2-Cyano-6-(trifluoromethyl)-4H-pyran-4-one: A novel versatile CF 3-containing building block

Article abstract of DOI:10.1016/j.jfluchem.2012.01.006

A highly electrophilic pyrone, 2-cyano-6-(trifluoromethyl)-4H-pyran-4-one, was synthesized. The reactions of this cyanopyrone with N-nucleophiles can proceed with or without substitution of the cyano group to give a wide range of novel trifluoromethylated compounds. An oxindole derivative was synthesized from a phenylhydrazide using unusual (acidic) conditions.

Full text of DOI:10.1016/j.jfluchem.2012.01.006

Journal of Fluorine Chemistry 137 (2012) 22–26
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
2-Cyano-6-(trifluoromethyl)-4H-pyran-4-one: A novel versatile CF3-containing
building block
a
b
a
Boris I. Usachev a, , Dmitrii L. Obydennov , Gerd-Volker Ro¨schenthaler , Vyacheslav Ya. Sosnovskikh
*
a Department of Chemistry, Ural Federal University, Kuybysheva st., 48, 620026 Ekaterinburg, Russia
b School of Engineering and Science, Jacobs University Bremen gGmbH, Campus Ring 1, 28759 Bremen, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
A highly electrophilic pyrone, 2-cyano-6-(trifluoromethyl)-4H-pyran-4-one, was synthesized. The
reactions of this cyanopyrone with N-nucleophiles can proceed with or without substitution of the cyano
group to give a wide range of novel trifluoromethylated compounds. An oxindole derivative was
synthesized from a phenylhydrazide using unusual (acidic) conditions.
Received 21 December 2011
Received in revised form 24 January 2012
Accepted 24 January 2012
Available online 16 February 2012
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
2-Cyano-6-(trifluoromethyl)-4H-pyran-4-
one
Carbamoylated aminoenones
Rotamers
Trifluoromethylated 2-pyridones
Oxindole
1. Introduction
2. Results and discussion
Trifluoromethylated and other fluoroalkylated pyrones [1] are
still poorly investigated compounds. The pyrone ring activated by
the trifluoromethyl group easily reacts with some nucleophilic
reagents, resulting in CF3-bearing heterocycles [1a,c–h,j,m,n].
However, the scope of nucleophiles, which are known to give
preparatively useful results in the reactions with CF3-pyrones, is
currently very limited.
2-Cyano-4-pyrones described in the literature [2] can be
prepared from the corresponding 4-pyrone-2-carboxamides [2a–
d], -carbaldehyde oximes [2e], -carbaldehyde dimethylhydrazones
[2f], and from kojic acid derivatives [2g–i]. Chemical properties of
2-cyanopyrones practically were not investigated. It is known that
azide anion reacts with 6- [2a–c] and 5-aryl-substituted [2c] 2-
cyano-4-pyrones on the cyano group without affecting the pyrone
ring to produce 2-tetrazolyl-4-pyrones. Alcoholysis of 2-cyano-5-
methoxy-4-pyrone also proceeds at the cyano group to give the
corresponding esters [2g]. Reactions of the 2-cyano-4-pyrones
with other nucleophiles are unknown so far.
We have shown that dehydration of pyronecarboxamide 1 [1g]
with trifluoroacetic anhydride in the presence of pyridine [2a]
leads to the formation of 2-cyano-6-(trifluoromethyl)-4-pyrone 2
(through intermediate A) in 61% yield (Scheme 1). It was found that
pyrone 2 due to the activation of the conjugated system by two
electron-withdrawing groups (CF3 and CN) is a highly electrophilic
substrate, which is able to react with different nucleophiles with or
without affecting the pyrone ring.
These reactions can be formally separated into two groups: the
reactions proceeding with substitution of the cyano group and the
reactions proceeding without substitution of the cyano group
(Scheme 2).
To the first group belong the reactions of 2 with amines and
hydrazines in polar protic solvents, whereas the second group
includes the reactions with phenylhydrazine in a nonpolar solvent
(toluene) and hydroxylamine. Thus, cyanopyrone 2 easily reacted
with both benzylamine and aniline in EtOH at ꢀ20 8C to produce
carbamoylated aminoenones 3a,b in 86–78% yield (Scheme 2). This
reaction describes a very high reactivity of the pyrone ring of 2 in
contrast to the pyrone ring of other 2-cyano-4-pyrones. Isolated
products 3 show that the reaction mechanism includes nucleo-
philic attack by the NH2 group of an amine at the C-2 and C-6 atoms
of 2.
In this paper, we report the synthesis and some properties of 2-
cyano-6-(trifluoromethyl)-4-pyrone, the first representative of
trifluoromethylated cyano-4-pyrones.
The regiochemistry of the reactions of 2 with hydrazine and
phenylhydrazine in EtOH is similar to those observed in the case of
* Corresponding author.
E-mail address: boris.usachev@mail.ru (B.I. Usachev).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2012.01.006

B.I. Usachev et al. / Journal of Fluorine Chemistry 137 (2012) 22–26
23
nucleophilic addition to the cyano group to give amidoxime 7 in
77% yield (Scheme 2). This reaction path can be explained by
O
O
4
(CF3CO)2O, Py
5
6
3
2
hardness of hydroxylamine, which is
a harder base then
0
20 oC
hydrazines, and reacts with a harder acid then the C-2 atom,
the carbon of the cyano group. The structures of compounds 3–7
were confirmed from NMR, IR spectra and elemental analysis. In
the 1H NMR spectra of carbamoylated aminoenones 3, the
NH2
F3C
O
1
F3C
O1 CN
2, 61%
O
characteristic singlets due to the methylene (
(3b)) and vinyl ( 5.75 (3a); 6.04 (3b)) protons were observed. The
8.57
d 3.36 (3a); 3.64
O
d
amide and enamine NH protons in 3a appeared as triplets at
d
(3JNH;CH ¼ 5:9 Hz) and 10.25 (3JNH;CH ¼ 6:7 Hz), whereas the same
2
2
protons in 3b appeared as singlets at
d 10.16 and 11.26,
O
CF3
F3C
O
respectively.
In the 1H NMR spectra (DMSO-d6) of hydrazides 4, two sets of
signals belonging to syn-4 and anti-4 rotamers [3] were observed
(Scheme 3). The corresponding protons (besides the PhNH
protons) in the corresponding sin- and anti-rotamers have almost
the same chemical shifts. Intramolecular hydrogen bond-stabilized
syn-4a,b rotamers (major) can be recognized in the 1H NMR
spectra by the low-field signals of the CONH protons, which
NH
O
A
Scheme 1.
the amine attack. These reactions afforded derivatives of 2-(3-
(trifluoromethyl)pyrazol-5-yl)acetic acid 4a,b in 44 and 70% yields,
respectively. The interaction of 2 with o-phenylenediamine in
acetic acid solution at ambient conditions led to the formation of
benzimidazole derivative 5 (the double attack of two NH2 groups at
the C-2 carbon), which was isolated from a complex mixture of
other products in 13% yield.
It was found that phenylhydrazine attacks pyrone 2 in a non-
polar medium at the atom C-4, and this result is in agreement with
our previous findings on a strong solvent influence on the reaction
route by using pyrones related to 2 as substrates [1f]. Heating 2
with this nucleophile in toluene resulted in the formation of
phenylhydrazone 6, but the yield of this compound did not exceed
33% because resinification. The difference in the regioselectivity of
nucleophilic attack can be explained by the effective stabilization
of highly polar cyclic tetrahedral addition intermediates (attack at
the C-2 carbon of the pyrone ring) in polar solvents, which cannot
be easily formed in nonpolar media. Surprisingly, the reaction
appeared at
protons in the minor (anti-) rotamers appeared as signals at the
higher field ( 8.55 and 9.25, respectively). According to the
d 9.25 (syn-4a) and 9.84 (syn-4b), whereas the same
d
spectral data the equilibria molar ratios of syn-4 to anti-4 in DMSO-
d6 are 95:5 (4a) and 84:16 (4b) (Scheme 3).
In the 19F NMR spectrum (DMSO-d6, C6F6) of 4a two singlets due
to the CF3 groups in syn- (
d
102.3) and anti- (
d
102.4) rotamers were
observed. The corresponding singlets at
d
101.8 and 101.9 were
found in the 19F NMR spectrum of 4b. The 19F NMR spectroscopy
confirms the ratios of the rotamers as stated above. The
regioisomeric 3-CF3-pyrazolic structure of 4b was confirmed by
the synthesis of the parent carboxylic acid (see below).
In the 1H NMR spectrum of benzimidazole derivative 5 besides
the signals of the aromatic protons, singlets due to the methylene
(
d
3.42) and vinyl (
protons appeared as singlets at
spectrum (DMSO-d6, C6F6) of 5 a high-field singlet at d
d
5.81) protons were observed. Two labile
10.63 and 12.33. In the 19F NMR
87.0 due to
d
between
2
and hydroxylamine in ethanol proceeds by the
the CF3 group was observed, thus additionally confirming the
enolized diketone structure. In the 1H NMR spectra of compounds 6
and 7, the protons H-3 and H-5 appeared as characteristic doublets
in the range of
[1g].
Derivatives synthesized from 2-cyano-6-(trifluoromethyl)-4-
pyrone 2 can be used in subsequent transformations for the
preparation of novel trifluoromethylated building blocks. Thus,
treatment of carbamoylated aminoenones 3a,b with HCl in THF,
led to the formation of 4-hydroxy-6-(trifluoromethyl)-2-pyridones
8a,b, the first representatives of trifluoromethylated 3,5-unsub-
stituted 4-hydroxy-2-pyridones, in 98 and 45% yields, respectively
(Scheme 4).
O
F3C
NHNHR
d
6.8–7.7 (4J = 2.2 Hz), proving their pyrone nature
N
N
4a R = H, 44%
R
b R = Ph, 70%
RNHNH2,
EtOH
R
NH
O
O
H2N
NH2
H
N
O
O
RNH2
F3C
NHR
N
H
3a R = Bn, 86%
F3C
-
-CN
b R = Ph, 78%
5, 13%
O
F3C
O
CN
2
NH2OH
PhNHNH2,
PhMe
O
O
NNHPh
NOH
NH2
F3C
F3C
O
CN
6, 33%
7, 77%
Scheme 2.
Scheme 3.

24
B.I. Usachev et al. / Journal of Fluorine Chemistry 137 (2012) 22–26
OH
explained by relatively high stability of the main intermediate B
R
due to its push-pull electronic structure (Scheme 4). The structure
of oxindole 10 was confirmed from 1H NMR, IR spectroscopies, and
elemental analysis. In the 1H NMR spectrum of 10 besides signals
due to nine protons of the benzene rings, singlets due to the
HCl
NH
O
O
F3C
NHR
F3C
N
R
O
a R = Bn
b R = Ph
methine (d 5.11), pyrazole (d 6.66), and NH (d 10.64) protons were
3a,b
8a, 98%
b, 45%
observed.
Heating amidoxime 7 with trifluoroacetic anhydride in the
presence of pyridine gave 2-(trifluoromethyl)-6-[5-(trifluoro-
methyl)-1,2,4-oxadiazol-3-yl]-4-pyrone 11 in 81% yield. Pyrone
11 was characterized by conventional spectroscopic methods.
O
O
F3C
4
F3C
NHNHPh
3
OH
HCl
5
N
N
2 N
3. Conclusion
N
N
N
1 R
4a,b
9a, 41%
b, 80%
Ph
a R = H
Thus, we have synthesized the first representative of trifluor-
omethylated cyano-4-pyrones, 2-cyano-6-(trifluoromethyl)-4-
pyrone, shown its high reactivity towards N-nucleophiles and
revealed its rich chemistry. It was found that this highly
electrophilic pyrone can be used as a novel CF3-containing
building block for the regioselective syntheses of various
trifluoromethylated heterocycles. These results will be very useful
for development of chemistry of other functionalized CF3(RF)-
bearing cyano-4-pyrones and related compounds.
b R = Ph
TsOH,
HO
HO
F3C
F3C
NH
NH2
NH
+
NH2
-H+
N
N
Ph
Ph
B
C
H+
4. Experimental
O
+
HO NH3
NH
F3C
F3C
4.1. General
NH
+
-NH4
1H, 19F and 13C NMR spectra were recorded on Bruker AVANCE
DRX-400 spectrometer. Chemical shifts for 1H NMR spectra are
reported in parts per million (ppm) downfield from TMS. 19F NMR
N
N
N
N
Ph
Ph
D
10, 44%
spectra were externally referenced against C6F6 (
d
= ꢀ163 relative
to CFCl3). Coupling constants (J) are given in hertz (Hz). Infrared
spectra (IR) were recorded on Nicolet 6700 spectrometer, equipped
with attenuated total reflection accessory (ATR), absorbance
frequencies are given at maximum of intensity in cmꢀ1
O
O
O
.
(CF3CO)2O
Py,
4.2. 2-Cyano-6-(trifluoromethyl)-4H-pyran-4-one (2)
N
O
NOH
NH2
F3C
F3C
O
4-Oxo-6-(trifluoromethyl)-4H-pyran-2-carboxamide [1g]
1
N
7
(8.0 g, 38.6 mmol) was added to a mixture of dioxane (75 mL)
and pyridine (7.8 mL). To the mixture cooled in an ice bath was
gradually added with stirring trifluoroacetic anhydride (9.7 mL).
The mixture was stirred for 5 min on ice and then 30 min at
ambient conditions. The resulting solution was diluted with water
(100 mL) and the product was extracted twice with chloroform
(50 mL portions). In distillation, the main fraction was collected at
98–102 8C/ꢁ25 Torr to give compound 2 as a colourless liquid
11, 81%
CF3
Scheme 4.
Hydrolysis of the hydrazides 4a,b in the presence of HCl
resulted in the formation of 2-[3-(trifluoromethyl)pyrazol-5-
yl]acetic (9a, 41%) and 2-[1-phenyl-3-(trifluoromethyl)pyrazol-
5-yl]acetic (9b, 80%) acids, which were prepared for the first time.
The regioisomeric 3-CF3-pyrazolic structure of 9b was confirmed
by the 13C NMR spectroscopy. In the 13C NMR spectrum of 9b, a
low-field quartet due to the most deshielded pyrazole carbon C-3
(4.45 g, 61%); nmax (ATR) 2340, 1673, 1407, and 1349 cmꢀ1
; dH
(400 MHz, CDCl3) 6.84 (1H, d, J 2.0 Hz, H-5), 6.91 (1H, d, J 2.0 Hz, H-
3); H (400 MHz, DMSO-d6) 6.71 (1H, d, J 2.5 Hz, H-5), 6.92 (1H, d, J
d
2.5 Hz, H-3); dF (376.5 MHz, CDCl3, C6F6) 90.3 (s, CF3); [found: C,
44.39; H, 0.87; N, 7.71. C6H2F3NO2 requires C, 44.46; H, 1.07; N,
7.41%].
at
chemistry.
It is known, that oxindole derivatives can be synthesized
d
141.0 (2JC,F = 37.5 Hz) was observed, confirming this regio-
through deprotonation of some phenylhydrazides with strong
bases (Brunner reaction, an analog to the Fischer indole synthesis)
[4a,b] as well as via alkylidenation of N,N0-dimethylated phenyl-
hydrazides using phosphoranes [4c]. There are no data on the use
of acidic conditions (conditions of the Fischer reaction) for the
formation of the indole ring via cyclization of phenylhydrazides.
We have found that phenylhydrazide 4b undergoes transformation
into indole 10 (44%) by heating in toluene in the presence of TsOH
within 4 h (Scheme 4). This reaction is the first example of indole
synthesis from a phenylhydrazide in the conditions of the Fischer
reaction. The formation of the oxindole in acidic conditions can be
4.3. (Z)-N-benzyl-5-(benzylamino)-6,6,6-trifluoro-3-oxohex-4-
enamide (3a)
A cooled to ꢀ20 8C solution of benzylamine (0.85 g, 7.8 mmol)
in ethanol (2 mL) was added to a cooled to ꢀ20 8C solution of 2
(0.50 g, 2.6 mmol) in ethanol (2 mL). The mixture was kept at
ꢀ20 8C for 2 d. The residue was filtered off, washed with cold
ethanol and the filtrate was diluted with water (5 mL). The residue
from the filtrate was filtered off, washed with water and dried. The
combined residue was crystallized from a mixture of hexane
(25 mL) and toluene (7 mL) to give compound 3a (0.84 g, 86%) as

B.I. Usachev et al. / Journal of Fluorine Chemistry 137 (2012) 22–26
25
yellow crystals, mp 98 8C;
n
max (ATR) 3279, 1644, 1601, 1545, and
mixture was kept at ambient conditions for 7 d, and then diluted
with water (10 mL) with conc. HCl (3 drops). The resulting residue
was filtered off, crystallized from ethanol (5 mL), washed with
ethanol (1 mL) and dried to give compound 5 (44 mg, 13%) as an
orange solid, mp 254–256 8C (decomp.); nmax (ATR) 1681, 1597,
1496 cmꢀ1
;
d
H (400 MHz, DMSO-d6) 3.36 (2H, s, CH2), 4.28 (2H, d, J
5.9 Hz, CH2), 4.55 (2H, d, J 6.7 Hz, CH2), 5.75 (1H, s,55CH), 7.22–7.41
(10H, m, Ph), 8.57 (1H, t, J 5.9 Hz, CONH), 10.25 (1H, t, J 6.7 Hz, NH);
[found: C, 63.89; H, 4.88; N, 7.61. C20H19F3N2O2 requires C, 63.82;
H, 5.09; N, 7.44%].
1574, 1524 cmꢀ1
; dH (400 MHz, DMSO-d6) 3.42 (2H, s, CH2), 5.81
(1H, s,55CH), 7.17–7.27 (m, 2 H, arom.); 7.33 (td, J = 7.6, 1.3 Hz, 1 H,
arom.); 7.49 (1H, dd, J 8.0, 1.0 Hz, arom.), 10.63 (1H, s, NH), 12.33
4.4. (Z)-N-phenyl-5-(phenylamino)-6,6,6-trifluoro-3-oxohex-4-
enamide (3b)
(1H, s, OH); dF (376.5 MHz, DMSO-d6, C6F6) 87.0 (s, CF3); [found: C,
48.51; H, 3.59; N, 9.35. C12H9F3N2O2ꢂ1.5 H2O requires C, 48.49; H,
A cooled to ꢀ20 8C solution of aniline (0.74 g, 7.8 mmol) in
ethanol (2 mL) was added to a cooled to ꢀ20 8C solution of 2
(0.50 g, 2.6 mmol) in ethanol (2 mL). The reaction mixture was
kept at ꢀ20 8C for 2 d. The residue was filtered off, washed with
cold ethanol and the filtrate was diluted with water (5 mL). The
residue from the filtrate was filtered off, washed with water (2 mL)
and dried. The combined residue was crystallized from a mixture of
hexane (25 mL) and toluene (5 mL) to give compound 3b (0.71 g,
78%) as yellow crystals, mp 108 8C; nmax (ATR) 1689, 1659, 1626,
4.07; N, 9.42%].
4.8. 2-Cyano-6-(trifluoromethyl)-4H-pyran-4-one phenylhydrazone
(6)
Phenylhydrazine (0.16 g, 1.5 mmol) was added to a solution of
pyrone 2 (0.25 g, 1.3 mmol) in toluene (2 mL). The reaction
mixture was refluxed for 2 h and then cooled to ambient
temperature. The resulting residue was filtered off and recrys-
tallized from toluene to give compound 6 (0.12 g, 33%) as a red
solid, mp 214–215 8C; dH (400 MHz, DMSO-d6): 6.80 (1H, d, J
2.2 Hz, H-5), 6.82 (1H, t, J 7.3 Hz, Ph), 7.10 (2H, d, J 7.7 Hz, Ph), 7.23
(2H, t, J 7.5 Hz, Ph), 7.69 (1H, d, J 2.2 Hz, H-3); dF (376.5 MHz,
DMSO-d6, C6F6) 92.0 (s, CF3); [found: C, 55.79; H, 2.81; N, 14.99.
C13H8F3N3O requires C, 55.92; H, 2.89; N, 15.05%].
1596, 1578, and 1548 cmꢀ1
; dH (400 MHz, DMSO-d6) 3.64 (2H, s,
CH2), 6.04 (1H, s,55CH), 7.06 (1H, t, J 7.4 Hz, Ph), 7.20–7.44 (5H, m,
Ph), 7.59 (2H, dd, J 8.6, 1.0 Hz, Ph), 10.16 (1H, s, CONH), 11.26 (1H, s,
NH). dF (376.5 MHz, CDCl3, C6F6) 100.1 (s, CF3); [found: C, 62.08; H,
4.13; N, 8.09. C18H15F3N2O2 requires C, 62.07; H, 4.34; N, 8.04%].
4.5. 2-[3-(Trifluoromethyl)pyrazol-5-yl]acetohydrazide (4a)
4.9. 4-Oxo-6-(trifluoromethyl)-4H-pyran-2-amidoxime (7)
A cooledsolutionofpyrone 2 (0.20 g, 1.1 mmol) inethanol(1 mL)
was added to a cooled solution of hydrazine hydrate (3 drops) in
ethanol (1 mL). The reaction mixture was stirred at 0 8C for 1 h. The
residue was filtered off, washed with ethanol (1 mL) and dried to
give compound 4a (0.097 g, 44%) as colourless crystals, mp 184–
A solution of hydroxylamine prepared in ethanol (2 mL) from
NH2OHꢂHCl (0.36 g, 5.6 mmol) and KOH (0.23 g, 5.3 mmol) was
added to a cooled solution of pyrone 2 (0.50 g, 2.65 mmol) in
ethanol (2 mL). The reaction mixture was stirred at 0 8C for 30 min.
The residue was filtered off, crystallized from ethanol (25 mL) and
dried to give compound 7 (0.45 g, 77%) as a white solid, mp
185 8C; n ; dH
max (ATR) 3298, 3238, 3184, 1644, 1544, and 1499 cmꢀ1
(400 MHz, DMSO-d6) 3.49 (2H, s, CH2), 4.26 (2H, s, NH2), 6.48 (1H, s,
CH-pyraz.), 9.25 (1H, s, CONH), 13.1–13.7 (1H, br s, NH-pyraz.); dF
ꢁ237 8C (subl.);
n ; dH (400 MHz, DMSO-
max (ATR) 3290, 1640 cmꢀ1
(376.5 MHz, DMSO-d6, C6F6) 102.3 (s, CF3);
d
C (100 MHz, DMSO-d6)
d6) 6.10 (2H, s, NH2), 6.86 (1H, d, J 2.2 Hz, H-5), 7.04 (1H, d, J 2.2 Hz,
H-3), 10.73 (1H, s, OH); dF (376.5 MHz, DMSO-d6, C6F6) 92.4 (s,
CF3); [found: C, 37.81; H, 2.46; N, 12.52. C7H5F3N2O3 requires C,
37.85; H, 2.27; N, 12.61].
30.5 (CH2), 102.7 (C4), 121.9 (q, 1JC,F 267.9 Hz, CF3), 139.2 (C5), 140.9
(q, 2JC,F 36.7 Hz, C3), 167.1 (CO); [found: C, 34.58; H, 3.38; N, 26.85.
C6H7F3N4O requires C, 34.62; H, 3.39; N, 26.92%].
4.6. N0-phenyl-2-[N-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-
4.10. N-benzyl-4-hydroxy-6-(trifluoromethyl)-2-pyridone (8a)
yl]acetohydrazide (4b)
To a solution of enaminone 3a (0.10 g, 0.27 mmol) in ethanol
(2 mL) was added conc. HCl (0.5 mL). The mixture was kept for 3
weeks at ambient temperature. The reaction mixture was diluted
with water (10 mL), the resulting residue was crystallized from a
mixture of petroleum ether and toluene (4:1, 10 mL) to give
compound 8a (70 mg, 98%) as beige solid, mp 166–167 8C.
Alternatively, compound 8a was prepared by treatment of a
solution of enaminone 3a (0.11 g, 0.29 mmol) in THF (2 mL) with
conc. HCl (0.5 mL). The mixture was refluxed for 6 h and then
diluted with water (10 mL) to give compound 8a in 47% yield, mp
166–167 8C (toluene); nmax (ATR) 3093, 1658, 1630, 1560,
A cooled to ꢀ20 8C solution of pyrone 2 (1.0 g, 5.3 mmol) in
ethanol (5 mL) was added to a cooled to ꢀ20 8C solution of
phenylhydrazine (1.25 g, 11.6 mmol) in ethanol (5 mL). The
reaction mixture was kept at ꢀ5 8C conditions for 2 d. Then the
reaction mixture was diluted with water (50 mL), the resulting
residue was filtered off, washed with water (5 mL), dried and
crystallized from toluene to give compound 4b (1.33 g, 70%) as a
white solid, mp 151–152 8C; dH (400 MHz, DMSO-d6): syn-4b (84%)
3.78 (2H, s, CH2), 6.55 (2H, d, J 7.6 Hz, Ph), 6.69 (1H, t, J 7.3 Hz, Ph),
6.88 (1H, s, pyraz.), 7.10 (2H, t, J 7.5 Hz, Ph), 7.56–7.62 (5 H, m, Ph),
7.73 (1H, d, J 2.4 Hz, PhNHNH), 9.84 (1H, d, J 2.4 Hz, PhNHNH), anti-
4b (16%) 3.79 (2H, s, CH2), 6.56 (2H, d, Ph), 6.76 (1H, t, J 7.3 Hz, Ph),
6.83 (1H, s, pyraz.), 7.14 (2H, t, J 7.5 Hz, Ph), 7.43–7.47 (2H, m, Ph),
7.51–7.55 (3H, m, Ph), 7.95 (1H, s, PhNHNH), 9.25 (1H, s, PhNHNH);
1496 cmꢀ1
; dH (400 MHz, DMSO-d6) 5.18 (2H, s, CH2), 5.95 (1H,
d, J 2.4 Hz, H-3), 6.57 (1H, d, J 2.4 Hz, H-5), 7.01 (2H, d, J 7.3 Hz, Ph),
7.22 (1H, t, J 7.3 Hz, Ph), 7.30 (2H, t, J 7.3 Hz, Ph), 10.9–11.9 (1H, br
s, OH); [found: C, 58.01; H, 3.97; N, 5.22. C13H8F3N3O requires C,
58.00; H, 3.74; N, 5.22%].
d
F (376.5 MHz, DMSO-d6, C6F6) syn-4b (84%) 101.8 (s, CF3); anti-4b
(16%) 101.9 (s, CF3); [found: C, 59.70; H, 4.08; N, 15.38.
18H15F3N4O requires C, 60.00; H, 4.20; N, 15.55].
C
4.11. N-phenyl-4-hydroxy-6-(trifluoromethyl)-2-pyridone (8b)
4.7. (Z)-1-(1H-Benzo[d]imidazol-2-yl)-5,5,5-trifluoro-4-
To a solution of enaminone 3b (0.10 g, 0.29 mmol) in THF (2 mL)
was added conc. HCl (0.5 mL). The mixture was refluxed for 6 h and
then diluted with water (10 mL). The resulting residue was
crystallized from toluene (2 mL) to give compound 8b (33 mg, 45%)
hydroxypent-3-en-2-one (5)
To a solution of pyrone 2 (0.20 g, 1.1 mmol) in acetic acid (2 mL)
was added o-phenylenediamine (0.12 g, 1.2 mmol). The reaction
as beige solid, mp 208–209 8C; dH (400 MHz, DMSO-d6) 5.89 (1H, d,

26
B.I. Usachev et al. / Journal of Fluorine Chemistry 137 (2012) 22–26
J 2.2 Hz, H-3), 6.55 (1H, d, J 2.2 Hz, H-5), 7.22–7.32 (2H, m, Ph),
7.43–7.53 (3H, m, Ph), 11.42 (1H, br s, OH); [found: C, 56.17; H,
3.16; N, 5.56. C12H8F3NO2 requires C, 56.48; H, 3.16; N, 5.49%].
(0.22 g, 81%) as colourless crystals, mp 87–88 8C; dH (400 MHz,
DMSO-d6) 7.26 (1H, d, J 2.0 Hz), 7.30 (1H, d, J 2.0 Hz); dF
(376.5 MHz, DMSO-d6, C6F6) 92.5 (3F, s, pyrone-CF3); 98.0 (3F, s,
oxadiaz.-CF3); [found: C, 36.04; H, 0.67; N, 9.35. C9H2F6N2O3
requires C, 36.02; H, 0.67; N, 9.33%].
4.12. 2-[3-(Trifluoromethyl)pyrazol-5-yl]acetic acid (9a)
Hydrazide 4a (0.24 g, 1.15 mmol) was refluxed in conc. HCl
(2 mL) for 4 h. After cooling the reaction mixture to ꢀ20 8C, the
residue (N2H4ꢂ2 HCl) was filtered off, the filtrate was collected,
water and HCl were evaporated the filtrate and the residue was
crystallized from a mixture of petroleum ether and toluene to give
compound 9a (91 mg, 41%) as a white solid, mp 140–141 8C; dH
(400 MHz, DMSO-d6) 3.7 (2H, s, CH2), 6.55 (1H, s, pyraz.), 12.5–12.9
(1H, br s, NH), 13.45 (1H, br s, CO2H); [found: C, 37.16; H, 2.65; N,
14.45. C6H5F3N2O2 requires C, 37.13; H, 2.50; N, 14.43].
Acknowledgments
The authors thank Ural Federal University and the Deutsche
Forschungsgemeinschaft for financial support (grant No. RO 362/
45-1).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2012.01.006.
4.13. 2-[N-phenyl-3-(trifluoromethyl)pyrazol-5-yl]acetic acid (9b)
Phenylhydrazide 4b (0.20 g, 0.60 mmol) was added to conc. HCl
(7 mL). The reaction mixture was refluxed for 6 h, cooled to
ambient temperature, and then diluted with water (8 mL). The
resulting residue was filtered off and crystallized from a mixture of
petroleum ether and toluene (1:1, 5 mL) to give compound 9b
(0.12 g, 80%) as colourless crystals, mp 125–126 8C; nmax (ATR)
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(10)
A mixture of phenylhydrazide (0.20 g, 0.55 mmol) and TsOH
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passed through silica gel (1 cm3), and the solvent from filtrate was
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nmax (ATR) 3084, 1705, 1621, 1483; dH (400 MHz, DMSO-d6) 5.11
(1H, s, CH), 6.66 (1H, s, pyraz.), 6.80 (1 H, d, J 7.8 Hz, arom.), 6.94
(1H, t, J 7.5 Hz, arom.), 7.08 (1H, d, J 7.5 Hz, arom.), 7.21 (1H, t, J
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