Regioselective solvent-sensitive reactions of 6-(trifluoromethyl)comanic acid and its derivatives with phenylhydrazine

Article abstract of DOI:10.1016/j.tetlet.2009.05.056

6-(Trifluoromethyl)comanic acid reacts regioselectively with phenylhydrazine in water to give 5-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-3-carboxylic acid. Similar reaction in dioxane leads to 3-[3,3,3-trifluoro-2-(phenylhydrazono)

Full text of DOI:10.1016/j.tetlet.2009.05.056

Tetrahedron Letters 50 (2009) 4446–4448
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective solvent-sensitive reactions of 6-(trifluoromethyl)comanic
acid and its derivatives with phenylhydrazine
a
b
a
Boris I. Usachev a, , Dmitrii L. Obydennov , Mikhail I. Kodess , Vyacheslav Ya. Sosnovskikh
*
a Department of Chemistry, Ural State University, pr. Lenina 51, 620083 Ekaterinburg, Russia
b Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 620041 Ekaterinburg, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
6-(Trifluoromethyl)comanic acid reacts regioselectively with phenylhydrazine in water to give 5-[3,3,3-
trifluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-3-carboxylic acid. Similar reaction in diox-
ane leads to 3-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-5-carboxylic acid. A
strong solvent influence on the reaction route was also found for 6-(trifluoromethyl)comanic acid
derivatives.
Received 6 April 2009
Revised 5 May 2009
Accepted 15 May 2009
Available online 22 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
We recently described a convenient synthesis of 6-(trifluoro-
methyl)comanic acid [6-(trifluoromethyl)-4-oxo-4H-pyran-2-car-
boxylic acid], its ethyl ester and amide.1 These cyclic conjugated
enones, due to the presence of several reactive positions towards
nucleophilic attack, represent very useful CF3-containing building
blocks in organic synthesis.
The structures of the pyrazoles 4 and 5 were confirmed from 1H,
13C and 19F NMR spectra using 2D 1H–13C HSQC and HMBC exper-
iments, IR spectra and elemental analysis. Theoretically, the reac-
tion of 3 with phenylhydrazine could provide four isomeric
It is known2 that unsubstituted
ylhydrazine and p-nitrophenylhydrazine to give pyrazoles
(Scheme 1). Earlier investigators3 have described a number of reac-
tions of various -pyrone derivatives with hydrazines, however,
c-pyrone 1 reacts with phen-
O
2
N
R
NHNH2
NNH
R
N
c
O
the structures of the products have generally not been deduced
correctly.
1
2
R
R = H, NO2
In this Letter, we describe the regioselective reactions of 6-(tri-
fluoromethyl)comanic acid, its ethyl ester, amide and sodium salt
with phenylhydrazine under various conditions.
Scheme 1.
We discovered that these reactions were selective based on the
nature of the solvent. Thus, heating 6-(trifluoromethyl)comanic
acid 3 with 2.2 equiv of phenylhydrazine hydrochloride in water
gave 5-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-
pyrazole-3-carboxylic acid 4 in 64% yield. The same reactants in
the polar aprotic solvent dioxane led to the formation of the iso-
meric structure, 3-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]-1-
phenyl-1H-pyrazole-5-carboxylic acid 5, in 30% yield (Scheme 2).
The 1H NMR spectrum of the crude product did not show any sig-
nals due to regioisomer 4.
O
O
HO
Ph
HO
3
5
4
4
NNHPh
CF3
5
NNHPh
N
N
3
1'
5
1'
N
N
CF3
PhNHNH2 HCl,
H2O,
.
Ph
PhNHNH2,
dioxane,
4
O
OH
F3C
O
O
Heating 3 with phenylhydrazine in non-polar toluene provided
a mixture of isomeric pyrazoles 4 and 5 (ratio 1:2), which was
characterized by 1H NMR and elemental analysis. This solvent-
3
CF3
N
CF3
PhHNN
O
PhHNN
O
dependent reaction is important in
c-pyrone chemistry, because
N
Ph
N
N
it allows the regioselective syntheses of isomeric pyrazoles.
Ph
OH
OH
4'
5'
* Corresponding author.
E-mail address: Boris.Usachev@mail.ru (B.I. Usachev).
Scheme 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.056

B. I. Usachev et al. / Tetrahedron Letters 50 (2009) 4446–4448
4447
pyrazoles: 4, 5, 4 and 5 (Scheme 2). However, in the 13C NMR spec-
tra of the products synthesized in water and dioxane, the charac-
teristic quartets due to the C@N hydrazonic carbon atoms at
about d 127 (2JC,F ꢀ 33 Hz) were observed thus excluding struc-
ylhydrazine (22% yield), which could be transformed into
carboxylic acid 4 by heating in dilute HCl (81% yield) (Scheme 4).
The structure of 13 was confirmed by 1H, 13C NMR (DMSO-d6),
IR, EI-MS spectroscopies and elemental analysis. In the 1H NMR
spectrum, 20 aromatic protons, one pyrazole proton as a singlet
at d 6.48 and a singlet due to two methylene protons at d 4.06 were
observed. In the EI-MS, fragmentation of 13 occurred as a cluster of
ion peaks [2Á387À+2H++Na+]+, [387À+2Na+]+, [387À+H++Na+]+,
[387À+2H+]+. This spectrum demonstrates the existence of the pyr-
azolyl carboxylate anion of molecular weight 387.
´
´
´
´
tures 4 and 5. The product prepared in water was characterized
as pyrazole 4 (a derivative of pyrazole-3-carboxylic acid). In its
1H-coupled 13C NMR spectrum, carbon C-3 (the most deshielded
carbon of the pyrazole ring) appeared as a doublet at d 144.5
(2JC3,H4 = 3.7 Hz). The 13C NMR spectrum also showed a doublet
of triplets at d 137.8 (2JC5,H4 = 8.6 Hz, 2JC5,H1 = 7.9 Hz), which corre-
´
sponds to carbon C-5 (correlations with the signals at d 6.46 (H-4)
and d 4.05 were observed). The spin–spin couplings were con-
firmed by 1H–13C HMBC experiments. The structure of pyrazole 5
(a derivative of pyrazole-5-carboxylic acid), prepared in dioxane,
was proved using a similar approach. In the 1H-coupled 13C NMR
spectrum, the most deshielded (by the C@N moiety) carbon C-3 ap-
peared as a multiplet at d 146.2, whereas carbon C-5 appeared as a
doublet at d 134.9 (2JC5,H4 = 7.7 Hz). Characteristic cross-peaks in
the 1H–13C HMBC spectrum were observed between the methylene
protons and carbons C-3, C@N (phenylhydrazonic moiety), CF3 and
C-4.
The strong solvent influence on the reaction route can be ex-
plained as follows: in a protic medium, phenylhydrazine attacks
predominantly at position 2 of the pyrone ring, rather than at the
carbonyl carbon atom (Scheme 5). In this case, the formation of
intermediate A is facilitated by protonation of the carbonyl oxygen
atom with a solvent molecule. The trifluoromethyl group could
also influence the stability of A due to hyperconjugation between
the C–F bonds and the diene moiety. In an aprotic solvent the reac-
tion pathway includes attack of phenylhydrazine at the carbonyl
carbon. This attack is facilitated by a possible intramolecular pro-
ton transfer in transition state B without participation of the
solvent.
Ethyl 6-(trifluoromethyl)comanoate
6
was reacted with
2.2 equiv of phenylhydrazine in protic polar ethanol (6 is insoluble
in water) to give, as expected, ethyl 5-[3,3,3-trifluoro-2-(phenylhyd-
razono)propyl]-1-phenyl-1H-pyrazole-3-carboxylate 7. Keeping
the reaction mixture at room temperature for two days allowed
preparation of 7 as a crystalline ethanolate-hydrate solvate 8 (69%,
mp 106 °C) which can be transformed into unsolvated pyrazole 7
(mp 199–200 °C) by adding a catalytic amount of HCl or another acid
to an ethanolic solution of 8. Unsolvated pyrazole 7 can also be syn-
thesized rapidly by heating the reaction mixture for 2 h (Scheme 3).
On the other hand, the reaction of 6 with phenylhydrazine in reflux-
ing toluene for 2 h gave 10 as the only isomer in 34% yield. In contrast
to pyrones 3 and 6, less reactive amide 9 reacts with phenylhydr-
azine in EtOH to produce 3-[3,3,3-trifluoro-2-(phenylhydrazon-
o)propyl]-1-phenyl-1H-pyrazole-5-carboxamide 11 in 15% yield
(Scheme 3). In this case, the reaction in dioxane or toluene does
not produce a pyrazole derivative, and gives a complex mixture of
products instead.
We also found that the trifluoromethyl group in pyrazole 7 and
its solvate 8 could be easily hydrolyzed into a carboxylic function
by treatment with KOH in EtOH to give the corresponding dipotas-
sium salt 14. A possible mechanism for the facile substitution of
the fluorine atoms in these compounds includes elimination of
HF by deprotonation of the NH group with hydroxide (ethoxide)
(Scheme 6). Treatment of 14 with HCl gave the corresponding
dicarboxylic acid 15 in 85% yield. The structure of 15 (monohy-
drate) and its dipotassium salt was confirmed by 1H NMR and IR
spectroscopies, and elemental analysis. The 1H NMR spectrum
(DMSO-d6) of 15 showed two broad signals for the protons of the
carboxylic groups at d 12.5–14.0.
The signal of the deshielded NH proton at about d 12.0 proves
that this proton forms an intramolecular hydrogen bond (IHB) with
the oxygen of the carbonyl group (for compounds 4, 5, 7 and 11,
the corresponding narrow signal was observed at d 10.27–10.30).
The presence of an IHB confirms the Z-isomeric structure of the
dicarboxylic acid 15. Treatment of 14 with HCl under harsher con-
Sodium 6-(trifluoromethyl)comanoate 12 is a more reactive c-
pyrone than amide 9 towards phenylhydrazine. Treatment of 12
with excess phenylhydrazine in water at 20 °C for two days affor-
ded the sodium salt 13 as a solvate with two molecules of phen-
NaO2C
HO2C
N
O
O
NNHPh
CF3
NNHPh
CF3
PhNHNH2
H2O, 20 oC
HCl,
N
N
N
NaO2C
CF3
O
O
Ph
Ph
.
4
12
2PhNHNH2
EtO
EtO
13
NNHPh
CF3
NNHPh
CF3
HCl
N
N
EtOH
Scheme 4.
N
N
Ph
Ph
.
.
EtOH H2O
7
PhNHNH ,
PhNHNH2,
EtOH
EtOH
2
8
20 oC, 2 d
R = OEt
80 oC, 2 h
R = OEt
H
OH
H
O
O
O
O
O
-H+,
-
CO2H
NHNHPh
R
O
6 (R = OEt)
9 (R = NH2)
OH
F3C
F3C
O
F3C
-HO
3
O
A
PhNHNH2, toluene,
R = OEt
PhNHNH2, EtOH,
R = NH2
H2NNHPh
H
≠
O
O
O
NHNHPh
O
EtO
H2N
H2NNHPh
OH
NNHPh
CF3
NNHPh
CF3
N
Ph
N
Ph
OH
O
N
F3C
O
N
F3C
O
O
11
3
10
B
Scheme 3.
Scheme 5.

4448
B. I. Usachev et al. / Tetrahedron Letters 50 (2009) 4446–4448
O
N
phenylhydrazine molecules; hydrolysis reactions of the a-difluoro-
O
Ph
N
EtO
KO
methylene group in these hydrazones were not described). Impor-
tantly, solvate 8 is more reactive to hydrolysis than 7 and gives a
higher yield of 14 (Table 1, entry 9). It should be noted that no
hydrolysis products were isolated when the same reaction was
conducted using pyrazoles 4, 5, 10 and 11.
KOH, EtOH
NNHPh
CF3
H
.
.
.
N
N
N
O
N
Ph
Ph
OK
14
7, 8
In summary, we have demonstrated novel regioselective sol-
vent-sensitive reactions of 6-(trifluoromethyl)comanic acid and
its derivatives, which give a number of highly functionalized deriv-
atives of 1-phenyl-1H-pyrazole-5-carboxylic acids and 1-phenyl-
1H-pyrazole-3-carboxylic acids. These results are of interest for
the development of the chemistry of trifluoromethylated (fluor-
-2F-
OH-
HO- (EtO-)
-EtO-
O
N
O
EtO
EtO
-
NPh
NPh
CF2
N
N
N
N
-F-
oalkylated) c-pyrones.
N
Ph
CF2
F
Ph
D
C
Acknowledgement
This research was supported by the RFBR (Grant No. 06-03-
04004).
O
N
CO2H
N
Ph
HO
HCl
HCl
N
14
H
.
N
.
.
AcOH,
N
References and notes
N
O
Ph
Ph
OH
1. Usachev, B. I.; Bizenkov, I. A.; Sosnovskikh, V. Ya. Russ. Chem. Bull. 2007, 558.
2. Ainsworth, C.; Jones, R. G. J. Am. Chem. Soc. 1954, 76, 3172.
3. (a) Deshapande, S. S.; Dingankar, Y. V.; Kopil, D. N. J. Indian Chem. Soc. 1934, 11,
595; (b) Bedekar, D. N.; Kaushal, R. P.; Deshapande, S. S. J. Indian Chem. Soc. 1935,
12, 465.
15
CO2H
16
N
H
Scheme 6.
4. Knunyants, I. L.; Bargamova, M. D. Izv. Akad. Nauk SSSR, Ser. Khim. 1977, 26, 1776.
5. Synthesis of 5-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-
3-carboxylic acid (4). A mixture of 3 (1.0 g, 4.8 mmol) and PhNHNH2ÁHCl (1.53 g,
10.6 mmol) was refluxed in 5% aqueous HCl (10 mL) for 10 min. After cooling,
the residue was filtered off and recrystallized from toluene (150 mL). Yield 64%,
mp 230–232 °C, colourless solid.
Table 1
Synthesis of the pyrazole derivatives
Entry
Substrate
Solvent
Product
Yield (%)
Mp (°C)
IR (KBr) 3271, 1694, 1602, 1496 cmÀ1 1H NMR (400 MHz, DMSO-d6) d 4.05 (s,
;
1
2
3
4
5
6
7
8
9
3, 13
3
3
6
6
6
9
12
7, 8
14
14
H2O
45
64,a,b 81c
30
45
43
69
230–232
222–223
201–204
199–200
106
´
´
2H, CH2), 6.46 (s, 1H, H-4), 6.93 (tt, 1H, H-4, J = 7.3, 1.1 Hz), 7.17 (dd, 2H, H-2, H-
´
´
Dioxane
Toluene
EtOH
EtOH
Toluene
EtOH
H2O
EtOH–H2O
H2O
56
´
´
´
6, J = 8.6, 1.1 Hz), 7.30 (dd, 2H, H-3, H-5, J = 8.6, 7.3 Hz), 7.51 (tt, 1H, H-4, J = 7.1,
´
´
´
´
´
´
´
´
1.5 Hz), 7.59 (t, 2H, H-3, H-5, J = 7.6 Hz), 7.63 (dd, 2H, H-2, H-6, J = 8.5, 1.5 Hz),
4 + 5 (1:2)
7
8
10
11
13
14
15
16
10.30 (s, 1H, NH), 12.5–13.8 (br s, 1H, OH); 13C NMR (100 MHz, DMSO-d6) d
´
´
22.38 (t, CH2, J = 131.3 Hz), 108.21 (dt, C4, J = 178.5, 3.1 Hz), 113.46 (dt, C2, C6,
J = 161.0, 6.5 Hz), 121.27 (dt, C4, J = 160.6, 7.8 Hz), 121.94 (qt, CF3, JC,F = 272.4,
1
´
34
15
22
106
´
´
´
´
4.2 Hz), 124.98 (ddd, C2, C6, J = 164.1, 7.7, 4.2 Hz), 125.83 (qt, C@N,
201–203
218–220
239–242
186–187
281–282
´
2
2
´
´
JC,F = 33.7 Hz, J = 3.5 Hz), 128.76 (dt, C4, J = 163.4, 6.8 Hz), 129.19 (ddd, C3,
´
´
´
´
´
C5, J = 159.4, 8.0, 1.3 Hz), 129.44 (ddd, C3, C5, J = 163.5, 7.5, 1.5 Hz), 137.81 (dt,
23,d 69e
85
´
´
´
C5, J = 8.6, 7.9 Hz), 138.63 (t, C1, J = 7.8 Hz), 143.77 (m, C1), 144.51 (d, C3,
J = 3.7 Hz), 162.98 (s, C@O). Anal. Calcd for C19H15F3N4O2: C, 58.76; H, 3.89; N,
14.43. Found: C, 58.49; H, 3.81; N, 14.64.
10
11
AcOH–H2O
63
6. Synthesis of 3-[3,3,3-trifluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-
5-carboxylic acid (5). A mixture of 3 (1.0 g, 4.8 mmol) and freshly distilled
PhNHNH2 (1.15 g, 10.6 mmol) was refluxed in dry dioxane (30 mL) for 1.5 h.
After cooling, the solvent was evaporated and the residue was treated with 5%
aqueous HCl (20 mL). The aqueous solution was decanted, the crude product
triturated with CCl4 and the solid was filtered off. Yield 30%, mp 222–223 °C,
colourless solid.
a
Reagent: PhNHNH2ÁHCl.
Prepared from 3.
Prepared from 13.
Prepared from 7.
Prepared from 8.
b
c
d
e
IR (KBr) 3289, 1708, 1604, 1533, 1500 cmÀ1
;
1H NMR (400 MHz, DMSO-d6) d
´
4.02 (s, 2H, CH2), 6.84 (s, 1H, H-4), 6.90 (tt, 1H, H-4, J = 7.3, 1.1 Hz), 7.19 (dd, 2H,
ditions (heating in AcOH–H2O) resulted in the formation of the
Fischer reaction product, pyrazolyl-indole derivative 16 with two
carboxylic groups in 63% yield. The structure of 16 was proved to
be the pyrazolyl-indole by conventional spectroscopic methods.
Facile nucleophilic substitution of
ylhydrazones of trifluoromethylketones is not known (Knunyants
and Bargamova4 described substitution of
-fluorine atoms in
phenylhydrazones of fluoroalkyl aldehydes under the action of
´
´
´
´
H-2, H-6, J = 8.6, 1.1 Hz), 7.28 (dd, 2H, H-3, H-5, J = 8.6, 7.3 Hz), 7.40–7.49 (m, 5H,
Ph), 10.29 (s, 1H, NH), 13.37 (br s, 1H, OH); 13C NMR (100 MHz, DMSO-d6) d
´
´
23.16 (t, CH2, J = 131.3 Hz), 111.34 (dt, C4, J = 179.1, 2.8 Hz), 113.32 (dt, C2, C6,
J = 161.1, 6.7 Hz), 120.97 (dt, C4, J = 160.3, 7.1 Hz), 122.13 (q, CF3,
JC,F = 272.4 Hz), 125.57 (d, C2, C6, J = 163.1 Hz), 128.60 (q, C@N,
JC,F = 32.9 Hz), 128.22 (dt, C4, J = 162.1, 7.5 Hz), 128.50 (ddd, C3, C5, J = 162.7,
´
´
´
´
1
2
´
´
´
´
´
´
´
a-fluorine atoms in phen-
´
´
7.0, 1.8 Hz), 129.14 (ddd, C3, C5, J = 159.7, 7.9, 1.5 Hz), 134.90 (d, C5, J = 7.7 Hz),
´
´
´
139.90 (t, C1, J = 8.3 Hz), 144.02 (t, C1, J = 7.8 Hz), 146.22 (m, C3), 159.69 (d,
C@O, J = 0.9 Hz). Anal. Calcd for C19H15F3N4O2: C, 58.76; H, 3.89; N, 14.43.
Found: C, 58.54; H, 3.77; N, 14.61.
a