Regioselective cyclocondensation of ethyl 2-ethoxymethylidene-3-oxo-3- polyfluoroalkylpropionates with thiazolylhydrazines

Article abstract of DOI:10.1134/S1070428008120166

Ethyl 2-ethoxymethylidene-3-oxo-3-polyfluoroalkylpropionates reacted in a regioselective fashion with thiazolylhydrazines to give the corresponding ethyl 1-thiazolyl-5-fluoroalkyl-1H-pyrazole-4-carboxylates. The product structure was determined on the basis of NMR and X-ray diffraction data.

Full text of DOI:10.1134/S1070428008120166

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 12, pp. 1811–1815. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © M.V. Pryadeina, A.B. Denisova, Ya.V. Burgart, V.I. Saloutin, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44,
No. 12, pp. 1838–1842.
Regioselective Cyclocondensation of Ethyl
2-Ethoxymethylidene-3-oxo-3-polyfluoroalkylpropionates
with Thiazolylhydrazines
M. V. Pryadeinaa, A. B. Denisovab, Ya. V. Burgarta, and V. I. Saloutina
a Postovskii Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences,
ul. Akademicheskaya/S. Kovalevskoi 22/20, Yekaterinburg, 620041 Russia
e-mail: saloutin@ios.uran.ru
b Ural State Technical University, ul. Mira 19, Yekaterinburg, 620002 Russia
Received August 30, 2007
Abstract—Ethyl 2-ethoxymethylidene-3-oxo-3-polyfluoroalkylpropionates reacted in a regioselective fashion
with thiazolylhydrazines to give the corresponding ethyl 1-thiazolyl-5-fluoroalkyl-1H-pyrazole-4-carboxylates.
The product structure was determined on the basis of NMR and X-ray diffraction data.
DOI: 10.1134/S1070428008120166
Pyrazole derivatives attract persistent attention due
to their biological activity, in particular anesthetic [1].
A number of non-narcotic analgesics have been
designed on the basis of pyrazolone derivatives, e.g.,
Phenazone, Aminophenazone, and Metamizole [1].
Fluoroalkyl-containing pyrazoles were covered by
patents as substances possessing anti-inflammatory,
analgesic, and antipyretic activity, highly efficient in-
secticides and herbicides, medical agents for the treat-
ment of hyperglycemia, heat-resistant dyes, and surfac-
tants [2]. A novel non-steroidal anti-inflammatory
drug, Celecoxib {4-[5-(4-methylphenyl)-3-(trifluoro-
methyl)-1H-pyrazol-1-yl]benzenesulfonamide} has
found application in medicine. It is believed that this
compound is a selective inhibitor of cyclooxygenase-2
which promotes synthesis of prostaglandins involved
in the inflammation development [3]. There are pub-
lished data on bactericidal [4], hypotensive [5], fungi-
cidal, and herbicidal [6] activity of such pyrazole
derivatives as thiazolylpyrazoles. Trifluoromethyl-sub-
stituted thiazol-2-ylpyrazoles were patented as blood
platelet aggregation inhibitors and were recommended
for the treatment of thromboses and concomitant vas-
cular disorders [7].
pounds and their derivatives with hydrazine and substi-
tuted hydrazines. Reactions with 1,3-dicarbonyl com-
pounds having a functional group in the 2-position
give rise to functionalized pyrazoles. Transformations
of 2-ethoxymethylidene-substituted ethyl acetoacetate
and ethyl trifluoroacetoacetate in reactions with aryl-
hydrazines were reported [8] to produce ethyl 5-methyl-
(trifluoromethyl)-1H-pyrazole-4-carboxylates.
We examined reactions of ethyl 2-ethoxymethyli-
dene-3-fluoroalkyl-3-oxopropionates Ia and Ib with
a number of thiazolyl-substituted hydrazines IIa–IIf
(Scheme 1). Taking into account that both electrophiles
I and nucleophiles II possess several nonequivalent
reaction centers, formation of different products,
including regioisomeric ones, may be expected as
a result of concurrent processes. Esters Ia and Ib read-
ily reacted with hydrazines IIa–IIf in boiling ethanol
to give compounds IIIa–IIIi as the only products. Ac-
cording to the 1H NMR and mass spectra, the products
were ethyl pyrazolecarboxylates. However, these data
did not allow us to distinguish between two possible
regioisomers A (5-RF) and B (3-RF).
COOEt
COOEt
RF
RF
The goal of the present study was to synthesize
functionalized fluoroalkyl-containing thiazolylpyra-
zoles. A classical method for building up pyrazole ring
is based on cyclocondensation of 1,3-dicarbonyl com-
N
N
N
N
R
R
A
B
1811

PRYADEINA et al.
1812
Scheme 1.
RF
RF
N
OEt
OEt
R1
R2
R1
COOEt
R1
R2
COOH
N
S
N
S
N
S
EtOH, Δ
NaOH
NHNH2
+
RF
N
N
N
R2
O
O
Ia, Ib
IIa–IIf
IIIa–IIIi
IVa–IVe
I, RF = CF3 (a), H(CF2)2 (b); II, R1R2 = benzo (a); R2 = H, R1 = MeOCO (b), EtOCO (c), Ph (d), 4-BrC6H4 (e), 4-MeC6H4 (f);
III, RF = CF3, R1R2 = benzo (a), R2 = H, R1 = MeOCO (b), 4-BrC6H4 (c), 4-MeC6H4 (d); RF = H(CF2)2, R1R2 = benzo (e), R2 = H,
R1 = MeOCO (f), EtOCO (g), Ph (h), 4-MeC6H4 (i); IV, RF = CF3, R1 = HOCO, R2 = H (a); RF = H(CF2)2, R1 = HOCO, R2 = H (b);
R1R2 = benzo (c); R2 = H, R1 = Ph (d), 4-MeC6H4 (e).
To elucidate the structure of compounds IIIa–IIIi,
we have resorted to 19F NMR spectroscopy. It is
known that the chemical shift of fluorine atoms in the
19F NMR spectra of trifluoromethyl-substituted pyra-
zoles is very characteristic. The CF3 signal in the spec-
tra of 4-fluoro [9] and 4-unsubstituted pyrazoles [10]
appears in a stronger field (δF ~101 ppm relative to
C6F6) for 3-CF3 isomers as compared to the corre-
sponding signals of 5-CF3 isomers (δF ~105 ppm). In
the 19F NMR spectra of IIIa–IIId in DMSO-d6, the
CF3 fluorine atoms resonated at δF ~106 ppm, which is
better consistent with 5-CF3 isomers.
zine II at the ethoxymethylidene fragment of ester I
occurs in the initial step, and next follows intramolec-
ular ring closure with participation of the fluoroacyl
fragment and secondary amino group, the ester moiety
in I remaining intact.
The presence of an ethoxycarbonyl group in mole-
cules IIIa–IIIi opens the way to their subsequent mod-
ification. Alkaline hydrolysis of pyrazolecarboxylates
IIIb, IIIe, IIIf, IIIh, and IIIi gave the corresponding
pyrazole-4-carboxylic acids IVa–IVe whose structure
1
was confirmed by H NMR spectroscopy, mass spec-
trometry, and elemental analysis. It should be noted
that hydrolysis of compounds IIIb and IIIf involved
both ester groups (in the pyrazole and thiazole rings).
The assumed structure was proved by the X-ray
diffraction data for a single crystal of compound IIIa
(see figure). Tetrafluoroethyl-substituted pyrazoles
IIIe–IIIi were assigned structure A by comparing their
1H NMR spectra with those of trifluoromethyl-substi-
tuted analogs IIIa–IIId. In this case, the most charac-
teristic was the chemical shift of the CH proton (3-H)
in the pyrazole ring (see table). It is seen that the
position of its signal almost does not change in going
from trifluoromethyl to tetrafluoroethyl derivatives.
EXPERIMENTAL
The IR diffuse reflectance spectra (400–4000 cm–1)
were recorded on a Perkin–Elmer Spectrum One spec-
trometer with Fourier transform. The NMR spectra
were measured from solutions in DMSO-d6 on Bruker
19
DRX-400 (1H, 400.13 MHz, Me4Si; F: 376.44 MHz,
C6F6; IIIa–IIIi) and Bruker WM-250 spectrometers
(1H: 250.13 MHz, Me4Si; IVa–IVe). Elemental anal-
yses were obtained on a Perkin–Elmer PE 2400 Series
II analyzer. The mass spectra (electron impact, 70 eV)
were run on a Varian MAT-311A instrument.
Thus we have demonstrated that cyclocondensation
of ethyl 2-ethoxymethylidene-3-fluoroalkyl-3-oxopro-
pionates with thiazolylhydrazines regioselectively
yields the corresponding ethyl 5-polyfluoroalkyl-1-
(thiazol-2-yl)-1H-pyrazole-4-carboxylates. Presum-
ably, condensation of the free amino group in hydra-
The X-ray diffraction data for compound IIIa were
acquired at 295(2) K on an XCalibur 3 diffractometer
(ω/2θ scanning, MoKα irradiation, λ = 0.71073 Å,
graphite monochromator, CCD detector); triclinic crys-
tals, C14H10F3N3O2S, M 341.31, space group P1¯, unit
cell parameters: a = 7.8490(7), b = 9.9010(15), c =
10.5404(11) Å; α = 108.387(11)°, β = 98.734(8)°, γ =
S1
C6
N1
C1
C10
C5
C7
C14
N2
O1
C9
F1
C13
C2
F2
C8
C11
C12
O2
C4
N3
C3
102.114(10)°; V = 738.71(15) Å3; Z = 2; dcalc
=
F3
1.534 g/cm3; μ(MoKα) = 0.265 cm–1; 216 parameters,
2θmax = 31.72°, –11 ≤ h ≤ 11, –14 ≤ k ≤ 14, –15 ≤ l ≤
15. Total of 12619 reflections were measured, 4562 of
which were independent (Rint = 0.0269); 2406 reflec-
Structure of the molecule of ethyl 1-(benzothiazol-2-yl)-5-
trifluoromethyl-1H-pyrazole-4-carboxylate (IIIa) according
to the X-ray diffraction data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

REGIOSELECTIVE CYCLOCONDENSATION OF ETHYL 2-ETHOXYMETHYLIDENE-...
1813
Chemical shifts (δ, ppm) of CH protons in the heterorings of
compounds IIIa–IIIi
tions with Fo > 4σ(Fo). The structure was solved by the
direct method and was refined by the least-squares
procedure using SHELXL-97 software [11] to R =
0.0355, wR2 = 0.0712; goodness of fit 1.001. The com-
plete set of crystallographic data was deposited to
the Cambridge crystallographic Data Center (entry
no. CCDC 655 617; http://www.ccdc.cam.ac.uk/
deposit; CCDC, 12 Union Road, Cambridge CB2
1EZ, UK; fax: (44) 01223 336033; e-mail:
deposit@ccdc.cam.ac.uk].
Compound no.
3-H (pyrazole)
5-H (thiazole)
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
8.50
8.46
8.45
8.44
8.49
8.45
8.45
8.45
8.44
–
8.67
8.34
8.20
–
8.64
8.61
8.27
8.19
Initial fluoroalkyl-containing esters Ia and Ib were
synthesized as described in [12].
Thiazolylpyrazoles IIIa–IIIi (general procedure).
A mixture of 0.001 mol of ester Ia or Ib and 0.001 mol
of hydrazine IIa–IIf in 15 ml of ethanol was heated for
30–40 min under reflux. The mixture was cooled, and
the precipitate was filtered off, recrystallized from
ethanol, and dried.
Yield 0.308 g (69%), mp 102–103°C. IR spectrum, ν,
cm–1: 3100, 3067, 2984–2935 (C–H); 1727 (C=O);
1
1576, 1529 (C=C, C=N); 1282–1158 (C–F). H NMR
spectrum, δ, ppm: 1.32 t (3H, CH2CH3, J = 7.1 Hz),
4.35 q (2H, OCH2, J = 7.1 Hz), 7.70 d.m (2H, C6H4,
J = 8.5 Hz), 7.90 d.m (2H, C6H4, J = 8.5 Hz), 8.34 s
(1H, 5′-H), 8.45 s (1H, 3-H). 19F NMR spectrum:
δF 106.48 ppm, d (CF3, J = 0.6 Hz). Mass spectrum,
m/z (Irel, %): 447 (100) [M + H]+, 446 (19) [M]+, 445
(96) [M – H]+, 400 (20) [M – HOEt]+, 133 (10.8), 89
(13.4). Found, %: C 43.02; H 2.46; F 12.78; N 9.40.
C16H11BrF3N3O2S. Calculated, %: C 43.07; H 2.48;
F 12.77; N 9.42.
Ethyl 1-(benzothiazol-2-yl)-5-trifluoromethyl-
1H-pyrazole-4-carboxylate (IIIa). Yield 0.249 g
(73%), mp 120–122°C. IR spectrum, ν, cm–1: 3100,
3067 (C–H); 1727 (C=O); 1577, 1529 (C=C, C=N);
1
1251–1101 (C–F). H NMR spectrum, δ, ppm: 1.33 t
(3H, CH2CH3, J = 7.1 Hz), 4.36 q (2H, OCH2, J =
7.1 Hz), 7.57 d.d.d (1H, 6′-H, J = 7.9, 7.8, 1.2 Hz),
7.62 d.d.d (1H, 5′-H, J = 8.0, 7.8, 1.3 Hz), 8.05 d.d.d
(1H, 4′-H, J = 8.0.0, 1.2, 0.7 Hz), 8.22 d.d.d (1H, 7′-H,
J = 7.9, 1.3, 0.7 Hz), 8.50 br.s (1H, 3-H). 19F NMR
spectrum: δF 106.46 ppm, d (CF3, J = 0.7). Mass spec-
trum, m/z (Irel, %): 341 (100) [M]+, 313 (24.7), 296
(67.9) [M – OEt]+, 201 (7.8), 148 (9.1), 134 (17)
[benzothiazole]+, 108 (6.5), 90 (6.2), 69 (7.2). Found,
%: C 49.30; H 2.95; F 16.62; N 12.33. C14H10F3N3O2S.
Calculated, %: C 49.27; H 2.95; F 16.70; N 12.31.
Ethyl 1-[4-(4-methylphenyl)thiazol-2-yl]-5-tri-
fluoromethyl-1H-pyrazole-4-carboxylate (IIId).
Yield 0.305 g (80%), yellow powder, mp 118–119°C.
IR spectrum, ν, cm–1: 3120, 2985–2916 (C–H); 1737
(C=O); 1572, 1527 (C=C, C=N); 1255–1053 (C–F).
1H NMR spectrum, δ, ppm: 1.32 t (3H, CH2CH3, J =
7.1 Hz), 2.35 s (3H, CH3), 4.35 q (2H, OCH2, J =
7.1 Hz), 7.30 d.m (2H, C6H4, J = 8.0 Hz), 7.84 d.m
(2H, C6H4, J = 8.0 Hz), 8.20 s (1H, 5′-H), 8.44 s (1H,
3-H). 19F NMR spectrum: δF 106.50 ppm, s (CF3).
Mass spectrum, m/z (Irel, %): 381 (100) [M]+, 353
(16.4), 336 (13.6) [M – OEt]+, 205 (24.6), 147 (21.5),
115 (11.2), 91 (8.9). Found, %: C 53.24; H 3.56;
F 14.80; N 10.97. C17H14F3N3O2S. Calculated, %:
C 53.54; H 3.70; F 14.94; N 11.02.
Methyl 2-(4-ethoxycarbonyl-5-trifluoromethyl-
1H-pyrazol-1-yl)thiazole-4-carboxylate (IIIb). Yield
0.293 g (84%), mp 135–137°C. IR spectrum, ν, cm–1:
3134, 3111, 3031–2945 (C–H); 1735 (C=O); 1575,
1
1535 (C=C, C=N); 1245–1105 (C–F). H NMR spec-
trum, δ, ppm: 1.31 t (3H, CH2CH3, J = 7.1 Hz), 3.87 s
(3H, OCH3), 4.34 q (2H, OCH2, J = 7.1 Hz), 8.46 br.s
(1H, 3′-H), 8.67 s (1H, 5-H). 19F NMR spectrum:
δF 106.56 ppm, d (CF3, J = 0.7 Hz). Mass spectrum,
m/z (Irel, %): 349 (98) [M]+, 318 (35.5), 304 (100)
[M – OEt]+, 290 (24.5) [M – CO2Me]+, 263 (12.8), 137
(13.8), 83 (29.6), 59 (9.4). Found, %: C 41.30; H 2.88;
F 16.28; N 12.10. C12H10F3N3O4S. Calculated, %:
C 41.26; H 2.89; F 16.32; N 12.03.
Ethyl 1-(benzothiazol-2-yl)-5-(1,1,2,2-tetra-
fluoroethyl)-1H-pyrazole-4-carboxylate (IIIe). Yield
0.326 g (88%), mp 110–112°C. IR spectrum, ν, cm–1:
3110, 2985–2907 (C–H); 1714 (C=O); 1599, 1566,
1
1539 (C=C, C=N); 1251–1088 (C–F). H NMR spec-
Ethyl 1-[4-(4-bromophenyl)thiazol-2-yl]-5-tri-
fluoromethyl-1H-pyrazole-4-carboxylate (IIIc).
trum, δ, ppm: 1.31 t (3H, CH2CH3, J = 7.1 Hz), 4.33 q
(2H, OCH2, J = 7.1 Hz), 7.42 t.t (1H, HCF2, J = 52.5,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

PRYADEINA et al.
1814
5.9 Hz), 7.56 d.d.d (1H, 5′-H, J = 7.9, 7.6, 1.3 Hz),
7.63 d.d.d (1H, 6′-H, J = 8.0, 7.6, 1.3 Hz), 8.05 d.d.d
(1H, 4′-H, J = 7.9, 1.3, 0.7 Hz), 8.21 d.d.d (1H, 7′-H,
J = 8.0, 1.3, 0.7 Hz), 8.49 s (1H, 3-H). 19F NMR spec-
trum, δF, ppm: 26.85 d.t (2F, HCF2, J = 52.5, 9.4 Hz),
53.39 m (2F, CF2). Mass spectrum, m/z (Irel, %): 373
(100) [M]+, 328 (70.8) [M – OEt]+, 300 (14.6), 281
(17.8), 201 (23.6), 185 (48.4), 161 (13.4), 141 (40.4),
108 (16.3), 90 (16.1), 69 (14.1) 51 (9.3). Found, %:
C 48.17; N 2.69; F 20.27; N 11.29. C15H11F4N3O2S.
Calculated, %: C 48.26; N 2.97; F 20.36; N 11.26.
Ethyl 1-[4-(4-methylphenyl)thiazol-2-yl]-5-
(1,1,2,2-tetrafluoroethyl)-1H-pyrazole-4-carbox-
ylate (IIIi). Yield 0.310 g (75%), mp 139–141°C. IR
spectrum, ν, cm–1: 3129, 3030–2910 (C–H); 1731
(C=O); 1562, 1524 (C=C, C=N); 1218–1054 (C–F).
1H NMR spectrum, δ, ppm: 1.32 t (3H, CH2CH3, J =
7.1 Hz), 2.35 s (3H, CH3), 4.33 q (2H, OCH2, J =
7.1 Hz), 7.24 t.t (1H, HCF2, J = 52.4, 5.8 Hz), 7.30 d.m
(2H, C6H4, J = 8.0 Hz), 7.82 d.m (2H, C6H4, J =
19
8.0 Hz), 8.19 s (1H, 5′-H), 8.44 s (1H, 3-H). F NMR
spectrum, δF, ppm: 26.52 d.t (2F, HCF2, J = 52.4,
9.7 Hz), 52.81 m (2F, CF2). Mass spectrum, m/z
(Irel, %): 413 (100) [M]+, 385 (10.6), 368 (14.9)
[M – OEt]+, 224 (11.6), 147 (22.3), 115 (11.6), 91
(10.0), 77 (3.3). Found, %: C 52.18; H 3.71; F 18.20;
N 10.19. C18H15F4N3O2S. Calculated, %: C 52.30;
H 3.66; F 18.38; N 10.16.
Methyl 2-[4-ethoxycarbonyl-5-(1,1,2,2-tetra-
fluoroethyl)-1H-pyrazol-1-yl]thiazole-4-carboxylate
(IIIf). Yield 0.290 g (76%), mp 125°C. 1H NMR spec-
trum, δ, ppm: 1.31 t (3H, CH2CH3, J = 7.1 Hz), 3.88 s
(3H, OCH3), 4.32 q (2H, OCH2, J = 7.1 Hz), 7.26 t.t
(1H, HCF2, J = 52.8, 5.8 Hz), 8.45 s (1H, 3′-H), 8.64 s
19
(1H, 5-H). F NMR spectrum, δF, ppm: 26.55 d.t (2F,
2-[4-Carboxy-5-(trifluoromethyl)-1H-pyrazol-1-
yl]thiazole-4-carboxylic acid (IVa). A mixture of
0.175 g (0.5 mmol) of compound IIIb and 0.040 g
(1 mmol) of sodium hydroxide in ethanol was heated
for 5–15 min under reflux. The solvent was distilled
off, the residue was dissolved in water, and the solu-
tion was acidified to pH ~5–6 with concentrated
hydrochloric acid. The precipitate was filtered off,
washed with ethanol, and dried. Yield 0.124 g (81%),
HCF2, J = 52.8, 9.4 Hz), 52.93 m (2F, CF2). Mass
spectrum, m/z (Irel, %): 381 (86.0) [M]+, 361 (16.0),
350 (31.4), 336 (100) [M – OEt]+, 322 (18.7), 304
(57.2), 270 (13.6), 193 (30.5), 153 (16.8), 141 (37.5),
117 (19.6), 83 (39.7), 59 (18.2). Found, %: C 40.82;
H 2.88; F 19.92; N 10.97. C13H11F4N3O4S. Calculated,
%: C 40.95; H 2.91; F 19.93; N 11.02.
Ethyl 2-[4-ethoxycarbonyl-5-(1,1,2,2-tetrafluoro-
ethyl)-1H-pyrazol-1-yl]thiazole-4-carboxylate
(IIIg). Yield 0.321 g (84%), mp 106–108°C. IR spec-
trum, ν, cm–1: 3129, 1733 (C=O); 1572, 1529, 1459
(C=C, C=N); 1243–1076 (C–F). 1H NMR spectrum, δ,
ppm: 1.30 t (3H, CH2CH3, J = 7.1 Hz), 1.32 t (3H,
CH2CH3, J = 7.2 Hz), 4.31 q (2H, OCH2, J = 7.1 Hz),
4.33 q (2H, OCH2, J = 7.2 Hz), 7.30 t.t (1H, HCF2,
J = 53.0, 5.6 Hz), 8.45 s (1H, 3′-H), 8.61 s (1H, 5-H).
19F NMR spectrum, δF, ppm: 26.45 d.t (2F, HCF2, J =
52.8, 9.5 Hz), 53.94 m (2F, CF2). Found, %: C 42.96;
H 3.32; F 15.67; N 11.57. C13H12F4N3O4S. Calculated,
%: C 42.98; H 3.33; F 15.69; N 11.57.
1
mp 215°C. H NMR spectrum, δ, ppm: 8.19 s (1H,
3′-H), 8.45 s (1H, 5-H), 13.25 br.s (2H, COOH). Mass
spectrum, m/z (Irel, %): 307 (100) [M]+, 290 (10.1), 263
(17.2), 187 (27.3), 163 (10.9), 127 (13.6), 99 (28.3), 83
(86.4), 69 (21.7), 58 (25.2). Found, %: C 35.09;
H 1.27; F 18.40; N 13.59. C9H4F3N3O4S. Calculated,
%: C 35.19; H 1.31; F 18.55; N 13.68.
Compounds IVb–IVe were synthesized in a simi-
lar way.
2-[4-Carboxy-5-(1,1,2,2-tetrafluoroethyl)-1H-
pyrazol-1-yl]thiazole-4-carboxylic acid (IVb) was
obtained from 0.191 g (0.5 mmol) of compound IIIf.
Ethyl 1-(4-phenylthiazol-2-yl)-5-(1,1,2,2-tetra-
1
fluoroethyl)-1H-pyrazole-4-carboxylate (IIIh). Yield
Yield 0.122 g (72%), mp 210–212°C. H NMR spec-
1
0.248 g (62%), mp 129–131°C. H NMR spectrum, δ,
trum, δ, ppm: 7.29 t.t (1H, HCF2, J = 53.4, 5.8 Hz),
8.18 s (1H, 3′-H), 8.42 s (1H, 5-H). Mass spectrum,
m/z (Irel, %): 339 (100) [M]+, 319 (61.9), 270 (46.2),
219 (23.4), 177 (33.2), 161 (35.2), 141 (67.6), 117
(100), 101 (23.6), 83 (90.9), 71 (23.0), 58 (40.5), 51
(46.1). Found, %: C 35.29; H 1.38; F 22.25; N 12.30.
C10H5F4N3O4S. Calculated, %: C 35.41; H 1.49;
F 22.40; N 12.39.
ppm: 1.32 t (3H, CH2CH3, J = 7.1 Hz), 4.33 q (2H,
OCH2, J = 7.1 Hz), 7.25 t.t (1H, HCF2, J = 52.4,
5.9 Hz), 7.41–7.52 m (3H, C6H5), 7.94 m (2H, C6H5),
8.27 s (1H, 5′-H), 8.45 s (1H, 3-H). 19F NMR spec-
trum, δF, ppm: 26.54 d.t (2F, HCF2, J = 52.4, 9.8 Hz),
52.83 m (2F, CF2). Mass spectrum, m/z (Irel, %): 399
(100) [M]+, 354 (28) [M – OEt]+, 210 (15.4), 177 (7.8),
134 (36.5), 102 (13.8), 89 (11.8), 77 (10.2). Found, %:
C 51.06; H 3.12; F 19.00; N 10.43. C17H13F4N3O2S.
Calculated, %: C 51.13; H 3.28; F 19.03; N 10.52.
1-(Benzothiazol-2-yl)-5-(1,1,2,2-tetrafluoro-
ethyl)-1H-pyrazole-4-carboxylic acid (IVc) was ob-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

REGIOSELECTIVE CYCLOCONDENSATION OF ETHYL 2-ETHOXYMETHYLIDENE-...
1815
REFERENCES
tained from 0.171 g (0.5 mmol) of compound IIIe.
Yield 0.135 g (78%), mp 177–179°C. H NMR spec-
1
1. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
Moscow: Novaya Volna, 2002, vol. 1, p. 159.
2. Pashkevich, V.M. and Saloutin, V.I., Usp. Khim., 1985,
trum, δ, ppm: 7.28 t.t (1H, HCF2, J = 54.3, 5.8 Hz),
7.47–7.60 m (2H, Harom), 8.02–8.09 m (2H, Harom),
8.26 s (1H, 3-H). Mass spectrum, m/z (Irel, %): 345
(100) [M]+, 328 (35.6), 281 (22.5), 201 (46.1), 184
(78.3), 161 (14.1), 134 (42.1), 108 (25.0), 90 (25.9), 69
(26.3), 51 (17.9). Found, %: C 45.19; H 1.97; F 21.95;
N 12.06. C13H7F4N3O2S. Calculated, %: C 45.22;
H 2.04; F 22.01; N 12.17.
vol. 54, p. 1997.
3. Nasonov, E.L. Terapevt. Arkhiv., 2001, no. 5; Yakovle-
va, L.V., Shapoval, O.N., and Zupanets, I.A., Sovremen-
nye aspekty ratsional’nogo obezbolivaniya v meditsin-
skoi praktike: Prakticheskoe rukovodstvo (Modern
Aspects of Rational Anesthesia in Medical Practice.
A Practical Guide), Treshchinskii, A.I., Usenko, L.V.,
and Zupanets, I.A., Eds., Kiev: MORION, 2000, p. 6.
4. Harode, R. and Jain, V., Indian Drugs, 1984, vol. 21,
p. 442; Balakrishna, K. and Prashantha, G., Indian J.
Heterocycl. Chem., 1999, vol. 8, p. 241.
1-(4-Phenylthiazol-2-yl)-5-(1,1,2,2-tetrafluoro-
ethyl)-1H-pyrazole-4-carboxylic acid (IVd) was
obtained from 0.199 g (0.5 mmol) of compound IIIh.
1
Yield 0.158 g (85%), mp 168–170°C. H NMR spec-
trum, δ, ppm: 7.11 t.t (1H, HCF2, J = 53.1, 6.0 Hz),
7.29–7.46 m (3H, C6H5), 7.84 m (2H, C6H5), 8.09 s
(1H, 5′-H), 8.22 s (1H, 3-H). Mass spectrum, m/z
(Irel, %): 371 (100) [M]+, 300 (5.6), 227 (15.3), 210
(28.2), 134 (61.6), 102 (20.7), 89 (21.8), 77 (22.0), 69
(7.3), 51 (15.2). Found, %: C 48.39; H 2.37; F 20.29;
N 11.20. C15H9F4N3O2S. Calculated, %: C 48.52;
H 2.44; F 20.47; N 11.32.
5. Gulhan, T.Z. and Pierre, C., Eur. J. Med. Chem., 2000,
vol. 35, p. 635.
6. Singh, S.P., Segal, S., Tarar, L.S., and Dhawan, S.N.,
Indian J. Chem., Sect. B, 1990, vol. 29, p. 310.
7. Sanfilippo, P.J., Andrade-Gordon, P., Urbanski, M.J.,
Beers, K.N., Eckardt, A., Falotico, R., Ginsberg, M.H.,
Offord, S., and Press, J.B., J. Med. Chem., 1995,
vol. 38, p. 34; Donohue, B.A., Michelotti, E.L.,
Reader, J.C., Reader, V., Stirling, M., and Tice, C.M.,
J. Comb. Chem., 2002, vol. 4, p. 23.
8. Bagrov, F.V., Russ. J. Org. Chem., 2000, vol. 36, p. 191;
Emelina, E.E., Iz’’yurov, A.L., Ermakov, N.V., and
Ershov, B.A., Russ. J. Org. Chem., 1996, vol. 32,
p. 430; Beck, J.R. and Wright, F.L., J. Heterocycl.
Chem., 1987, vol. 24, p. 739.
9. Sloop, J.C., Bumgardner, C.L., and Loehle, W.D.,
J. Fluorine Chem., 2002, vol. 118, p. 135.
10. Singh, S.P., Kapoor, J.K., Kumar, D., and Thread-
gill, M.D., J. Fluorine Chem., 1997, vol. 83, p. 73.
11. Sheldrick, G.M., SHELXS 97, Göttingen, Germany:
1-[4-(4-Methylphenyl)thiazol-2-yl]-5-(1,1,2,2-
tetrafluoroethyl)-1H-pyrazole-4-carboxylic acid
(IVe) was obtained from 0.207 g (0.5 mmol) of com-
pound IIIi. Yield 0.154 g (68%), mp 186–188°C.
1H NMR spectrum, δ, ppm: 2.38 s (1H, CH3), 7.10 t.t
(1H, HCF2, J = 53.0, 6.0 Hz), 7.23 d.m (2H, C6H4, J =
7.9 Hz), 7.76 d.m (2H, C6H4, J = 7.9 Hz), 7.99 s (1H,
5′-H), 8.18 s (1H, 3-H). Mass spectrum, m/z (Irel, %):
385 (100) [M]+, 340 (7.3), 326 (7.1), 224 (18.9), 159
(8.4), 150 (6.4), 147 (27.2), 115 (16.6), 91 (16.4), 77
(7.3), 65 (6.7). Found, %: C 49.80; H 2.79; F 19.67;
N 10.81. C16H11F4N3O2S. Calculated, %: C 49.87;
H 2.88; F 19.72; N 10.90.
Univ. of Göttingen, 1997.
12. Pryadeina, M.V., Burgart, Ya.V., Saloutin, V.I., Slepu-
khin, P.A., Kazheva, O.N., Shilov, G.V., D’yachen-
ko, O.A., and Chupakhin, O.N., Russ. J. Org. Chem.,
2007, vol. 43, p. 945.
This study was performed under financial support
by the State Program for Support of Leading Scientific
Schools (project no. 3758.2008.3).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008