Synthesis and some properties of 6-di(tri)fluoromethyl-and 5-di(tri)fluoroacetyl-3-methyl-1-phenylpyrano[2,3-c]pyrazol-4(1H)-ones

Article abstract of DOI:10.1007/s11172-006-0199-x

Condensation of 4-acetyl-5-hydroxy-3-methyl-1-phenylpyrazole with R ^FCO₂Et (R^F = CF₂H, CF₃) in the presence of LiH affords 4-di(tri)fluoroacetoacetyl-5-hydroxy-3-methyl-1- phenylpyrazoles from which 6

Full text of DOI:10.1007/s11172-006-0199-x

2846
Russian Chemical Bulletin, International Edition, Vol. 54, No. 12, pp. 2846—2850, December, 2005
Synthesis and some properties of 6ꢀdi(tri)f luoromethylꢀ and
5ꢀdi(tri)f luoroacetylꢀ3ꢀmethylꢀ1ꢀphenylpyrano[2,3ꢀc]pyrazolꢀ4(1H )ꢀones
V. Ya. Sosnovskikh,ꢀ M. A. Barabanov, B. I. Usachev, R. A. Irgashev, and V. S. Moshkin
A. M. Gorky Ural State University,
51 prosp. Lenina, 620083 Ekaterinburg, Russian Federation.
Fax: +7 (343) 261 5978. Eꢀmail: Vyacheslav.Sosnovskikh@usu.ru
Condensation of 4ꢀacetylꢀ5ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀphenylpyrazole with RFCO2Et
(RF = CF2H, CF3) in the presence of LiH affords 4ꢀdi(tri)fluoroacetoacetylꢀ5ꢀhydroxyꢀ3ꢀ
methylꢀ1ꢀphenylpyrazoles from which 6ꢀdi(tri)fluoromethylꢀ and 5ꢀdi(tri)fluoroacetylꢀ3ꢀ
methylꢀ1ꢀphenylpyrano[2,3ꢀc]pyrazolꢀ4(1H )ꢀones were synthesized. The reactions of pyranoꢀ
pyrazoles with hydrazine hydrate, ethyl mercaptoacetate, or aromatic amines proceed at the
C(6) atom with pyrone ring opening and formation of aminoenones, pyrazoles, or thiophenes
with the 5ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀphenylꢀ4ꢀpyrazolyl fragment.
Key words: 6ꢀdi(tri)fluoromethylꢀ and 5ꢀdi(tri)fluoroacetylꢀ3ꢀmethylꢀ1ꢀphenylpyraꢀ
no[2,3ꢀc]pyrazolꢀ4(1H )ꢀones, diethoxymethyl acetate, substituted pyrazoles, thiophenes and
thieno[3´,2´:4,5]pyrano[2,3ꢀc]pyrazolꢀ5(3H )ꢀone.
It is known1 that 2ꢀpolyfluoroalkylchromones can be
used for syntheses of different RFꢀcontaining heterocycles.
For instance, the reaction of 2ꢀCF3ꢀchromones with ethyl
mercaptoacetate is a redox process that affords 1,2ꢀdiꢀ
hydroꢀ2ꢀtrifluoromethylꢀ4Hꢀthieno[2,3ꢀc]chromenꢀ
4ꢀones.2,3 The replacement of the benzene ring in
2ꢀCF3ꢀchromones by the pyridine cycle stops the reacꢀ
tion at the step of formation of ethyl [3ꢀ(4,6ꢀdimethylꢀ2ꢀ
oxoꢀ1,2ꢀdihydropyridinꢀ3ꢀyl)ꢀ3ꢀoxoꢀ1ꢀtrifluoromethylꢀ
propyl]sulfanyl acetate (Scheme 1).4,5 Therefore, it was
of interest to reveal the behavior in the reaction with ethyl
mercaptoacetate of the heterocyclic system, whose pyꢀ
rone ring containing the CF3 group in the corresponding
position is annelated to the pyrazole fragment.
In the present work, we performed the condensation
of 4ꢀacetylꢀ5ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀphenylpyrazole with
RFCO2Et (RF = CF2H, CF3) and prepared for the
first time 4ꢀdi(tri)fluoroacetoacetylꢀ5ꢀhydroxyꢀ3ꢀmethylꢀ
1ꢀphenylpyrazoles (1a,b). The latter were used, in turn,
as the starting compounds for the synthesis of the
target 6ꢀdi(tri)fluoromethylꢀ3ꢀmethylꢀ1ꢀphenylpyraꢀ
no[2,3ꢀc]pyrazolꢀ4(1H )ꢀones (2a,b) and 5ꢀdi(tri)fluoroꢀ
acetylꢀ3ꢀmethylꢀ1ꢀphenylpyrano[2,3ꢀc]pyrazolꢀ4(1H )ꢀ
ones (3a,b). Owing to the presence of electronꢀwithꢀ
drawing RFꢀ and RFCO groups in compounds 2 and 3,
one could expect that they would be highly reactive and
synthetically valuable RFꢀcontaining compounds that alꢀ
low the preparation of different heterocycles with a
pharmacophoric pyrazolone substituent.6
Scheme 1
Results and Discussion
Data on the synthesis and chemical properties of
RFꢀcontaining pyranopyrazoles 2 and 3 are lacking. At
the same time, the methods for synthesis7—10 and biologiꢀ
cal activity11 of their nonfluorinated analogs, as well
as the tautomeric structures of the starting 4ꢀacylꢀ5ꢀ
hydroxypyrazoles12—15 and 4ꢀacylacetylꢀ5ꢀhydroxyꢀ1ꢀ
phenylpyrazoles,7 were studied in rather detail. We found
that the condensation of 4ꢀacetylꢀ5ꢀhydroxyꢀ3ꢀmethylꢀ
1ꢀphenylpyrazole with ethyl diꢀ and trifluoroacetates in
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2750—2754, December, 2005.
1066ꢀ5285/05/5412ꢀ2846 © 2005 Springer Science+Business Media, Inc.

Synthesis of pyrano[2,3ꢀc]pyrazolꢀ4ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005 2847
Scheme 2
RF = CF3 (a), CF2H (b)
the presence of LiH in THF affords diketones 1a and 1b
in 93 and 87% yields, respectively. Diketones 1a and 1b
exist in a CDCl3 solution almost exclusively in the
ketoenol form (Scheme 2). The 1H NMR spectra of these
compounds exhibit a singlet of the vinyl proton at
δ 6.16—6.24 and two strongly broadened singlets of the
enol (δ 14.4—14.5) and pyrazole (δ 11.7) hydroxyls, which
agrees well with published data7 for nonfluorinated anaꢀ
logs of diketones 1a,b. The intensity of the singlet of
the СH2 group at δ 4.14—4.16 suggests that the content
of the diketo form is only 3—4%, which is lower than
that in the case of 4ꢀacylacetylꢀ5ꢀhydroxyꢀ1ꢀphenylpyrꢀ
azoles (6—20%).7
The treatment of compounds 1a,b with concentrated
H2SO4 at ~20 °С is accompanied by pyrone ring cloꢀ
sure, and 6ꢀdi(tri)fluoromethylꢀ3ꢀmethylꢀ1ꢀphenylpyraꢀ
no[2,3ꢀc]pyrazolꢀ4(1H )ꢀones 2a,b are formed in 67—74%
yields (Scheme 3). Their 1H NMR spectra contain signals
of aromatic protons and, in addition, a singlet of the
methyl group (δ 2.64) and a singlet of the vinyl proton at
δ 6.71 and 6.54 for compounds 2а and 2b, respectively.
The reaction of diketones 1a,b with excess diethoxyꢀ
methyl acetate at 140—150 °С for 15 min gives
5ꢀdi(tri)fluoroacetylꢀ3ꢀmethylꢀ1ꢀphenylpyraꢀ
no[2,3ꢀc]pyrazolꢀ4(1H )ꢀones 3a,b. Trifluoromethylated
pyranopyrazole 3а is formed only as covalent hydrate,
which is characteristic of 3ꢀtrifluoroacetylchromones,16
whereas pyranopyrazole 3b, according to the 1H and
19F NMR spectra, contains only 7—9% of the hydrate
form (see Scheme 3).
We found that the reaction of 6ꢀCF3ꢀpyranopyrazole
2а with excess ethyl mercaptoacetate in the presence of
triethylamine proceeds at the C(6) atom followed by pyꢀ
rone ring opening and intramolecular condensation of
the aldol type. Unlike the earlier studied 2ꢀCF3ꢀchroꢀ
mones2,3 and their 8ꢀaza analogs,4,5 this transformation is
not accompanied by the reduction of an intermediate
under the action of ethyl mercaptoacetate and leads to the
synthesis of ester 4, which is hydrolyzed on heating with
dilute H2SO4 to acid 5. On reflux in toluene with thionyl
chloride and triethylamine, acid 5 undergoes ring closure
to form a new heterocyclic system: 1ꢀmethylꢀ3ꢀphenylꢀ7ꢀ
trifluoromethylthieno[3´,2´:4,5]pyrano[2,3ꢀc]pyrazolꢀ
5(3H )ꢀone (6) (Scheme 4).
Scheme 3
Pyranopyrazole 2а is nitrated at the paraꢀposition of
the benzene ring to form 3ꢀmethylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ6ꢀ
trifluoromethylpyrano[2,3ꢀc]pyrazolꢀ4(1H )ꢀone (7), and
the reaction with hydrazine hydrate affords the expected
bipyrazole 8 in 85% yield (Scheme 5). Compound 8 was
prepared from diketone 1а (76% yield).
As a whole, pyranopyrazoles 2 are less reactive than
earlier17 studied 8ꢀazachromones. For instance, we failed
to perform the reactions of compound 2а with pyrrolidine,
ethylenediamine, hydroxylamine, methylhydrazine, and
benzamidine. In all cases, either a complex mixture of
products were formed, or the starting pyranopyrazole 2а
recovered.
Unlike compounds 2 in which the nucleophilic attack
to the С(6) atom is sterically hindered, compounds 3
react readily at this center even with aromatic amines.
RF = CF3 (a), CF2H (b)

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Sosnovskikh et al.
Scheme 4
Scheme 6
Scheme 5
Thus, the reaction of 6ꢀRFꢀ and 5ꢀRFCOꢀcontaining
pyranopyrazoles 2 and 3 with Nꢀ and Sꢀnucleophiles starts
from the attack at the С(6) atom and affords, depending
on the nature of the reactant, aminoenones, pyrazoles,
and thiophenes with the 5ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀphenylꢀ
4ꢀpyrazolyl fragment.
Experimental
IR spectra were recorded on a Perkin—Elmer Spectrum
BXꢀII instrument in KBr pellets. 1H and 19F NMR spectra were
obtained on a Bruker DRXꢀ400 spectrometer with working freꢀ
quencies of 400.1 and 376.5 MHz, respectively, and Me4Si and
C6F6 as internal standards. 4ꢀAcetylꢀ5ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀ
phenylpyrazole was synthesized by the procedure described elseꢀ
where.18
1ꢀ(5ꢀHydroxyꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ4,4,4ꢀ
trifluorobutaneꢀ1,3ꢀdione (1a). Finely powdered LiH (0.28 g,
35.0 mmol) was added to a solution of ethyl trifluoroacetate
(2.0 g, 14.1 mmol) and 4ꢀacetylꢀ5ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀphenylꢀ
pyrazole (2.0 g, 9.3 mmol) in anhydrous THF (10 mL). The
resulting reaction mixture was refluxed for 3 h. Then the solvent
was distilled off to dryness in a water bath under reduced presꢀ
sure, and a mixture of AcOH (5 mL) and concentrated HCl
(4 mL) was added to the residue. The mixture was refluxed for
5 min and poured onto crushed ice (40 g). The precipitate that
formed was filtered off, washed with water, dried, and recrystalꢀ
lized from toluene. Diketone 1a was obtained as yellowish crysꢀ
tals in a yield of 2.7 g (93%), m.p. 116—117 °C. Found (%):
C, 53.66; H, 3.39; N, 8.74. C14H11F3N2O3. Calculated (%):
C, 53.85; H, 3.55; N, 8.97. IR, ν/cm–1: 1655, 1590, 1568, 1501.
1H NMR (CDCl3), δ: 2.50 (s, 3 H, Mе); 6.24 (s, 1 H, =CH);
However, it turned out that when reacting with aniline,
they lose the di(tri)fluoroacetyl group and gave aminoꢀ
enone 9 as a mixture of Eꢀ and Zꢀisomers in a ratio of 9 : 1
(Jtrans = 12.5 Hz, Jcis = 7.9 Hz), while the reaction of 3а
with less basic pꢀnitroaniline ceased at the step of pyrone
ring opening, due to which trifluoroacetylated aminoꢀ
enone 10 was formed in 72% yield (the configuration of
the double bond was not determined). Based on the elꢀ
emental analysis data and a broadened singlet at δ 3.6 in
1
the H NMR spectrum, one can conclude that this comꢀ
pound exists as hydrate. The treatment of pyranopyrazole
3а in propanꢀ2ꢀol with hydrazine hydrate at ~20 °С proꢀ
duces dipyrazolyl ketone 11 in 52% yield (Scheme 6).

Synthesis of pyrano[2,3ꢀc]pyrazolꢀ4ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005 2849
7.34 (tt, 1 H, H(4´), Jo = 7.5 Hz, Jm = 1.3 Hz); 7.45—7.50 (m,
2 H, H(3´), H(5´)); 7.77—7.81 (m, 2 H, H(2´), H(6´)); 11.7
(br.s, 1 H, OH of pyrazole); 14.5 (br.s, 1 H, OH of enol).
1ꢀ(5ꢀHydroxyꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ4,4ꢀ
difluorobutaneꢀ1,3ꢀdione (1b) was synthesized similarly to comꢀ
pound 1а in 87% yield as colorless needleꢀlike crystals, m.p.
89—90 °C (toluene). Found (%): C, 57.37; H, 4.23; N, 9.64.
C14H12F2N2O3. Calculated (%): C, 57.15; H, 4.11; N, 9.52. IR,
ν/cm–1: 1643, 1563, 1495. 1H NMR (CDCl3), δ: 2.50 (s, 3 H,
Mе); 6.10 (t, 1 H, CF2H, 2JH,F = 54.2 Hz); 6.16 (s, 1 H, =CH);
7.33 (tt, 1 H, H(4´), Jo = 7.5 Hz, Jm = 1.3 Hz); 7.45—7.49 (m,
2 H, H(3´), H(5´)); 7.78—7.82 (m, 2 H, H(2´), H(6´)); 11.7
(br.s, 1 H, OH of pyrazole); 14.4 (br.s, 1 H, OH of enol).
3ꢀMethylꢀ6ꢀtrifluoromethylꢀ1ꢀphenylpyrano[2,3ꢀc]pyrazolꢀ
4(1H )ꢀone (2a). Diketone 1a (4.7 g, 0.015 mol) was added by
small portions with stirring to concentrated H2SO4 (19 mL),
and the resulting solution was kept for 24 h at ~20 °C. Then the
reaction mixture was poured onto ice, and the precipitate that
formed was filtered off, dried, and recrystallized from a hexꢀ
ane—toluene (1 : 1) mixture. Compound 2а was obtained
as colorless needleꢀlike crystals in a yield of 2.95 g (67%),
m.p. 129—130 °C. Found (%): C, 57.03; H, 3.07; N, 9.47.
C14H9F3N2O2. Calculated (%): C, 57.15; H, 3.08; N, 9.52. IR,
ν/cm–1: 3039, 1672, 1598, 1557, 1530. 1H NMR (CDCl3), δ:
2.64 (s, 3 H, Mе); 6.71 (s, 1 H, =CH); 7.42 (tt, 1 H, H(4´), Jo =
7.5 Hz, Jm = 1.3 Hz); 7.52—7.57 (m, 2 H, H(3´), H(5´));
7.75—7.78 (m, 2 H, H(2´), H(6´)). 19F NMR (CDCl3), δ:
91.49 (s, CF3).
2JH,F = 56.1 Hz); 8.09 (s, 1 H, =CH). 19F NMR (CDCl3), δ,
compound 3b: 31.03 (d, CF2H, 2JH,F = 53.3 Hz); hydrate (9%):
28.98 (d, CF2H, JH,F = 56.1 Hz).
2
Ethyl 3ꢀ(5ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀ
trifluoromethylthiopheneꢀ2ꢀcarboxylate (4). A mixture of pyranoꢀ
pyrazole 2а (0.52 g, 1.77 mmol), ethyl mercaptoacetate (0.64 g,
5.3 mmol), and triethylamine (0.1 mL) was kept for 10 h at
80 °C, then methanol (3 mL) was added, and the mixture was
cooled. The yellowish precipitate that formed was filtered off,
washed with 70% methanol and water, dried, and recrystallized
from a hexane—toluene (2 : 1) mixture. Compound 4 was obꢀ
tained as colorless crystals in a yield of 0.22 g (31%), m.p.
194—195 °C. Found (%): C, 54.46; H, 3.81; N, 7.12.
C18H15F3N2O3S. Calculated (%): C, 54.54; H, 3.81; N, 7.07.
1
IR, ν/cm–1: 1727, 1614, 1594, 1557, 1500. H NMR (CDCl3),
δ: 1.42 (t, 3 H, Me, J = 7.1 Hz); 2.33 (s, 3 H, Mе); 4.43 (q, 2 H,
CH2, J = 7.1 Hz); 7.29 (br.t, 1 H, H(4´), Jo = 7.4 Hz); 7.42—7.47
(m, 3 H, =CH, H(3´), H(5´)); 7.77—7.81 (m, 2 H, H(2´),
H(6´)); 9.3 (br.s, 1 H, OH). 1H NMR (DMSOꢀd6), δ: 1.22 (t,
3 H, Me, J = 7.1 Hz); 2.12 (s, 3 H, Mе); 4.25 (q, 2 H, CH2, J =
7.1 Hz); 7.25 (t, 1 H, H(4´), Jo = 7.4 Hz); 7.45—7.49 (m, 2 H,
H(3´), H(5´)); 7.73—7.76 (m, 2 H, H(2´), H(6´)); 7.84 (q, 1 H,
=CH, 4JH,F = 1.0 Hz); 10.8—12.2 (br.s, 1 H, OH).
3ꢀ(5ꢀHydroxyꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀtriꢀ
fluoromethylthiopheneꢀ2ꢀcarboxylic acid (5). Ester 4 (0.21 g,
0.53 mmol) was added to a solution containing concentrated
H2SO4 (2 mL) and water (1 mL), and the resulting mixture was
kept for 1 h at 110 °C: until the formation of a homogeneous
solution from which acid 5 began to crystallize soon. The mixꢀ
ture was diluted with cold water (5 mL) and left to stand for 24 h
at 4 °C. The precipitate that formed was filtered off, washed
with water (10 mL), and dried. Acid 5 was obtained as colorless
crystals in a yield of 0.13 g (67%), m.p. 216—218 °C. Found (%):
C, 52.27; H, 2.94; N, 7.57. C16H11F3N2O3S. Calculated (%):
C, 52.17; H, 3.01; N, 7.61. IR, ν/cm–1: 3060, 1730, 1597, 1575,
1547, 1501. 1H NMR (DMSOꢀd6), δ: 2.12 (s, 3 H, Mе); 7.25
(br.t, 1 H, H(4´), Jo = 7.4 Hz); 7.45—7.50 (m, 2 H, H(3´),
H(5´)); 7.74—7.78 (m, 3 H, =CH, H(2´), H(6´)); 9.0—14.0
(br.s, 2 H, OH, CO2H).
1ꢀMethylꢀ3ꢀphenylꢀ7ꢀtrifluoromethylthieno[3´,2´:4,5]pyraꢀ
no[2,3ꢀc]pyrazolꢀ5(3H )ꢀone (6). A mixture of acid 5 (0.1 g,
0.27 mmol), triethylamine (0.07 g, 0.7 mmol), and thionyl chloꢀ
ride (0.16 g, 1.4 mmol) in anhydrous toluene (15 mL) was reꢀ
fluxed for 20 min. Then the darkened solution was cooled, filꢀ
tered off from the precipitate, and concentrated by evaporation.
The crystals that precipitated were filtered off and recrystallized
from hexane containing several drops of toluene. Compound 6
was obtained as light yellow needleꢀlike crystals in a yield of
0.04 g (42%), m.p. 208—209 °C. Found (%): C, 54.97; H, 2.61;
N, 8.00. C16H9F3N2O2S. Calculated (%): C, 54.86; H, 2.59;
N, 8.00. IR, ν/cm–1: 3094, 1745, 1575, 1518. 1H NMR
6ꢀDifluoromethylꢀ3ꢀmethylꢀ1ꢀphenylpyrano[2,3ꢀc]pyrazolꢀ
4(1H )ꢀone (2b) was synthesized similarly to compound 2а as
colorless needles in 74% yield, m.p. 135—136 °C. Found (%):
C, 60.88; H, 3.71; N, 10.25. C14H10F2N2O2. Calculated (%):
C, 60.87; H, 3.65; N, 10.14. IR, ν/cm–1: 3038, 1669, 1597,
1553, 1527. 1H NMR (CDCl3), δ: 2.64 (s, 3 H, Mе); 6.48 (t,
1 H, CF2H, 2JH,F = 53.5 Hz); 6.54 (s, 1 H, =CH); 7.40 (tt, 1 H,
H(4´), Jo = 7.5 Hz, Jm = 1.3 Hz); 7.51—7.56 (m, 2 H, H(3´),
H(5´)); 7.75—7.79 (m, 2 H, H(2´), H(6´)). 19F NMR (CDCl3),
2
δ: 39.84 (dd, CF2H, JH,F = 53.5 Hz, 4JH,F = 0.6 Hz).
3ꢀMethylꢀ1ꢀphenylꢀ5ꢀ(2,2,2ꢀtrifluoroꢀ1,1ꢀdihydroxyꢀ
ethyl)pyrano[2,3ꢀc]pyrazolꢀ4(1H )ꢀone (3a). A solution of diꢀ
ketone 1а (0.31 g, 1 mmol) in diethoxymethyl acetate (1.0 g,
6.0 mmol) was stored for 15 min at 140—150 °C. After cooling,
the resulting mixture was diluted with hexane (3 mL), and the
crystals that precipitated upon keeping were filtered off, washed
with hexane, and dried. Hydrate 3a was obtained as colorꢀ
less crystals in a yield of 205 mg (60%), m.p. 150—151 °C.
Found (%): C, 52.61; H, 3.21; N, 7.90. C15H11F3N2O4. Calcuꢀ
lated (%): C, 52.95; H, 3.26; N, 8.23. IR, ν/cm–1: 3220, 1654,
1
1597, 1538, 1490. H NMR (DMSOꢀd6), δ: 2.54 (s, 3 H, Mе);
7.46 (t, 1 H, H(4´), Jo = 7.4 Hz); 7.57—7.62 (m, 2 H, H(3´),
H(5´)); 7.80—7.84 (m, 2 H, H(2´), H(6´)); 8.25 (br.s, 2 H,
2 OH); 8.48 (s, 1 H, =CH).
(DMSOꢀd6), δ: 2.60 (s, 3 H, Mе); 7.44 (tt, 1 H, H(4´), Jo
=
5ꢀDifluoroacetylꢀ3ꢀmethylꢀ1ꢀphenylpyrano[2,3ꢀc]pyrazolꢀ
4(1H )ꢀone (3b) was synthesized similarly to compound 3а in
64% yield, m.p. 185—186 °C. Found (%): C, 59.20; H, 3.28;
N, 9.23. C15H10F2N2O3. Calculated (%): C, 59.22; H, 3.31;
N, 9.21. 1H NMR (CDCl3), δ, compound 3b: 2.66 (s, 3 H, Mе);
6.91 (t, 1 H, CF2H, 2JH,F = 53.3 Hz); 7.43 (tt, 1 H, H(4´), Jo =
7.5 Hz, Jm = 1.3 Hz); 7.52—7.57 (m, 2 H, H(3´), H(5´));
7.73—7.77 (m, 2 H, H(2´), H(6´)); 8.35 (s, 1 H, =CH); hydrate
(7%): 2.63 (s, 3 H, Mе); 5.57 (s, 2 H, 2 OH); 5.77 (t, 1 H, CF2H,
7.4 Hz, Jm = 1.2 Hz); 7.58—7.63 (m, 2 H, H(3´), H(5´));
7.81—7.84 (m, 2 H, H(2´), H(6´)); 8.38 (q, 1 H, =CH,
4JH,F = 1.1 Hz).
3ꢀMethylꢀ1ꢀ(4ꢀnitrophenyl)ꢀ6ꢀtrifluoromethylpyraꢀ
no[2,3ꢀc]pyrazolꢀ4(1H )ꢀone (7). Pyranopyrazole 2а (0.2 g,
0.68 mmol) was introduced with stirring and cooling into a
mixture of 68% HNO3 (0.22 mL) and concentrated H2SO4
(0.22 mL). The reaction mixture was heated for 20 min at 60 °C,
cooled, and poured onto crushed ice (30 g). The precipitate that

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Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005
Sosnovskikh et al.
formed was filtered off, washed with water, dried, and recrystalꢀ
lized from ethanol. Compound 7 was obtained as colorless crysꢀ
tals in a yield of 140 mg (61%), m.p. 183—184 °C. Found (%):
C, 49.59; H, 2.28; N, 12.55. C14H8F3N3O4. Calculated (%):
C, 49.57; H, 2.38; N, 12.39. IR, ν/cm–1: 3046, 1674, 1613,
1597, 1563, 1525, 1503. 1H NMR (CDCl3), δ: 2.65 (s, 3 H, Mе);
6.77 (s, 1 H, =CH); 8.05 (d, 2 H, H(2´), H(6´), Jo = 9.2 Hz);
8.43 (d, 2 H, H(3´), H(5´), Jo = 9.2 Hz).
5ꢀHydroxyꢀ3ꢀmethylꢀ1ꢀphenylꢀ4ꢀ[3(5)ꢀtrifluoromethylꢀ
pyrazolꢀ5(3)ꢀyl]pyrazole (8). A solution of diketone 1а or
pyranopyrazole 2а (0.6 mmol) and 25% hydrazine hydrate (0.4 g,
2 mmol) in ethanol (3 mL) was refluxed for 15 min, cooled, and
diluted with water (7 mL) containing 0.3 mL of concentrated
HCl. The precipitate that formed was filtered off, washed with
water, dried, and recrystallized from toluene containing several
drops of butanol. The yields were 76% from 1а and 85% from 2а,
colorless needles, m.p. 236—237 °C. Found (%): C, 54.58;
H, 3.42; N, 18.03. C14H11F3N4O. Calculated (%): C, 54.55;
H, 3.60; N, 18.18. IR, ν/cm–1: 3326, 3069, 1670, 1630, 1591,
1556, 1502. 1H NMR (DMSOꢀd6), δ: 2.34 (s, 3 H, Mе); 6.75 (s,
1 H, =CH); 7.28 (br.t, 1 H, H(4´), Jo = 7.4 Hz); 7.47—7.52 (m,
2 H, H(3´), H(5´)); 7.72—7.76 (m, 2 H, H(2´), H(6´)); 12.0
(br.s, 1 H, OH); 13.37 (s, 1 H, NH).
0.4 mmol) was added. The resulting yellow solution was kept for
24 h at ~20 °C, after which the solvent was evaporated, and the
residue was washed with methanol and dried. Compound 11 was
obtained as light yellow crystals in a yield of 51 mg (52%),
m.p. 255—257 °C. Found (%): C, 52.25; H, 3.18; N, 16.04.
C
15H11F3N4O2•0.5H2O. Calculated (%): C, 52.18; H, 3.50;
N, 16.23. IR, ν/cm–1: 3140, 3049, 1627, 1597, 1568, 1503.
1H NMR (DMSOꢀd6), δ: 2.34 (s, 3 H, Mе); 7.32 (tt, 1 H, H(4´),
Jo = 7.4 Hz, Jm = 1.2 Hz); 7.47—7.52 (m, 2 H, H(3´), H(5´));
7.66—7.70 (m, 2 H, H(2´), H(6´)); 8.60 (s, 1 H, =CH);
13.84 (br.s, 1 H, NH); no OH signal is observed. 19F NMR
(DMSOꢀd6), δ: 102.70 (s, CF3).
This work was financially supported by the U.S. Civilꢀ
ian Research and Development Foundation and the Minꢀ
istry of Education and Science of the Russian Federation
(Grants EKꢀ005ꢀX1 and Y1ꢀ005ꢀ04).
References
1. V. Ya. Sosnovskikh, Usp. Khim., 2003, 72, 550 [Russ. Chem.
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(E)ꢀ3ꢀAnilinoꢀ1ꢀ(5ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ
4ꢀyl)propꢀ2ꢀenꢀ1ꢀone (9). A solution of pyranopyrazole 2b
(70 mg, 0.23 mmol) and aniline (43 mg, 0.46 mmol) in methaꢀ
nol (1 mL) was kept for 24 h at ~20 °C. The precipitated crystals
were filtered off, washed with methanol, and dried. Comꢀ
pound 9 was obtained as yellow crystals in a yield of 40 mg
(55%), m.p. 156—157 °C. The same compound was obtained
from pyranopyrazole 2а on reflux for 10 min with aniline in
propanꢀ2ꢀol (43%). Found (%): C, 70.11; H, 5.23; N, 12.99.
C19H17N3O2•0.25H2O. Calculated (%): C, 70.46; H, 5.45;
N, 12.97. IR, ν/cm–1: 1671, 1643, 1600, 1591, 1531, 1499.
1H NMR (CDCl3), δ, Eꢀisomer (90%): 2.44 (s, 3 H, Mе); 5.87
(d, 1 H, =CH, J = 12.5 Hz); 7.07—7.22 (m, 5 H, NH, H arom.);
7.35—7.44 (m, 4 H, H arom.); 7.92—7.96 (m, 2 H, H arom.);
8.30 (t, 1 H, =CHN, J = 13.0 Hz); Zꢀisomer (10%): 2.49 (s,
3 H, Mе); 5.53 (d, 1 H, =CH, J = 7.9 Hz); 7.07—7.44 (m, 8 H,
H arom.); 7.85—7.88 (m, 2 H, H arom.); 11.24 (d, 1 H, NH, J =
13.0 Hz).
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1ꢀ(5ꢀHydroxyꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ2ꢀ
(4ꢀnitroanilinomethylene)ꢀ4,4,4ꢀtrifluorobutaneꢀ1,3ꢀdione (10).
A solution of pyranopyrazole 2а (100 mg, 0.29 mmol) and
pꢀnitroaniline (60 mg, 0.44 mmol) in propanꢀ2ꢀol (3 mL) was
refluxed for 10 min. Then the solvent was evaporated, and the
residue was recrystallized from methanol. Compound 10 was
obtained as yellow crystals in a yield of 100 mg (72%), m.p.
157—158 °C. Found (%): C, 52.76; H, 3.60; N, 11.48.
11. V. Colotta, D. Catarzi, F. Varano, F. Melani, G. Filacchioni,
L. Cecchi, L. Trincavelli, C. Martini, and A. Lucacchini,
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USSR, 1977, 13 (Engl. Transl.)].
C
21H15F3N4O5•H2O. Calculated (%): C, 52.73; H, 3.58;
N, 11.71. IR, ν/cm–1: 1644, 1599, 1555, 1534, 1504, 1490.
1H NMR (DMSOꢀd6), δ: 2.44 (s, 3 H, Mе); 3.58 (br.s, 2 H,
H2O); 7.41 (t, 1 H, H(4´), Jo = 7.4 Hz); 7.55—7.60 (m, 2 H,
H(3´), H(5´)); 7.61—7.73 (m, 4 H, C6H4); 7.95 (d, 1 H, =CH,
J = 12.3 Hz); 8.22—8.26 (m, 2 H, H(2´), H(6´)); 10.25 (br.s,
1 H, OH); 12.14 (br.d, 1 H, NH, J ≈ 12.0 Hz).
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Int. Ed., 2003, 52, 1758].
(5ꢀHydroxyꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ4ꢀyl)[3(5)ꢀtriꢀ
fluoromethylꢀ1Hꢀpyrazolꢀ4ꢀyl]methanone (11). Pyranopyrazole
2а (100 mg, 0.29 mmol) was dissolved on heating in propanꢀ2ꢀol
(3 mL), and a 25% solution of hydrazine hydrate (80 mg,
18. B. S. Jensen, Acta Chem. Scand., 1959, 13, 1668.
Received July 11, 2005