tura,
Sofia, 1971, p. 377 (in Bulgarian).
References
1. Ya. A. Veselov, E. I. Krasnikova, I. M. Veselovskii, Antibiotiꢀ
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2. N. M. Rudoi, T. A. Smailova, S. K. Mardanov, Problemy
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Received December 24, 2009;
in revised form September 13, 2010