Regioselective synthesis of trifluoromethylated 3-(pyrazolyl)indoles on the basis of 6-(trifluoromethyl)comanic acid

Article abstract of DOI:10.1016/j.jfluchem.2011.12.008

A number of trifluoromethylated 3-(pyrazolyl)indoles was synthesized from 2-(trifluoromethyl)comanic acid, its ethyl ester and amide via intermediate isomeric 5(3)-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]pyrazole-3(5)- carboxylic acids and their deriva

Full text of DOI:10.1016/j.jfluchem.2011.12.008

Journal of Fluorine Chemistry 135 (2012) 278–284
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Regioselective synthesis of trifluoromethylated 3-(pyrazolyl)indoles on the
basis of 6-(trifluoromethyl)comanic acid
*
Boris I. Usachev , Dmitrii L. Obydennov, Vyacheslav Ya. Sosnovskikh
Department of Chemistry, Ural Federal University, pr. Lenina 51, 620083 Ekaterinburg, Russia
A R T I C L E I N F O
A B S T R A C T
Article history:
A number of trifluoromethylated 3-(pyrazolyl)indoles was synthesized from 2-(trifluoromethyl)comanic
acid, its ethyl ester and amide via intermediate isomeric 5(3)-[3,3,3-trifluoro-2-(phenylhydrazono)-
propyl]pyrazole-3(5)-carboxylic acids and their derivatives.
Received 23 August 2011
Received in revised form 10 December 2011
Accepted 14 December 2011
Available online 22 December 2011
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
6-(Trifluoromethyl)comanic acid
3-(Pyrazolyl)indoles
Trifluoromethylated heterocycles
Fischer reaction
Regioselectivity
1. Introduction
pyl]-1-phenyl-1H-pyrazole-3-carboxylic acid derivatives 2,
whereas in an aprotic solvent the reaction afforded the derivatives
Trifluoromethylated indoles are not a widely distributed group
of compounds and attract attention due to two pharmacophoric
fragments: the indole moiety and the trifluoromethyl group. 2-
(Trifluoromethyl)indole and its 3-substituted derivatives have
been synthesized via various approaches [1–20]. Most pertinent to
the present research are the reactions involving phenylhydrazones
of the regioisomeric 3-[3,3,3-trifluoro-2-(phenylhydrazono)pro-
pyl]-1-phenyl-1H-pyrazole-5-carboxylic acid 3.
Two approaches pointed above allow preparation of some CF3-
indoles by the Fischer reaction using phenylhydrazones of
a-
trifluoromethyl ketones as the substrates and either MeSO3H (in
AcOH) [18] or p-TsOH (in toluene) [19,20] as promotors. However,
when we tried to use these approaches for 2a to prepare the
corresponding trifluoromethylated 3-(pyrazolyl)indole, only trace
amounts of the expected indole were detected by 1H and 19F NMR.
In this paper, we describe our results concerning the
regioselective synthesis of some trifluoromethylated 3-(pyrazoly-
l)indoles from phenylhydrazones 2 and 3, and show a wide variety
of novel compounds, which can be obtained by using only one, the
base structure, 6-(trifluoromethyl)comanic acid 1a. 2-Trifluoro-
methyl-3-(pyrazolyl)indoles are described for the first time
(Scheme 1).
of
a
-trifluoromethyl ketones [18–20].
The synthesis of trifluoromethylated indoles is of great
significance in medicinal chemistry, because it is known, that
some representatives of this group of compounds possess anti-
diabetic activity [21]. Moreover, various 3-(pyrazolyl)indoles,
which were synthesized earlier using different approaches [22–
34], exhibit a broad spectrum of biological activity [24–35], but 4-
[5-(indol-3-yl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfona-
mide is the most potent inhibitor of PDK-kinase among other
investigated 4-[5-hetaryl-3-(trifluoromethyl)pyrazol-1-yl]benze-
nesulfonamides [36,37].
Recently we have found [38] that the reactions of non-
symmetrically substituted polyelectrophilic substrates such as
6-(trifluoromethyl)comanic acid and its derivatives 1 [39], with
phenylhydrazine were exclusively selective based on the nature of
the solvent. Treatment of these pyrones with PhNHNH2 in a polar
protic solvent gave 5-[3,3,3-trifluoro-2-(phenylhydrazono)pro-
2. Results and discussion
We have found that phenylhydrazones 2 as well as 3 can be
transformed into the first representatives of 2-CF3-3-(pyrazoly-
l)indoles, regioisomeric compounds 4 and 5, respectively in 25–
73% yield by heating in MeSO3H in the presence of P4O10 (15%). 3-
(Pyrazolyl)indoles 5, derivatives of pyrazol-5-carboxylic acid, were
synthesized by both approaches, via using MeSO3H/AcOH18 and
MeSO3H/P4O10 (Scheme 2). The structures of indoles 4 and 5 were
confirmed by NMR and IR spectroscopies, and elemental analysis.
* Corresponding author. Tel.: +7 343 261 6824; fax: +7 343 261 5978.
E-mail address: boris.usachev@mail.ru (B.I. Usachev).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.12.008

B.I. Usachev et al. / Journal of Fluorine Chemistry 135 (2012) 278–284
279
O
mixture of products, whereas the use of N2H4ꢀ2HCl (2.2 equiv) in
water according to 1H NMR spectra gave a mixture of regioisomeric
pyrazoles 6 and 7 (Scheme 3). Insoluble in water isomer 6 was
easily separated from the reaction mixture by filtration (30% yield)
and soluble isomer 7 was not isolated, but transformed rapidly to
phenylhydrazone 8 by treatment of the residue, prepared after
evaporation of water from the filtrate, with excess phenylhydra-
zine hydrochloride (56% yield). Analogously, compound 6 was
transformed into the corresponding phenylhydrazone 9 (63%
yield) by treatment with excess PhNHNH2ꢀHCl. The stable enol
form of ketone 6 (according to the 1H NMR spectrum) can be
explained by the formation of strong intramolecular hydrogen
bond (IHB) between the enol OH group and pyrazole nitrogen
X
3
N2
4
O
5
1
N
2''
1''
H
N
3''
4''
2'
X
1'
CF3
2a,b
N
F3C
O
3'
4'
O
1a-c
O
X
3''
2''
atom. In the 1H NMR spectra of 6 singlets due to the vinyl (
and pyrazole ( 6.82) protons were observed. The labile protons
appeared as broad signals at
9.55 and 13.30. In the 19F NMR
spectrum of compound 6, the trifluoromethyl group appeared as a
singlet at 101.5 confirming that this compound belongs to class of
CF3-pyrazoles [40,41]. Phenylhydrazones of -trifluoromethyl
d 6.39)
a X = OH
b X = OEt
c X = NH2
4''
5
1''
1
d
4
N
d
3
N2
H
N
d
2'
1'
CF3
3a-c
a
N
3'
4'
ketones such as 2, 3 and 8 are the E-isomers (CF3 is a more bulky
O
Scheme 1. Starting compounds for the synthesis of trifluoromethylated 3-
(pyrazolyl)indoles.
F3C
O
1a
CO2H
In the 1H NMR spectra (DMSO-d6) the signals of the indole protons
were similar to those observed for other 2-trifluoromethylindoles
[14,18–20]. The pyrazole proton in derivatives of 1-phenylpyr-
azole-3-carboxylic acid 4 appeared as a singlet in a little higher
.
2HCl
N2H4
field (
phenylpyrazole-5-carboxylic acid 5 (
spectra (DMSO-d6, C6F6) of 4 and 5 the signal at about
d
7.01–7.11) than the same proton in derivatives of 1-
7.16–7.24). In the 19F NMR
105–106
d
d
O
CF3
NH
corresponding to the trifluoromethyl group at the C-2 atom of the
indole moiety was observed [14]. In the 13C NMR spectra of
compound 4b, atoms C-2 and C-3 of the indole ring appeared as
OH
NH
N
H
characteristic quartets at
(3JC,F = 2.8 Hz). The carbon atom of the trifluoromethyl group
appeared as quartet at
121.0 (1JC,F = 269.7 Hz).
d
123.0 (2JC,F = 36.7 Hz) and 105.0
N
H
O
O
d
O
7
F3C
OH
There are no data in the literature on the reaction of non-
annulated 2-trifluoromethyl-4-pyrones with hydrazine. We have
investigated the reaction of 1a with N2H4 under various conditions
and found that the use of hydrazine as a free base led to a complex
6
.
HCl
PhNHNH2
O
N
O
X
CF3
NH
CF3
NH
X
O
OH
N
N
+
N
N
NH
N
O
HO
NHPh
N
Ph
N
N
PhHN
Ph
i
N
PhHN
CF3
O
HO
CF3
CF3
N
NPh
H
N
H
8
(E)-9
(Z)-9
3 : 2
2a,b
4a,b
a X = OH
b X = OEt
c X = NH2
X
O
MeSO3H, P4O10
O
X
Ph
N
N
O
N
HO
F3C
N Ph
N
N
i or ii
NH
NH
PhHN
CF3
3a-c
CF3
N
O
N
H
CF3
5a-c
i: MeSO3H, P4O10
,
N
H
N
H
OH
ii: MeSO3H, AcOH,
11
10
Scheme 2. Synthesis of regioisomeric trifluoromethylated 3-(pyrazolyl)indoles.
Scheme 3. Synthesis of N-unsubstituted trifluoromethylated 3-pyrazolylindoles.

280
B.I. Usachev et al. / Journal of Fluorine Chemistry 135 (2012) 278–284
Fig. 1. Molecular structure of 3b and its packing diagram (X-ray data, CCDC 822163).
group than CH2), and this postulate was confirmed earlier for
phenylhydrazones of other -trifluoromethyl ketones, bearing an
a0-CH2 group [20]. The E-isomeric structure of such phenylhy-
drazones of -trifluoromethyl ketones was unambiguously
confirmed by X-ray crystallographic analysis of phenylhydrazone
3b (Fig. 1, CCDC 822163). In contrast to 8, phenylhydrazone 9 is a
mixture of the E- and Z-isomers (ratio 3:2, 1H NMR data). Both of
these isomers were isolated from the mixture separately in
analytically pure forms. In the 1H NMR spectrum of 9 two sets of
signals of (E)-9 and (Z)-9 were observed. The characteristic NH
proton of the phenylhydrazonic moiety in major isomer (E)-9
1,1,1-trifluoro-5-(1-phenylpyrazol-3-yl)propan-2-one (14) (21%),
whereas thiopyrone 12b led to the formation only compound 13 in
14% yield (no isomer 14 was detected in a crude sample of
compound 13 prepared from 12b) (Scheme 4). Compounds 13 and
14 could be easily recognized using as an indicator the values of the
vicinal coupling constants between H3–H4 and H4–H5 in the 1H
NMR spectra. According to literature, in case of 13 the value of
3JH3,H4 has to be 1.6–2.0 Hz, whereas in case of 14 the value of
3JH4,H5 should be >2.0 Hz [22,23]. The observed value of the
coupling constant of 1.8 Hz for 13 and 2.1 Hz for 14 proves these
structures. Heating 13 in MeSO3H in the presence of P4O10 gave 3-
(1-phenylpyrazol-5-yl)-2-(trifluoromethyl)indole 15 in 60% yield.
The same reaction conducted in MeSO3H/AcOH afforded 15 in 65%
a
a
appeared as a singlet at d 10.26 confirming the E-isomeric structure
(almost the same values have phenylhydrazones 2 and 3) [38]. The
value of 10.26 indicates that even the substitution of the CF3 group
in the phenylhydrazonic moiety by the CO2H group has almost no
influence on the chemical shift of the NH proton. The methylene
O
and pyrazole protons in (E)-9 appeared as singlets at
d 4.05 and
6.26, respectively. Minor isomer (Z)-9 was presented in the 1H
NMR spectrum by singlets of the methylene and pyrazole protons
at
d
3.84 and 6.44, respectively, and a very low-field signal of the
12.2) due to the formation of the
F3C
X
phenylhydrazonic NH proton (
IHB between NH and C55O. The same low-field signal of the NH
proton was observed in the spectra of a structurally similar
d
12a X = O
b X = S
PhNHNH2
X = O,S
dicarboxylic acid, bearing at the
a-position a phenylhydrazonic
substituent ( 12.1) [38]. Heating the mixture of (E)-9 and (Z)-9 in
d
X = O
MeSO3H/P4O10 afforded 3-[3-(trifluoromethyl)pyrazol-5-yl]in-
dole-2-carboxylic acid 10 in 35% yield. Regioisomeric indole 11
was prepared from 8 in 39% yield using the same approach. The use
as a reaction medium MeSO3H/AcOH do not allow preparation of
10 or 11 even in a smaller yields due to resinification of the reaction
mixtures. The structures of the regioisomeric indoles 10 and 11
were confirmed by spectral methods and elemental analysis.
Thus, it has been shown, that the consecutive interaction of 6-
(trifluoromethyl)comanic acid as a CF3-pyrone with hydrazine as a
binucleophile, and then with phenylhydrazine, and treatment of
the intermediates under the conditions of the Fischer reaction
gives 3-[3-(trifluoromethyl)-5-yl]indole-2-carboxylic acid 10 and
regioisomeric 5-[2-(trifluoromethyl)indol-3-yl]-1H-pyrazole-3-
carboxylic acid 11. These reactions can be considered as a novel
approach for the regioselective synthesis of various trifluoro-
methylated 3-(hetaryl)indoles on the basis of 2-CF3-4-pyrones.
The use in this approach of other binucleophiles (instead of
hydrazine) could give a lot of new CF3-indoles functionalized in
position-3 with various heterocycles.
3JH3,H4 = 1.8 Hz
3JH4,H5 = 2.1 Hz
H5
N Ph
H3
H4
H4
N
N
N
Ph
PhHN
14
PhHN
13
CF3
N
CF3
N
i or ii
3JH4,H5 = 2.5 Hz
H5
Ph
N
N
N
H4
N
Ph
CF3
16
CF3
N
H
N
15
H
Recently we described a simple synthesis of 2-(trifluoro-
methyl)-4-pyrone 12a and -thiopyrone 12b from 1a [42]. We
have explored the reaction of 12 with phenylhydrazine and found
that pyrone 12a gave a mixture of phenylhydrazones of 1,1,1-
trifluoro-3-(1-phenylpyrazol-5-yl)propan-2-one (13) (16%) and
I: MeSO3H, P4O10,
ii: MeSO3H, AcOH,
Scheme 4. Synthesis of regioisomeric trifluoromethylated 3-(pyrazolyl)indoles
using 2-(trifluoromethyl)-4H-pyran-4-one and -4H-thiopyran-4-one.

B.I. Usachev et al. / Journal of Fluorine Chemistry 135 (2012) 278–284
281
Table 1
Trifluoromethylated pyrazole and indole derivatives.
Entry
Reagent
Product
Yield %
Mp 8C
dF ppm (DMSO-d6, C6F6)
1
2
1a
1b
1a
1b
1c
2a
2b
3a
3b
3c
1a
1a
6
2a
2b
3a
3b
3c
4a
4b
5a
5b
5c
6
64
230–232
199–200
222–223
106
96.7
58
96.7
3
30
96.6
4
34
96.6
5
19
201–203
242–243
205–206
240–241
152–153
207–208
231–232
166–167
170–190
196–197
172–173
256–257
222–224
166–167
67–68
96.6
6
45a
105.3
105.3
106.2
106.2
106.2
101.5
96.5
7
40a
8
73a, 46b
65a, 71b
60a,b
30
9
10
11
12
13
14
15
16
17
18
19
20
21
8
56
9
80
102.2, 102.3
102.2
102.3
102.6
106.2
96.7
6
(E)-9
(Z)-9
10
11
13
14
15
16
37
6
28
9
35a
8
39a
12a,b
12a
13
14
16c, 14d
21
96.6
60a, 65b
60a, 58b
192–193
214–215
105.3
106.2
a
The reaction was conducted in MeSO3H/P4O10
.
b
c
The reaction was conducted in AcOH/MeSO3H.
Prepared from 12a.
d
Prepared from 12b.
yield. Isomeric indole 16 was synthesized in 60% (MeSO3H/P4O10
and 58% (MeSO3H/AcOH) yields.
)
4.2. 5-[3,3,3-Trifluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-
pyrazol-3-carboxylic acid (2a)38
The results of the syntheses of the CF3-compounds as well as
their
F values are given in Table 1. The 19F NMR spectroscopy is a
good method to determine the regiochemistry of CF3-3-(pyrazo-
lyl)indoles. The table data show that the fluorines of the
trifluoromethyl group at the second position of 3-(pyrazolyl)in-
d
A mixture of acid 1a (1.0 g, 4.8 mmol) and PhNHNH2ꢀHCl
(1.53 g, 10.6 mmol) was refluxed in 10% HCl (10 mL) for 10 min.
After cooling the mixture to room temperature, the resulting
residue was filtered off and washed with water. The crude product
was recrystallized from toluene to give 2a (1.19 g, 64%) as a
colorless solid, mp 230–232 8C; dF (376.5 MHz, DMSO-d6) 96.7 (s,
CF3).
doles tend to appear at about
regioisomeric phenylhydrazones, the
d
105–106. In the case of the starting
F values for 2 are similar to
d
those observed for 3 (96.7 versus 96.6), whereas the DdF value
between the corresponding regioisomeric indoles 4 and 5 reaches
0.9 (105.3 versus 106.2).
4.3. Ethyl 1-phenyl-5-[3,3,3-trifluoro-2-(2-
phenylhydrazono)propyl]-1H-pyrazol-3-carboxylate (2b)
3. Conclusion
Ester 1b (1.0 g, 4.2 mmol) was added to a solution of freshly
distilled phenylhydrazine (1.0 g, 9.3 mmol) in ethanol (5 mL).
The reaction mixture was kept at room temperature for 4 days,
and then mixed with 20% HCl (2 mL). The residue was filtered
off, treated with hot ethanol (20 mL) acidified with HCl (3
drops). After cooling the mixture to ambient temperature the
resulting residue was filtered off and washed with ethanol
(5 mL) to give 2b (1.03 g, 58%) as a colourless powder, mp 199–
200 8C; nmax (KBr) 3239, 1724, 1622, 1603, 1532, 1501, 1490,
Thus, we have managed to achieve regiocontrolled synthesis of
trifluoromethylated indoles based on 6-(trifluoromethyl)comanic
acid, which are of interest for medicinal chemistry. The first
representatives of 2-CF3-3-(pyrazolyl)indoles were prepared.
4. Experimental
4.1. General
1476 cmꢁ1
; dH (400 MHz, DMSO-d6) 1.27 (3H, t, J 7.1 Hz, Me),
4.05 (2H, s, CH2), 4.27 (2H, q, J 7.1 Hz, OCH2), 6.51 (1H, S, 55CH),
6.93 (1H, tt, J 7.3, 1.0 Hz, Ar), 7.13–7.32 (4H, m, Ar), 7.50–7.65
(5H, m, Ph), 10.26 (1H, s, NH); dF (376.5 MHz, DMSO-d6) 96.7 (s,
CF3); dC (100 MHz, DMSO-d6, without proton decoupling) 14.10
(qt, Me, 1J 126.9, 2J 2.6 Hz), 22.38 (t, CH2, 1J 132.2 Hz), 60.45 (tq,
OCH2, 1J 148.2, 2J 4.5 Hz), 108.11 (dt, C4, 1J 179.3, 3J 3.2 Hz),
113.48 (dt, C20, E60, 1J 160.7, 2J 5.7 Hz), 121.26 (dt, C40, 1J 160.5, 2J
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, shifts for
19F NMR spectra are reported in ppm downfield from internal C6F6.
Coupling constants (J) are given in Hertz (Hz). The terms s, d, t, q, m
refer to singlet, doublet, triplet, quartet, multiplet; br refers to a
broad signal. 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
cmꢁ1. Elementalanalyses were performedwithPE 2400 instrument.
High resolution mass spectra were obtained on a MAT-8200
1
3
7.6 Hz), 121.93 (qt, CF3, JC,F 272.6, J 4.3 Hz), 125.10 (ddd, C200,
2
E600, 1J 164.2, 2J 7.6, 4.9 Hz), 125.61 (qtd, C–CF3, JC,F 33.2, 2J 7.2,
2
3J 3.0 Hz), 128.94 (dt, C400, 1J 162.5, J 7.3 Hz), 129.15 (dd, C30,
2
E50, 1J 159.4, J 8.2 Hz), 129.44 (dd, C300, E500, 1J 163.8, 2J 7.7 Hz),
138.24 (q, C5, 2J 8.4 Hz), 138.47 (td, C100, 2J 9.0, 4J 1.5 Hz), 143.13
2
spectrometer, using EI at 70 eV. Single-crystal XRD was performed
˚
(d, C3, J 3.9 Hz), 143.78 (q, C10, 2J 8.2 Hz), 161.37 (t, C55O, 3J
with graphite-monochromatic Mo K radiation (
l
= 0.71073 A) on a
3.3 Hz); [Found: C, 60.47; H, 4.45; N, 13.65. C21H19F3N4O2
requires C, 60.57; H, 4.60; N, 13.46%].
a
Bruker X8 APEX II CCD diffractometer at T = 295(2) K.

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B.I. Usachev et al. / Journal of Fluorine Chemistry 135 (2012) 278–284
4.4. 1-Phenyl-3-[3,3,3-trifluoro-2-(2-phenylhydrazono)propyl]-1H-
pyrazole-5-carboxylic acid (3a)38
C19H16F3ON5 requires 387.13070; [Found: C, 58.80; H, 4.27; N,
18.13. C19H16F3N5O requires C, 58.91; H, 4.16; N, 18.08%].
A mixture of acid 1a (1.0 g, 4.8 mmol) and freshly distilled
phenylhydrazine (1.15 g, 10.6 mmol) was refluxed in dry dioxane
(30 mL) for 1.5 h. After cooling the reaction mixture to room
temperature, the excess solvent was evaporated, the residue was
treated with 5% HCl (20 mL). The water layer was decanted, the
crude product was triturated with CCl4, and then filtered off and
washed with CCl4 to give 3a (0.56 g, 30%) as colourless solid, mp
222–223 8C; dF (376.5 MHz, DMSO-d6) 96.6 (s, CF3).
4.7. (Z)-3-[5-(Trifluoromethyl)-1H-pyrazol-3-yl]-2-hydroxyacrylic
acid (6)
A mixture of acid 1a (1.0 g, 4.8 mmol) and N2H4ꢀ2HCl (0.52 g,
5.0 mmol) was heated in water (10 mL) at 60 8C for 4 h. The
precipitated residue was filtered off, washed with water (3 mL) and
dried to give 6 (0.32 g, 30%) as white solid, mp 231–232 8C; nmax
(ATR) 3414, 1701, 1659 cmꢁ1
;
d
H (400 MHz, DMSO-d6) 6.39 (1H, s,
55CH), 6.82 (1H, s,55CH–pyraz.), 9.55 (1H, s, NH), 10.50–11.28 (1H,
br s, ?=), 13.27 (1H, br s, CO2H); F (376.5 MHz, DMSO-d6) 101.5 (s,
4.5. Ethyl 1-phenyl-3-[3,3,3-trifluoro-2-(2-
d
phenylhydrazono)propyl]-1H-pyrazole-5-carboxylate (3b)
CF3); [Found: C, 37.71; H, 2.23; N, 12.62. C7H5F3N2O3 requires C,
37.85; H, 2.27; N, 12.61%].
A mixture of ester 1b (1.0 g, 4.2 mmol) and freshly distilled
phenylhydrazine (1.07 g, 9.3 mmol) was refluxed in toluene (8 mL)
for 12 h. The excess solvent was then evaporated (rest volu-
me ꢂ 5 mL) and the residue was mixed with CCl4 (5 mL). The
resulting solution was cooled to 0 8C, the residue was recrystallized
from toluene to give 3b (0.59 g, 34%) as colourless crystals, mp
4.8. 3-[2-(Phenylhydrazono)-3,3,3-trifluoropropyl]-1H-pyrazole-5-
carboxylic acid (8)
A mixture of the residue, isolated after evaporation of water
from the filtrate from
6
(0.70 g, mp 205–215 8C) and
106 8C; nmax (KBr) 3293, 1736, 1604, 1542, 1528, 1504 cmꢁ1
;
dH
PhNHNH2ꢀHCl (0.29 g, 2.0 mmol) was heated at 70 8C for 1 h.
The resulting residue was filtered off and recrystallized from
toluene to give 8 (0.51 g, 56%) as a colourless solid, mp ꢂ167 8C;
(400 MHz, CDCl3) 1.23 (3H, t, J 7.1 Hz, Me), 3.82 (2H, s, CH2), 4.22
(2H, q, J 7.1 Hz, OCH2), 6.90 (1H, s, 55CH), 6.92 (1H, tt, J 7.5, 1.0 Hz,
Ar), 7.02–7.06 (2H, m, Ar), 7.21–7.25 (2H, m, Ar), 7.35–7.39 (2H, m,
Ph–pyraz.), 7.45–7.49 (3H, m, Ph–pyraz.), 9.56 (1H, s, NH); dF
n
max (ATR) 3466, 1716, 1665, 1615 cmꢁ1
; dH (400 MHz, DMSO-d6)
3.96 (2H, s, CH2), 6.53 (1H, s, 55CH), 6.90 (1H, t, J 7.3 Hz, Ph), 7.18
(2H, d, J 7.7 Hz, Ph), 7.28 (2H, dd, J 7.3, 7.7 Hz, Ph), 10.24 (1H, s, NH),
13.40 (1H, br s, CO2H); dF (376.5 MHz, DMSO-d6) 96.54 (F, CF3);
[Found: C, 50.24; H, 3.46; N, 17.55. C13H11F3N4O2 requires C,
50.00; H, 3.55; N, 17.94%].
(376.5 MHz, CDCl3) 92.9 (s, CF3); dH (400 MHz, DMSO-d6) 1.14 (3H,
t, J 7.1, Me), 4.03 (2H, s, CH2), 4.16 (2H, q, J 7.1 Hz, OCH2), 6.88 (1H,
s, 55CH), 6.90 (1H, tt, J 7.3, 1.0 Hz, Ar), 7.16–7.20 (2H, m, Ar), 7.25–
7.30 (2H, m, Ar), 7.40–7.49 (5H, m, Ph), 10.28 (1H, s, NH); dF
(376.5 MHz, DMSO-d6) 96.6 (s, CF3); dC (100 MHz, CDCl3) 13.95
(Me), 24.27 (CH2), 61.41 (OCH2), 111.47 (C4), 113.56 (C20, E60),
4.9. (E)- and (Z)-2-(2-Phenylhydrazono)-3-[5-(trifluoromethyl)-1H-
1
121.60 (C40), 121.84 (q, CF3, JC,F 272.0 Hz), 125.93 (C200, E600),
pyrazol-3-yl]propanoic acid (9)
2
128.03 (q, C–CF3, JC,F 34.1 Hz), 128.63 (C30, E50), 128.97 (C400),
129.20 (C300, E500), 135.06 (C5), 139.80 (C100), 143.75 (C10), 146.45
(C3), 158.61 (C55O); dC (100 MHz, DMSO-d6) 13.72 (Me), 23.11
(CH2), 60.98 (OCH2), 111.31 (C4), 113.32 (C20, E60), 120.99 (C40),
122.12 (q, CF3, 1JC,F 272.5 Hz), 125.61 (C200, E600), 127.67 (q, C–CF3,
2JC,F = 32.5 Hz), 128.43 (C400), 128.57 (C30, E50), 129.14 (C300, E500),
133.82 (C5), 139.70 (C100), 144.00 (C10), 146.43 (C3), 158.24;
[Found: C, 60.57; H, 4.61; N, 13.53. C21H19F3N4O2 requires C, 60.57;
H, 4.60; N, 13.46%]; the structure was solved from X-ray data by
direct method with SHELXS-97 program and refined by full matrix
least-squares on F2 with SHELXL-97 program [43]. All non-
hydrogen atoms were refined anisotropically, and hydrogen atoms
were located and included at their calculated position. The CCDC
deposition number is 822163. Unit cell parameters: a = 21.788(2),
b = 4.4981(3), c = 23.391(3). The crystal system is monoclinic,
space group P21/c.
A mixture of ketone 9 (250 mg, 1.1 mmol) and PhNHNH2ꢀHCl
(180 mg, 1.2 mmol) in ethanol (4 mL) was heated at 50 8C for 4 h.
Then the reaction mixture was diluted with water (10 mL), the
precipitate was filtered off to give a mixture of (E)-9 and (Z)-9 (3:2)
(280 mg, 80%) as a colourless powder, mp 170–190 8C; [Found: C,
50.18; H, 3.37; N, 17.65. C13H11F3N4O2 requires C, 50.00; H, 3.55; N,
17.94%].
4.10. (E)-2-(2-Phenylhydrazono)-3-[5-(trifluoromethyl)-1H-
pyrazole-3-yl]propanoic acid ((E)-9)
A mixture of (E)-9 and (Z)-9, prepared as described above,
was heated in toluene (10 mL) until the toluene boiled. The hot
mixture was filtered to give (E)-9 (130 mg, 37%) as a colourless
solid, mp 196–197 8C; nmax (ATR) 3229, 1720, 1603, 1577,
1499 cmꢁ1
; dH (400 MHz, DMSO-d6) 4.05 (2H, s, CH2), 6.26 (1H,
4.6. 1-Phenyl-3-[3,3,3-trifluoro-2-(2-phenylhydrazono)propyl]-1H-
s, 55CH), 6.92 (1H, t, J 6.9 Hz, Ph), 7.29 (2H, t, J 7.2 Hz, Ph), 7.34
(2H, d, J 7.2 Hz, Ph), 10.26 (1H, s, NNH), 12.2 (1H, br s, NH-
pyraz.), 13.49 (1H, s, CO2H); dF (376.5 MHz, DMSO-d6) 102.2 (c,
CF3).
pyrazole-5-carboxamide (3c)
A mixture of amide 1c (0.50 g, 2.4 mmol) and freshly distilled
phenylhydrazine (0.58 g, 5.7 mmol) in ethanol (2.5 mL) was
refluxed for 7 h. Then the reaction mixture was diluted with
water (15 mL) and conc. HCl (2 mL), and the water layer was
decanted. The residue was triturated with CCl4 (5 mL) to give a
yellow precipitate, which was filtered off and recrystallized from
toluene to give 3c (0.18 g, 19%) as a colourless solid, mp 201–
4.11. (Z)-2-(2-Phenylhydrazono)-3-[5-(trifluoromethyl)-1H-
pyrazol-3-yl]propanoic acid ((Z)-9)
The filtrate from (E)-9 was collected in a glass, the solvent was
evaporated, and the resulting residue was recrystallized from
AcOH–H2O (1:1) to give (Z)-9 (0.10 g, 28%) as a colourless solid, mp
172–173 8C; nmax (ATR) 3273, 1664, 1649, 1541, 1535 cmꢁ1
; dH
(400 MHz, DMSO-d6) 3.84 (2H, s, CH2), 6.44 (1H, s,55CH), 6.92 (1H,
t, J 6.9 Hz, Ph), 7.18 (2H, d, J 8.0 Hz, Ph), 7.25–7.29 (2H, m, Ph), 12.18
(1H, s, NNH), 13.46 (1=, s, CO2H); dF (376.5 MHz, DMSO-d6) 102.3
202 8C; nmax (KBr) 3282, 1710, 1614, 1555, 1528, 1501 cmꢁ1
; dH
(400 MHz, DMSO-d6) 4.00 (2H, s, CH2), 6.74 (1H, s,55CH), 6.89 (1H,
tt, J 7.3 Hz, Ar), 7.17–7.30 (4H, m, Ar), 7.34–7.47 (5H, m, Ph), 7.54
(1H, s, CONHH), 8.07 (1H, s, CONHH), 10.29 (1H, s, NNH); dF
(376.5 MHz, DMSO-d6) 96.6 (s, CF3); m/z (EI, 70 eV) 387 (100, M+),
291 (20), 252 (25); HRMS (EI, 70 eV): M+, found 387.13114.
(c, CF3).

B.I. Usachev et al. / Journal of Fluorine Chemistry 135 (2012) 278–284
283
4.12. 1-Phenyl-5-[3,3,3-trifluoro-2-(2-phenylhydrazono)propyl]-1H-
61.67; H, 3.52; N, 11.07. C19H12F3N3O2 requires C, 61.46; H, 3.26; N,
11.32%].
pyrazole (13)
A mixture of pyrone 12a (160 mg, 0.98 mmol) and freshly
distilled phenylhydrazine (250 mg, 2.3 mmol) was kept at 120 8C
within 1 h. After cooling to room temperature the mixture was
mixed with ethanol (1 mL), the resulting residue was filtered off,
washed with ethanol, dried and recrystallized from toluene (5 mL)
to give 13 (50 mg, 16%) as a colourless solid, mp 166–167 8C; nmax
4.14.2. Ethyl 5-[2-(trifluoromethyl)-1H-indol-3-yl]-1-phenyl-1H-
pyrazole-3-carboxylate (4b)
Yield 40% (A), colourless solid (toluene–petroleum ether), mp
205–206 8C; nmax (ATR) 3280, 1719, 1610 cmꢁ1
; dH (400 MHz,
DMSO-d6) 1.07 (3H, t, J 7.1 Hz, CH3), 4.07 (2H, buried m, CH2), 7.11
(1H, s, pyraz.), 7.12 (1H, td, J 7.6, 0.9 Hz, H-5), 7.19–7.22 (2H, m, H-
6, Ph), 7.27–7.36 (4H, m, Ph), 7.42 (1H, d, J 8.1 Hz, H-4), 7.50 (1H, d, J
(KBr) 1625, 1605, 1537, 1502, 1455 cmꢁ1
; dH (400 MHz, DMSO-d6)
4.03 (2H, s, CH2), 6.11 (1H, d, J 1.8 Hz, H-4-pyraz.), 6.92 (1H, tt, J 7.3,
1.1 Hz, H-40), 7.17 (2H, dd, J 8.6, 1.1 Hz, H-20, H-60), 7.29 (2H, dd, J
8.4, 7.4 Hz, H-30, H-50), 7.45 (1H, tt, J 6.9, 1.8 Hz, H-400), 7.54–7.60
(4H, m, Ar), 7,61 (1H, d, J 1.8 Hz, H-3-pyraz.); 10.02 (F, 1H, NH); dF
(376.5 MHz, DMSO-d6) 96.7 (s, CF3); [Found: C, 62.67; H, 4.29; N,
16.14. C18H15F3N4 requires C, 62.79; H, 4.39; N, 16.27%]. The
reaction of thiopyrone 12b with phenylhydrazine in ethanol
(reflux 4 h) gave pyrazole 13 in 14% yield.
8.4 Hz, H-7); 12.30 (1H, br s, NH); dF (376.5 MHz, DMSO-d6) 105.3
(s, CF3); dC (100 MHz, DMSO-d6) 14.2, 60.6, 105.0 (q, J 2.8 Hz),
112.1, 112.7, 119.8, 121.0 (q, J 269.7 Hz), 121.5, 123.0 (q, J 36.7 Hz),
124.0, 125.0, 126.1, 128.3, 129.0, 135.2, 135.3, 139.0, 143.6, 161.5;
[Found: C, 63.01; H, 4.10; N, 10.25. C21H16F3N3O2 requires C, 63.16;
H, 4.04; N, 10.52%].
4.14.3. 3-[2-(Trifluoromethyl)-1H-indol-3-yl]-1-phenyl-1H-
pyrazole-5-carboxylic acid (5a)
4.13. 1-Phenyl-3-[3,3,3-trifluoro-2-(2-phenylhydrazono)propyl]-1H-
Yield 73% (A), 46% (B, reflux for 8 h), colourless solid (toluene),
max (ATR) 1700, 1597, 1577, 1527, 1501 cmꢁ1
mp 240–241 8C; n ; dH
pyrazole (14)
(400 MHz, DMSO-d6) 7.20 (1H, s, pyraz.), 7.21 (1H, t, J 7.5 Hz, H-5),
7.36 (1H, t, J 7.7 Hz, H-6), 7.46–7.56 (4H, m, H-7, Ph), 7.60 (2H, d, J
7.4 Hz, Ph), 8.10 (1H, d, J 8.1 Hz, H-4); 12.50 (1H, s, NH), 13.33–
13.66 (1H, br s, CO2H); dF (376.5 MHz, DMSO-d6) 106.2 (s, CF3);
[Found: C, 61.60; H, 3.48; N, 11.09. C19H12F3N3O2 requires C, 61.46;
H, 3.26; N, 11.32%].
The residue, isolated after evaporation of toluene from the
filtrate from 13 was crystallized from ethanol to give 14 (71 mg,
21%) as a colourless solid, mp 67–68 8C; nmax (ATR) 1598, 1552,
1518, 1499, cmꢁ1
; dH (400 MHz, DMSO-d6) 4.02 (2H, s, CH2), 6.38
(1H, d, J 2.1 Hz, H-4-pyraz.), 6.90 (1H, t, J 7.2 Hz, H-40), 7.21 (2H, d, J
7.8 Hz, H-20, H-60), 7.28 (3H, m, H-30, H-50, H-400), 7.48 (2H, t, J
7.8 Hz, H-200, H-600), 7.79 (2H, d, J 7.9 Hz, H-300, H-500), 8,45 (1H, d, J
2.1 Hz, H-5-pyraz.); 10.28 (F, 1H, NH); dF (376.5 MHz, DMSO-d6)
96.6 (s, CF3); [Found: C, 62.79; H, 4.39; N, 16.27. C18H15F3N4
requires C, 62.61; H, 4.33; N, 16.26%].
4.14.4. Ethyl 3-[2-(trifluoromethyl)-1H-indol-3-yl]-1-phenyl-1H-
pyrazole-5-carboxylate (5b)
Yield 65% (A), 71% (B, reflux for 4 h), yellow solid (toluene–
petroleum ether), mp 155–156 8C; nmax (ATR) 3359, 1718, 1592,
1575, 1501 cmꢁ1
; dH (400 MHz, DMSO-d6) 1.20 (3H, t, J 7.1 Hz,
4.14. Syntheses of 2-CF3-3-(pyrazolyl)indoles
CH3), 4.24 (2H, q, J 7.1 Hz, CH2), 7.22 (1H, t, J 7.5 Hz, H-5), 7.24 (1H,
s, pyraz.), 7.37 (1H, t, J 7.5 Hz, H-6), 7.50–7.58 (4H, m, Ph), 7.59–
7.64 (2H, m, Ph, H-7), 8.09 (1H, d, J 8.1 Hz, H-4), 12.53 (1H, br s,
Method
A (using MeSO3H/P4O10): A CF3-phenylhydrazone
(0.48 mmol) was added to a mixture of MeSO3H (1.0 g) and
P4O10 (0.17 g). The reaction mixture was heated at 60 8C for 6 h.
The resulting solution was diluted with water (10 mL), the residue
was filtered off, and dried. Compounds 4a,b, 5b and 15 were solved
in hot toluene (5 mL), the hot solution was then passed through a
layer of silica gel (0.7 cm3), and the layer washed with hot toluene
(10 mL). After removal of the solvent, the solid residue was
recrystallized from a solvent. After crystallization, the majority of
the synthesized 3-(pyrazolyl)indoles contained 5–8% of the solvent
(toluene or another). Therefore, all crystallized indoles were dried
at 130 8C for 6 h.
NH); dF (376.5 MHz, DMSO-d6) 106.2 (s, CF3); dC (100 MHz, DMSO-
d6) 13.8, 61.1, 108.6 (q, J 2.9 Hz), 111.4 (q, J 3.0 Hz), 112.5, 121.2,
121.3 (q, J 37.3 Hz), 121.8 (q, J 269.1 Hz), 121.9, 124.8, 125.5,
125.7, 128.5, 128.6, 133.9, 135.4, 139.9, 144.1, 158.4; [Found: C,
63.65; H, 3.85; N, 10.12. C21H16F3N3O2 requires C, 63.16; H, 4.04;
N, 10.52%].
4.14.5. 3-[2-(Trifluoromethyl)-1H-indol-3-yl]-1-phenyl-1H-
pyrazole-5-carboxamide (5c)
Yield 60% (A) 60% (B, reflux for 4 h), colourless solid (toluene),
mp 207–208 8C; n ; dH
max (ATR) 3332, 3181 1664, 1626, 1601 cmꢁ1
Method
B
(using AcOH/MeSO3H):
A
CF3-phenylhydrazone
(400 MHz, DMSO-d6) 7.16 (1H, s, pyraz.), 7.17–7.27 (2H, m, Ph, H-
5), 7.36 (1H, t, J 7.2 Hz, H-6), 7.43 (1H, m, H-7), 7.47–7.67 (4H, m,
Ph), 7.66 (1H, c, NHH), 8.10 (1H, d, J 8.1 Hz, H-4), 8.24 (1H, c, NHH),
12.45 (1H, s, NH); dF (376.5 MHz, DMSO-d6) 106.2 (s, CF3); [Found:
C, 61.82; H, 3.77; N, 14.97. C19H13F3N4O requires C, 61.62; H, 3.54;
N, 15.13%].
(0.62 mmol) was added to a mixture of AcOH (4 mL) and MeSO3H
(0.12 g, 1.24 mmol). The reaction mixture was refluxed, and then
diluted with water (10 mL), the residue was filtered off, and dried.
Compounds 5b and 15 were solved in hot toluene (5 mL), the hot
solution was then passed through a layer of silica gel (0.7 cm3), and
the layer washed with hot toluene (10 mL). After removal of the
solvent, the solid residue was recrystallized from a solvent. After
crystallization, the majority of the synthesized 3-(pyrazolyl)in-
doles contained 5–8% of the solvent (toluene or another).
Therefore, all crystallized indoles were dried at 130 8C for 6 h.
4.14.6. 5-[2-(Trifluoromethyl)-1H-indol-3-yl]-1H-pyrazole-3-
carboxylic acid (11)
Yield 39% (A, the reaction mixture was kept at ambient
temperature for 48 h), white solid (AcOH–H2O), mp 222–224 8C;
nmax (KBr) 3289, 1708, 1604, 1533, 1500 cmꢁ1
; dH (400 MHz,
4.14.1. 5-[2-(Trifluoromethyl)-1H-indol-3-yl]-1-phenyl-1H-
pyrazole-3-carboxylic acid (4a)
DMSO-d6) 6.90 (1H, s, pyraz.), 7.21 (1H, t, J 7.6 Hz, H-5), 7.36 (1H, t,
J 7.4 Hz, H-6), 7.54 (1H, d, J 8.6 Hz, H-7), 7.89 (1H, br s, H-4), 12.45
(1H, s, NH-Ind), 12.18–14.52 (2H, br s, NH-pyraz., CO2H); dF
(376.5 MHz, DMSO-d6) 106.2 (s, CF3); dC (100 MHz, DMSO-d6)
108.0, 112.5, 118.5, 120.8, 121.1, 121.4, 121.6, 121.8 (q, J 269.1 Hz),
124.8, 125.0, 125.8, 135.4, 161.4; [Found: C, 52.70; H, 2.97; N,
14.01. C13H8F3N3O2 requires C, 52.89; H, 2.73; N, 14.23%].
Yield 45% (A), colourless solid (toluene), mp 242–243 8C; nmax
(ATR) 3284, 1689, 1599, 1534, 1485 cmꢁ1
; dH (400 MHz, DMSO-d6)
7.01 (1H, s, pyraz.), 7.08 (1H, t, J 7.2 Hz, H-5), 7.21–7.35 (7H, m, H-6,
H-4, Ph), 7.50 (1H, d, J 8.1 Hz, H-7), 12.70 (1H, s, NH), 13.0–13.1
(1H, br s, CO2H); dF (376.5 MHz, DMSO-d6) 105.3 (s, CF3); [Found: C,

284
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4.14.7. 2-(Trifluoromethyl)-3-(1-phenyl-1H-pyrazol-5-yl)-1H-indole
(15)
Yield 60% (A), 65% (B, reflux for 4 h), white solid (toluene–
petroleum ether), mp 192–193 8C; nmax (ATR) 3108, 1597, 1522,
1500, 1458 cmꢁ1
; dH (400 MHz, DMSO-d6) 6.61 (1H, buried d, H-
40), 7.06 (1H, t, J 7.5 Hz, H-5), 7.14–7.23 (4H, m, Ph), 7.24–7.35 (3H,
m, Ph, Ind), 7.50 (1H, d, J 8.3 Hz, H-7), 7.86 (1H, buried d, H-30),
12.61 (1H, s, NH); dF (376.5 MHz, DMSO-d6) 105.3 (s, CF3); dC
(100 MHz, DMSO-d6) 106.4 (q, J 2.8 Hz), 110.4, 112.7, 120.0, 121.2
(q, J 269.5 Hz), 121.3, 122.6 (q, J 36.6 Hz), 123.4, 124.9, 126.2, 127.2,
128.9, 133.1, 135.4, 139.8, 140.3; [Found: C, 66.17; H, 3.79; N,
12.56. C18H12F3N3 requires C, 66.05; H, 3.70; N, 12.84%].
4.14.8. 2-(Trifluoromethyl)-3-(1-phenyl-1H-pyrazol-3-yl)-1H-indole
(16)
Yield 60% (A), 58% (B, reflux for 4 h), white solid (toluene), mp
214–215 8C; nmax (ATR) 3164, 1597, 1588, 1573, 1510 cmꢁ1
; dH
(400 MHz, DMSO-d6) 6.79 (1H, buried d, H-4-pyraz.), 7.25 (1H, t, J
7.5 Hz, H-5), 7.32–7.40 (2H, m, Ar), 7.56 (3H, m, H-7, Ph), 7.95 (2H,
d, J 7.9 Hz, H-200, H-600), 8.19 (1H, d, J 8.1 Hz, H-4), 8.65 (1H, d, J
2.5 Hz, H-5-pyraz.), 12.41 (1H, s, NH); dF (376.5 MHz, DMSO-d6)
106.2 (s, CF3); [Found: C, 66.56; H, 3.47; N, 12.86. C18H12F3N3
requires C, 66.05; H, 3.70; N, 12.84%].
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Yield 35% (A, stirring at ambient temperature for 1 h and at
70 8C for 30 min), white powder (aqueous ethanol), mp 256–
257 8C; nmax (ATR) 3593, 3466, 3132, 1693, 1589 cmꢁ1
; dH
(400 MHz, DMSO-d6) 6.99 (1H, s, pyraz.), 7.17 (1H, t, J 7.5 Hz, =-
5), 7.34 (1H, t, J 7.5 Hz, =-6), 7.52 (1H, d, J 8.1 Hz, H-7), 7.18 (1H, d, J
8.1 Hz, =-4), 12.17 (1H, s, NH-pyraz.), 13.45 (1H, br s, CO2H), 13.71
(1H, s, NH-Ind); dF (376.5 MHz, DMSO-d6) 102.6 (s, CF3); dC
(100 MHz, DMSO-d6) 103.6, 108.0, 112.8, 120.5, 121.0, 122.0 (q, J
268.0 Hz), 125.2, 125.4, 126.2, 135.8, 136.8, 140.9 (q, J 34.3 Hz),
162.5; [Found: C, 51.03; H, 3.03; N, 13.70. C13H8F3N3O2ꢀ0.5H2O
requires C, 52.32; H, 2.89; N, 13.81%].
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Acknowledgment
This work was financially supported by the Ministry of
Education and Science (Contract No.
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