The regioselectivity of the formation of 2-pyrazolylthiazoles and their precursors from the reaction of 2-hydrazinothiazoles with 4,4,4-trifluoro-1-hetaryl-1,3-butanediones

Article abstract of DOI:10.1016/S0022-1139(02)00060-X

Reaction of 2-hydrazinothiazoles 1 with 1-thienyl-and 1-furyl-1,3-butanediones 2a,b in methanol in the presence of hydrochloric acid mainly leads to a mixture of pyrazoles 3 and pyrazolines 4 or pyrazoles 3 and 5 in strong acidic conditions. Isomeric hydrazones 6 and pyrazolines 4 were formed and isolated in these reactions in the absence of hydrochloric acid. It has been shown that the regioselectivity in the reaction of diketones 2 with hydrazine 1 is governed by both the concentration of acid and the nature of substituents in the 1,3-diketones 2. Cyclization of hydrazones 6 is shown to occur under milder conditions than dehydration for pyrazolines 4. The new heterocyclic compounds were prepared and fully characterized by NMR spectra and by X-ray analysis for 3c.

Full text of DOI:10.1016/S0022-1139(02)00060-X

Journal of Fluorine Chemistry 115 (2002) 183±192
The regioselectivity of the formation of 2-pyrazolylthiazoles and their
precursors from the reaction of 2-hydrazinothiazoles with
4,4,4-tri¯uoro-1-hetaryl-1,3-butanediones
Anna B. Denisovaa, Vyacheslav Ya. Sosnovskikha, Wim Dehaenb,*,
Suzanne Toppetb, Luc Van Meerveltb, Vasiliy A. Bakuleva,1
aToslab, The Urals State Technical University, 620002 Ekaterinburg, Russia
bDepartment of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Received 28 August 2001; received in revised form 15 March 2002; accepted 25 March 2002
Abstract
Reaction of 2-hydrazinothiazoles 1 with 1-thienyl- and 1-furyl-1,3-butanediones 2a,b in methanol in the presence of hydrochloric acid
mainly leads to a mixture of pyrazoles 3 and pyrazolines 4 or pyrazoles 3 and 5 in strong acidic conditions. Isomeric hydrazones 6 and
pyrazolines 4 were formed and isolated in these reactions in the absence of hydrochloric acid. It has been shown that the regioselectivity in the
reaction of diketones 2 with hydrazine 1 is governed by both the concentration of acid and the nature of substituents in the 1,3-diketones 2.
Cyclization of hydrazones 6 is shown to occur under milder conditions than dehydration for pyrazolines 4. The new heterocyclic compounds
were prepared and fully characterized by NMR spectra and by X-ray analysis for 3c. # 2002 Elsevier Science B.V. All rights reserved.
Keywords: Pyrazolylthiazoles; Regioselectivity; 2-Hydrazinothiazoles; 1,3-Diketones; 1H; 19F; 13C NMR
1. Introduction
There are no data in the literature preceding this work on
the in¯uence of the acidity of the reaction medium on the
regioselectivity of the condensation of heterocyclic hydra-
zines with tri¯uoromethyl 1,3-diketones. Clearly, this cor-
relation could be useful in future process development if any
of these compounds emerge as commercial products.
Heterocyclic compounds bearing a tri¯uoromethyl group
are of special interest as potential pesticides [1] and phar-
maceuticals [1±4]. The reaction of tri¯uoromethyl-1,3-dike-
tones with heterocyclic hydrazines has been shown to be an
ef®cient method to prepare such compounds, where the
pyrazole ring is conjugated to other heterocycles [5] and
many examples of such type of compounds have recently
been reported [5,6]. Tricyclic conjugated compounds con-
taining aromatic and non-aromatic heterocyclic rings are not
so common in the literature [5]. Furthermore, different
structures have been described for the reaction of similar
hydrazines [6±8] and even for the same reagents [7±9]. The
reason is that the reaction of 1,3-diketones, and especially
those bearing heterocyclic moieties, with hydrazines leads
to mixtures of regioisomeric pyrazoles. The most recent
advances in this area have been summarized by Singh
et al. [5].
2. Results and discussion
In a previous report, we have described that the reaction of
2-hydrazinothiazoles with 4,4,4-tri¯uoro-1-aryl-1,3-butane-
diones (Ar ˆ Ph, 2-naphthyl, 4-ClC6H4) to give the selective
formation of 2-(3-aryl-5-hydroxy-5-tri¯uoromethylpyra-
zolin-1-yl)thiazoles. These compounds in turn undergo
dehydration to aromatic 2-(3-aryl-5-tri¯uoromethylpyrazol-
1-yl)-4-thiazoles after re¯ux in acetic anhydride (Scheme 1)
[6]. At the same time, Singh et al. have found that the
reaction of these 1,3-diketones with thiazdyl hydrazine
generates a product with the opposite regioselectivity
[7,8]. Even more surprisingly, for reaction of thiosemicar-
bazide with diketone 2a, Singh et al. [7] and Pashkevich et al.
[9] have isolated products of opposite regioselectivity from
the reaction using identical reagents.
* Corresponding author. Tel.: ‡32-16-32-74-39; fax: ‡32-16-32-79-90.
E-mail address: wim.dehaen@chem.kuleuven.ac.be (W. Dehaen).
1 Co-corresponding author.
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 0 6 0 - X

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A.B. Denisova et al. / Journal of Fluorine Chemistry 115 (2002) 183±192
Scheme 1. (i) MeOH, reflux (ii) MeOH, HCl, reflux (iii) Ac2O, reflux.
These results prompted us to carry out a detailed study on
We have discovered that the reaction of 2-hydrazinothia-
zole 1a with diketone 2a in methanol in the presence of
concentrated hydrochloric acid (the molar ratio of 1a to HCl
being 1:0.26), leads to a mixture of 5-hydroxy-5-tri¯uor-
omethylpyrazoline 4a, pyrazole 3a, and 5-tri¯uoropyrazole
5a in a ratio of 26:69:5 as determined from the 19F NMR
the reactions of the 2-hydrazinothiazoles 1a±c with 1-thie-
nyl-4,4,4-tri¯uoro-1,3-butanedione 2a. We have also carried
out similar condensation reactions between 1a±c and 1-
furyl-4,4,4-tri¯uoro-1,3-butanedione 2b, to generate a series
of novel reaction products (Scheme 1).

A.B. Denisova et al. / Journal of Fluorine Chemistry 115 (2002) 183±192
185
Table 1
Quantitative composition of the product mixtures, obtained in the reaction of 1a with 2a with different amounts of acid
Compound
Regioselectivitya
7a (%)
6a (%)
4a (%)
3a (%)
5a (%)
Molar ratio of 1a to HCl
1:0
1:0.1
27
18
53
28
26
25
2
67
0.3
2.0
2.2
2.4
3.3
5
5
1:0.26
69
1:0.5
1:100
70
78
5
22
Chemical shift CF3 (ppm)
94.9
92.7
80.9
98.9
102.0
a The regioselectivity is defined as the ratio of sum of concentration of 6a and 3a to the sum of concentration for 7a, 4a and 5a.
spectra (the ratio 5-CF3/3-CF3 is 1:2.2). These results are in
contrast with the ®ndings of Singh et al. [7]. In the same
reaction, using a catalytic amount of HCl, they isolated
pyrazole 3a as the exclusive product. We have also found
that the nature and the ratio of these products depend on the
amount of acid used (see Table 1). Thus we obtained a
mixture of 3a and 5a in ratio 3.3:1 with a large excess of HCl
(100 molar eq. to 1a).
between 1:2.2 and 1:2.8 (see Section 3). Compounds 4d±f
can be easily prepared as pure samples by crystallization of
mixtures 4d±f/3d±f from ethanol.
We have shown that hydrazones 6a,c and pyrazolines 4a,c
transform to pyrazoles 3a,c and 5a,c, respectively after
re¯ux in methanol, containing more than 1.5 eq. of hydro-
chloric acid. The conversion time for 6 was considerably less
than that for 4 (0.5±1.5 and 36±54 h, respectively). Com-
plete and fast conversion of 4 to 5 for all samples can be
achieved in re¯uxing acetic anhydride, as described earlier
[6].
Regioisomeric pyrazoles 3 and 5 could be readily dis-
tinguished by their 1H, 19F and 13C NMR spectra. The
signals of the CF3 groups of compounds 3 in the 19F
NMR spectra show up at 98.8±98.9 ppm, which is 3 ppm
up®eld in comparison with pyrazoles 5 (Table 1). This is in
accordance with the data for isomeric pyrazoles described
by Singh et al. [5]. Thus, the signals for C4±H in the 1H NMR
spectra of compounds 5 are deshielded 0.3±0.4 ppm in
comparison with 3. Interestingly, the signal of C3±H corre-
sponding to the furan ring in compound 3f is shifted down-
®eld (0.5 ppm) in comparison with 5f. This effect can be
explained by a negative anisotropy effect. The same
deshielding for 3c is less than 0.1 ppm.
We have found that hydrazine 1a will slowly react with
diketones 2a in the absence of hydrochloric acid. A mixture
of four products including hydrazones 6a and 7a, pyrazo-
lines 4a and pyrazole 3a is obtained (in a ratio of
9:13.5:26.5:1 according to 19F NMR spectral data). Taking
into account that the two series of the products 6 and 3 on
one side, and 7, 4 and 5 on the other side, results from two
different reaction pathways from of 1a with 2a, we can
calculate the regioselectivity for this reaction as the ratio of
the sum of the concentrations of 6 and 3 to the sum of the
concentrations for 7, 4 and 5 (see Table 1). It is shown in the
Table 1 that the regioselectivity is opposite when we com-
pare the results for the reactions with and without acid. It is
also shown that the regioselectivity depends on the amount
of HCl used. Products 3a±6a were separated by column
chromatography. Compound 7a was identi®ed in the mix-
ture by 19F NMR spectroscopy. It should be noted that 3a can
be isolated by crystallization from ethanol of the mixture 3a
and 5a prepared in the presence of hydrochloric acid.
Reactions of hydrazines 1b,c with diketone 2a in the
presence of 0.26 eq. of hydrochloric acid (relative to 1b)
lead to analogous mixtures of compounds 3b,c, 4b,c and
5b,c (see Section 3), which were also separated by column
chromatography. The percentage of 5a±c did not exceed 5%.
A condensation reaction between 1c and 2a is accompanied
by transesteri®cation to form 3c0.
The isomers 3 and 5 could also be distinguished by their
13C NMR spectroscopic data. The signals belonging to the
C3 and C5 position of the pyrazole ring resonated at different
frequencies. Thus, the C5 signals for 5a±f were quartets at
131±132 ppm (2JCÀCF of 40±42 Hz). The C3 signals for 3a±
3
f appeared as quartets at 143 ppm (2JCÀCF of 38.2±38.6 Hz).
3
It is interesting to note that some carbon atoms, such as C4 of
the pyrazole ring and C2 of the thiophene (or furan) ring
were sensitive to the change of their chemical environment.
The signals for C4 of the pyrazole ring for compounds 5a±c
were deshielded 1.8±2.8 ppm in comparison to 3a±c; for
furan-containing derivatives 5d±f and 3d±f this deshielding
reaches 3.6±4.5 ppm. The signals for C2 of the thiophene (or
furan) ring of products 5 also are signi®cantly deshielded
7.1±8.3 ppm (respectively 3.6 ppm) in comparison with that
for 3. The CF3 carbon quartet for 3a±f appeared around
120.5 ppm, whereas the same for 5a±f showed up around
119 ppm.
Interestingly, the replacement of the 2-thienyl moiety by
the 2-furyl group in 1,3-diketones lead to a difference in
regioselectivity. The reaction was carried out under the same
conditions. Thus, in reactions of hydrazines 1a±c with 2-
furyl diketone 2b the ratio of 5-CF3/3-CF3 products is varied
on the substituent in hydrazine moiety at 0.26 eq. of hydro-
chloric acid relative to 1 between 1.1:1 and 1.25:1, respec-
tively, while for thienyl-containing compounds, the ratio is

186
A.B. Denisova et al. / Journal of Fluorine Chemistry 115 (2002) 183±192
Fig. 1. Molecular structure of 2-(5-(2-thienyl)-3-trifluoromethylpyrazol-1-yl)-4-ethoxycarbonylthiazole 3c.
Finally, we could remove all doubt about the structure of
6a,c were situated at 36.7 ppm. The CF3 carbon quartets for
6a,c appeared at 120.9 ppm.
The data obtained in this study allow us to draw some
conclusions regarding the mechanism of the reaction of
2-hydrazinothiazoles 1 with 1,3-diketones 2.
the two regioisomers by solving the crystal structure of 3c by
X-ray diffraction. The X-ray analysis for the regioisomeric
pyrazole of type 5 (R ˆ 4-chlorophenyl, thienyl is substi-
tuted by 4-¯uorophenyl) has already been reported by us [6].
Two conformations of 3c are observed in the solid state for
both the CF3 and thiophene substituents (Fig. 1).2
Selevanov et al. proposed a general scheme for the
reaction of hydrazines with 1,3-diketones [10]. Stop-¯ow
NMR techniques were used to characterize the intermedi-
ates, including b-ketohydrazinocarbinols, the monohydra-
zones of 1,3-diketones, 3,5-dihydroxypyrazolidines and
5-hydroxypyrazolines from the reaction of 1,3-diketones
with hydrazine and methylhydrazine [11]. They have also
shown that two pathways, respectively via 3,5-dihydroxy-
pyrazolidines and via hydrazone intermediates may occur,
leading to regioisomeric pyrazoles in these reactions. A
similar condensation with phenylhydrazine has been shown
to take place via hydrazone intermediates only, due to poor
nucleophilicity of this reagent [11]. On the other hand, Singh
et al. postulated the existence of 3,5-dihydroxypyrazolidines
in the reaction of arylhydrazines with 1,3-diketones. Based
on semiempirical calculations of the electronic density on
the pyrazolidine nitrogens for the dehydration reaction, they
rationalized the opposite regioselectivity for the reaction of
phenylhydrazine and 2,4-dinitrophenylhydrazine with 1,1,1-
tri¯uoropentane-2,4-dione [5].
The structures of precursors 4 and 6 were also con®rmed
1
by spectroscopic methods. The H NMR spectra of 4a±f
showed a typical ABpattern for the methylene groups at 3.6
and 4.0 ppm with 2JCH coupling of 18±19 Hz. The hydroxyl
groups resonated as sharp singlets at 8.3±8.45 ppm. In
2
1
contrast to 4, H NMR spectra of hydrazones 6a,c,f have
singlets corresponding to the methylene groups at 4.4 ppm
and broad singlets corresponding to the NH group at
12.5 ppm.
An inspection of the 13C NMR spectra of 4a±f showed
that the chemical shifts of the C4 signals for the dihydro-
pyrazoline rings were found at 44.6±45.5 ppm. The signals
of C5 were found back as quartets at 92.3±92.8 ppm with a
2
typical coupling constant JCF of 33.6 Hz. The signals
corresponding to the methylene groups of the hydrazones
3
2 Crystallographic data (excluding structure factors) have been deposited
with the Cambridge Crystallographic Data Center as a supplementary
publication number CCDC 161525. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: ‡44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
In this report, we have shown that reactions of diketones 2
bearing a tri¯uoromethyl group and a heterocyclic moiety
can proceed with participation of either of the carbonyl

A.B. Denisova et al. / Journal of Fluorine Chemistry 115 (2002) 183±192
187
groups to afford, in the absence of acid, mainly hydrazones
3. Experimental
6, 7 and pyrazolines 4. The formation of the latter most
probably took place via a hydrazone intermediate of type 7
that is a regioisomer of 6. Clearly, the hydrazone 7 is prone
to intramolecular cyclization of its NH moiety with the
highly reactive CF3CO group. On the other hand, the
hydrazones 6 will be in equilibrium with an unstable
pyrazoline 8. This equilibrium is normally completely
shifted to the hydrazone 6 (Scheme 1). The formation of
hydrazones 6 and 7 con®rms the data of Selevanov [11] that
elimination of water from the hydrazinocarbinol group to
form a hydrazone takes place more easily than its cycliza-
tion to 3,5-dihydroxypyrazolidines. At the same time, our
data on the isolation and identi®cation of isomeric hydra-
zones 6, 7 does not support the hypothesis of Singh et al.
that dehydration of isomeric 3,5-dihydroxypyrazolidines
rules the regioselectivity in this reaction. If 3,5-dihydrox-
ypyrazolidines is an intermediate in this reaction then it
should eliminate water followed by ring opening to form
hydrazones 6 and 7.
Dehydration of compounds 4 and 6 (via 8) was carried out
in acidic media or with acetic anhydride to form aromatic
regioisomeric pyrazoles 5 and 3. We can assume that this
will occur via carbocation intermediates [5], which are more
dif®cult to form in the case of 4, where the tri¯uoromethyl
group is adjacent to the cationic center. Indeed, in this case it
is better to convert the hydroxy group of 4 to a better leaving
group (e.g. acetoxy) prior to aromatization.
If the regioselectivity of the reaction of methylhydrazine
with various diketones depends mainly on the relative
nucleophilicity of nitrogen atoms [10,11] the direction of
poor nucleophiles, such as 2-hydrazinothiazoles should be
governed by the relative reactivity of the two ketone groups
in 1,3-diketones. The observed variation of the regioselec-
tivity of the reaction of hydrazines 1 with diketones 2 upon
variation in acid catalyst can shed light on the reasons of
contradictory results obtained by different research groups.
One can assume that the acid present mainly protonates the
carbonyl group of 1 connected with the heterocyclic ring and
such activation favors the Michael 1,4-addition, rather than
the 1,2-addition of hydrazine [12] which shifts the chemistry
in favor of pyrazoles 3.3 Further work, testing this hypoth-
esis, is under way.
1H, 19F and 13C NMR spectra were recorded at 400, 376
and 100 MHz, respectively on a Bruker AMX 400 in either
(CD3)2SO or CDCl3 solutions. The internal standard for the
1
19F spectra was C6F6 and for H spectra used Me4Si. The
mass spectra were scanned at 70 eV on an MS 12 mass
spectrometer ®tted with a direct inlet system. Products were
analyzed by TLC on DC-Plastikfolen Kieselgel 60 F 254
plates. Melting point were taken in open capillaries and are
uncorrected. The 2-hydrazino-4-R-thiazoles (1a±c) were
prepared by steam distillation of respective hydrobromides
of 2-isopropylidenhydrazino-4-R-thiazoles, as reported ear-
lier [6]. Commercial samples of 2a,b were used.
3.1. General procedure 1: reactions of 2-
hydrazinothiazoles 1a±c with diketones 2a,b
in the presence of hydrochloric acid
3.1.1. 2-(5-(2-Thienyl)-3-trifluoromethyl-pyrazol-1-yl)-4-
(4-chlorophenyl)thiazole (3a) and 2-(5-hydroxy-3-(2-
thienyl)-5-trifluoromethylpyrazolin-1-yl)-4-(4-
chlorophenyl)-thiazole (4a)
A mixture of 1a (0.6 g, 2.66 mmol) in methanol (30 cm3),
containing hydrochloric acid (0.7 mmol, being a molar ratio
of 1:0.26), and 2a (0.61 g, 2.75 mmol) was re¯uxed during
3 h. The solvent was completely removed. In the residue,
three products 3a, 4a and 5a were present in the ratio of
69:26:5 as determined by the 19F NMR spectral data (the
ratio 5-CF3/3-CF3 is 1:2.2). Column chromatography using
dichloromethane±hexane (1:4) or hexane±ethyl acetate
(25:1), separated the mixture of 4a and 3a. The ®rst fraction
contained 3a, Rf 0.5 and the second fraction contained 4a, Rf
0.25. The product 5a was not separated, but obtained by
general procedure 2. 2-(5-(2-Thienyl)-3-tri¯uoromethyl-
pyrazol-1-yl)-4-(4-chlorophenyl)thiazole
(3a)
(0.7 g,
61%); mp 110 8C was described earlier ([7], 110 8C). 2-
(5-Hydroxy-3-(2-thienyl)-5-tri¯uoromethylpyrazolin-1-yl)-
4-(4-chlorophenyl)-thiazole (4a) (0.28 g, 26%), as white
crystals, mp 154±156 8C; 1H NMR ((CD3)2SO) d: 3.72
(d, 1H, J ˆ 18:6 Hz, pyrazole 4-H), 4.04 (d, 1H,
J ˆ 18:6 Hz, pyrazole 4-H), 7.20 (dd, 1H, J ˆ 5:0 Hz,
thienyl 4-H), 7.49 (d, 2H, J ˆ 8:4, phenyl 2-H and 6-H),
7.56 (dd, 1H, J ˆ 3:6 Hz, thienyl 5-H), 7.62 (s, 1H, thiazole
5-H), 7.77 (dd, 1H, J ˆ 5:0 Hz, thienyl 3-H), 7.94 (d, 2H,
J ˆ 8:4, phenyl 3-H and 5-H), 8.34 (s, 1H, OH); 13C NMR
((CD3)2SO) d: 45.5 (pyrazole 4-C), 92.8 (q, JCÀF ˆ 33:6 Hz,
pyrazole 5-C), 107.6 (thiazole 5-C), 123.1 (q,
JCÀF ˆ 284:8 Hz, CF3), 127.4 (phenyl 3-C and 5-C),
128.1 (thienyl 4-C), 128.6 (phenyl 2-C and 6-C), 129.7
(thienyl 3-C), 130.5 (thienyl 5-C), 132.1 (phenyl 4-C),
133.0 (thienyl 2-C), 133.3 (phenyl 1-C), 147.7 (pyrazole
3-C), 149.7 (thiazole 4-C), 162.9 (thiazole 2-C); 19F NMR
3 One referee suggested an alternative explanation for the regioselec-
tivity of the condensation reactions of 1 and 2 by assuming reversibility
for all reaction steps. Thus, the condensation products 6 or 7 can revert
to the starting materials with the involvement of water. In this case, the
product ratio under the reaction conditions without acid represents the
thermodynamic stability of the respective products. Acid would
influence the equilibrium by taking away products 6 and 8 by
irreversibly forming the product 3. However, isolated products such as
4a give only 5a on treatment with acid without the formation of any
side products with different regiochemistry. Thus, even if such
equilibration is taking place, it is slow compared to the acid-catalyzed
formation of the final products and is not likely to have an influence
on the regioselectivity.
‡
(CDCl3) d: 80.9 (s, CF3). MS (EI) m/z: 429/431 [M] (95/
‡
‡
46), 411/413 [M À H2O] (18/9), 360/362 [M À CF3] (100/
46). Anal. Calcd. for C17H11ClF3N3OS2: C, 47.50; H, 2.58;

188
A.B. Denisova et al. / Journal of Fluorine Chemistry 115 (2002) 183±192
Cl, 8.41; N, 9.78; S, 14.92. Found: C, 47.31; H, 2.50; Cl,
8.31; N, 9.65; S, 14.83.
7.44 (s, 1H, pyrazole 4-H), 7.69 (d, 1H, J ˆ 3:5 Hz, thienyl
3-H), 7.79 (d, 1H, J ˆ 5:1 Hz, thienyl 5-H), 8.62 (s, 1H,
thiazole 5-H); 13C NMR ((CD3)2SO) d: 14.0 (Me), 61.1
(OCH2), 107.1 (pyrazole 4-C), 120.5 (q, JCÀF ˆ 284:0 Hz,
CF3), 127.2 (pyrazole 5-C), 127.6 (thienyl 4-C), 130.0
(thienyl 3-C), 130.7 (thiazole 5-C), 131.3 (thienyl 5-C),
140.6 (thienyl 2-C), 143.0 (thiazole 4-C), 143.5 (q,
J ˆ 38:4 Hz, pyrazole 3-C), 158.2 (thiazole 2-C), 159.9
(CO); 19F NMR (CDCl3) d: 98.8 (s, CF3). MS (EI) m/z:
3.1.2. 2-(5-(2-Thienyl)-3-trifluoromethylpyrazol-1-yl)-4-
phenylthiazole (3b) and 2-(5-hydroxy-3-(2-thienyl)-5-
trifluoromethylpyrazolin-1-yl)-4-phenylthiazole (4b)
Following the general procedure 1, three products 3b, 4b
and 5b were obtained in a ratio 25.7:10.7:1 as determined by
the 19F NMR spectral data (the ratio 5-CF3/3-CF3 is 1:2.2).
The mixture of 3b and 4b was separated by column chro-
matography on silica, using hexane±ethyl acetate (28:1)
as the eluent. The ®rst fraction contained 3b, Rf 0.5, the
second was 4b, Rf 0.25. Compound 5b was obtained by
general procedure 2. 2-(5-(2-Thienyl)-3-tri¯uoromethylpyr-
azol-1-yl)-4-phenylthiazole (3b) (0.46 g, 45%); mp 62 8C
was described earlier ([7], 62 8C). 2-(5-Hydroxy-3-(2-thie-
nyl)-5-tri¯uoromethylpyrazolin-1-yl)-4-phenylthiazole (4b)
(0.3 g, 31%), as white solid, mp 153±155 8C; 1H NMR
((CD3)2SO) d: 3.73 (d, 1H, J ˆ 18:6 Hz, pyrazole 4-H),
4.03 (d, 1H, J ˆ 18:6 Hz, pyrazole 4-H), 7.19 (dd, 1H,
J ˆ 5:0 Hz, thienyl 4-H), 7.31 (dd, 1H, J ˆ 8:4 Hz, phenyl
4-H), 7.42 (dd, 2H, J ˆ 8:4 Hz, phenyl 3-H and 5-H), 7.54
(dd, 1H, J ˆ 3:7 Hz, thienyl 5-H), 7.55 (s, 1H, thiazole 5-H),
7.77 (dd, 1H, J ˆ 5:0 Hz, thienyl 3-H), 7.92 (d, 2H,
J ˆ 8:4 Hz, phenyl 2-H and 6-H), 8.31 (s, 1H, OH); 13C
NMR ((CD3)2SO) d: 45.5 (pyrazole 4-C), 92.8 (q,
JCÀF ˆ 33:6 Hz, pyrazole 5-C), 106.9 (thiazole 5-C),
123.0 (q, JCÀF ˆ 283:8 Hz, CF3), 125.7 (phenyl 3-C and
5-C), 127.7 (phenyl 4-C), 128.1 (thienyl 4-C), 128.6 (phenyl
2-C and 6-C), 129.7 (thienyl 3-C), 130.4 (thienyl 5-C), 132.1
(phenyl 4-C), 133.1 (thienyl 2-C), 134.4 (phenyl 1-C), 147.5
(pyrazole 3-C), 151.0 (thiazole 4-C), 162.7 (thiazole 2-C);
‡
‡
‡
373 [M] (100), 354 [M À F] (7), 344 [M À Et] (12), 328
‡
‡
[M À OEt] (20), 301 [M À COOEt] (38). Anal. Calcd. for
C14H10F3N3O2S2: C, 45.04; H, 2.70; N, 11.25; S, 17.17.
Found: C, 44.97; H, 2.68; N, 11.33; S, 17.03. 2-(5-(2-
Thienyl)-3-tri¯uoromethylpyrazol-1-yl)-4-methoxycarbo-
nylthiazole (3c0) (0.15 g, 15%), as white solid, mp 128±
1
130 8C; H NMR ((CD3)2SO) d: 3.86 (s, 3H, OCH3), 7.18
(dd, 1H, J ˆ 4:7 Hz, thienyl 4-H), 7.44 (s, 1H, pyrazole 4-
H), 7.66 (d, 1H, J ˆ 3:5 Hz, thienyl 3-H), 7.79 (d, 1H,
J ˆ 5:1 Hz, thienyl 5-H), 8.66 (s, 1H, thiazole 5-H); 13C
NMR ((CD3)2SO) d: 52.3 (OCH3), 107.0 (pyrazole 4-C),
120.5 (q, JCÀF ˆ 283:8 Hz, CF3), 127.2 (pyrazole 5-C),
127.8 (thienyl 4-C), 130.0 (thienyl 3-C), 130.9 (thiazole
5-C), 131.0 (thienyl 5-C), 140.6 (thienyl 2-C), 142.7 (thia-
zole 4-C), 143.5 (q, J ˆ 38:4 Hz, pyrazole 3-C), 158.1
(thiazole 2-C), 160.3 (CO); 19F NMR (CDCl3) d: 98.8 (s,
‡
‡
CF3). MS (EI) m/z: 359 [M] (100), 328 [M À OMe] (16),
‡
‡
301 [M À COOMe] (17), 290 [M À CF3] (7). Anal. Calcd.
for C13H8F3N3O2S2: C, 43.45; H, 2.24; N, 11.69; S, 17.84.
Found: C, 43.32; H, 2.16; N, 11.75; S, 17.69. 2-(5-Hydroxy-
3-(2-thienyl)-5-tri¯uoromethylpyrazolin-1-yl)-4-ethoxycar-
bonylthiazole (4c) (0.35 g, 34%), as yellow crystals, mp
107±109 8C. 1H NMR ((CD3)2SO) d: 1.32 (t, 3H,
J ˆ 7:1 Hz, Et), 3.71 (d, 1H, J ˆ 18:7 Hz, pyrazole 4-H),
4.04 (d, 1H, J ˆ 18:7 Hz, pyrazole 4-H), 4.28 (q, 2H,
J ˆ 7:1 Hz, Et), 7.20 (dd, 1H, J ˆ 4:7 Hz, thienyl 4-H),
7.54 (dd, 1H, J ˆ 3:7 Hz, thienyl 5-H), 7.78 (dd, 1H,
J ˆ 5:0 Hz, thienyl 3-H), 7.99 (s, 1H, thiazole 5-H), 8.31
(s, 1H, OH); 13C NMR ((CD3)2SO) d: 14.1 (Me), 45.3
(pyrazole 4-C), 60.4 (OCH2), 92.7 (q, JCÀF ˆ 33:6 Hz,
‡
19F NMR (CDCl3) d: 80.8 (s, CF3). MS (EI) m/z: 395 [M]
‡
‡
(88), 377 [M À H2O] (7), 326 [M À CF3] (100). Anal.
Calcd. for C17H12F3N3OS2: C, 51.64; H, 3.06; N, 10.63; S,
16.21. Found: C, 51.43; H, 3.02; N, 10.42; S, 16.33.
3.1.3. 2-(5-(2-Thienyl)-3-trifluoromethylpyrazol-1-yl)-4-
ethoxycarbonylthiazole (3c), 2-(5-(2-thienyl)-3-
trifluoromethylpyrazol-1-yl)-4-methoxycarbonylthiazole
(3c0) and 2-(5-hydroxy-3-(2-thienyl)-5-
trifluoromethylpyrazolin-1-yl)-4-ethoxycarbonylthiazole
(4c)
Following the general procedure 1, three products 3c, 3c0
and 4c (the concentration of 5c less then 1%) were obtained
in a ratio 1:2.84 (compounds 3c and 3c0 have the same
chemical shifts of CF3 groups) as determined by the 19F
NMR spectral data. This reaction was accompanied by
transesteri®cation of 3c to 3c0. The mixture of hexane±ethyl
acetate (10:1) has been used for separating 3c (Rf 0.5) and
3c0 (Rf 0.45), and continuing the elution with a mixture of
hexane±ethyl acetate (10:2.5) afforded 4c (Rf 0.3). 2-(5-(2-
Thienyl)-3-tri¯uoromethylpyrazol-1-yl)-4-ethoxycarbonyl-
thiazole (3c) (0.5 g, 50%), as white solid, mp 102±104 8C;
1H NMR ((CD3)2SO) d: 1.32 (t, 3H, J ˆ 7:0 Hz, Et), 4.32 (q,
2H, J ˆ 7:0 Hz, Et), 7.18 (dd, 1H, J ˆ 4:7 Hz, thienyl 4-H),
pyrazole 5-C), 122.5 (thiazole 5-C), 122.9 (q, JCÀF
ˆ
283:3 Hz, CF3), 128.1 (thienyl 4-C), 129.9 (thienyl 3-C),
130.7 (thienyl 5-C), 132.8 (thienyl 2-C), 143.2 (thiazole 4-
C), 148.1 (pyrazole 3-C), 160.7 (CO), 162.8 (thiazole 2-
C); 19F NMR (CDCl3) d: 80.8 (s, CF3). MS (EI) m/z: 391
‡
‡
‡
[M] (96), 346 [M À OEt] (11), 322 [M À CF3] (98).
Anal. Calcd. for C14H12F3N3O3S2: C, 42.96; H, 3.09; N,
10.74; S, 16.38. Found: C, 43.05; H, 2.98; N, 10.65; S,
16.42.
3.1.4. 2-(5-(2-Furyl)-3-trifluoromethylpyrazol-1-yl)-
4-(4-chlorophenyl) thiazole (3d) and 2-(3-(2-furyl)-
5-hydroxy-5-trifluoromethylpyrazolin-1-yl)-
4-(4-chlorophenyl) thiazole (4d)
Following the general procedure 1, three products 3d, 4d
and 5d in a ratio 2.8:2.0:1 as determined by the 19F NMR
spectral data were obtained (a ratio 5-CF3/3-CF3 is 1.07:1).

A.B. Denisova et al. / Journal of Fluorine Chemistry 115 (2002) 183±192
189
The mixture of 3d and 4d was chromatographically sepa-
rated, using hexane±ethyl acetate (26:1) as the eluent. The
®rst fraction contained 3d, Rf 0.5, the second contained 4d,
Rf 0.25. Compound 5d was obtained by the method,
described in general procedure 2. 2-(5-(2-Furyl)-3-tri¯uor-
omethylpyrazol-1-yl)-4-(4-chlorophenyl) thiazole (3d)
(0.30 g, 28%), as white crystals, mp 127±129 8C. 1H
NMR ((CD3)2SO) d: 6.71 (dd, 1H, J ˆ 3:5 Hz, furyl 4-
H), 7.15 (d, 1H, J ˆ 3:4 Hz, furyl 3-H), 7.41 (s, 1H, pyrazole
4-H), 7.53 (d, 2H, J ˆ 8:6 Hz, phenyl 2-H and 6-H), 7.88 (d,
2H, J ˆ 8:6 Hz, phenyl 3-H and 5-H), 7.91 (d, 1H,
J ˆ 1:8 Hz, furyl 5-H), 8.23 (s, 1H, thiazole 5-H); 13C
NMR ((CD3)2SO) d: 106.6 (pyrazole 4-C), 111.8 (furyl 4-
C), 113.3 (thiazole 5-C), 115.7 (furyl 3-C), 120.4 (q,
JCÀF ˆ 269:6 Hz, CF3), 127.4 (phenyl 3-C and 5-C),
128.9 (phenyl 2-C and 6-C), 132.0 (phenyl 4-C), 133.0
(phenyl 1-C), 136.4 (pyrazole 5-C), 141.1 (furyl 2-C),
143.3 (q, J ˆ 38:6 Hz, pyrazole 3-C), 145.0 (furyl 5-C),
150.1 (thiazole 4-C), 158.6 (thiazole 2-C); 19F NMR
27%), as white crystals, mp 76±78 8C. 1H NMR ((CD3)2SO)
d: 6.71 (dd, 1H, J ˆ 3:4 Hz, furyl 4-H), 7.16 (d, 1H,
J ˆ 3:4 Hz, furyl 3-H), 7.38 (m, 1H, phenyl 4-H), 7.41
(s, 1H, pyrazole 4-H), 7.46 (dd, 2H, J ˆ 7:2 Hz, phenyl
3-H and 5-H), 7.86 (d, 2H, J ˆ 7:2 Hz, phenyl 2-H and 6-H),
7.91 (m, 1H, furyl 5-H), 8.20 (s, 1H, thiazole 5-H); 13C NMR
((CD3)2SO) d: 106.6 (pyrazole 4-C), 111.9 (furyl 4-C),
113.3 (thiazole 5-C), 115.1 (furyl 3-C), 120.5 (q,
JCÀF ˆ 268:7 Hz, CF3), 125.8 (phenyl 3-C and 5-C),
128.6 (phenyl 4-C), 130.0 (phenyl 2-C and 6-C), 133.2
(phenyl 1-C), 136.5 (pyrazole 5-C), 141.2 (furyl 2-C),
143.4 (q, J ˆ 38:2 Hz, pyrazole 3-C), 145.1 (furyl 5-C),
151.5 (thiazole 4-C), 158.5 (thiazole 2-C); 19F NMR
‡
(CDCl3) d: 98.7 (s, CF3). MS (EI) m/z: 361 [M] (100),
‡
‡
342 [M À F] (5), 332 [M À CHO] (36). Anal. Calcd. for
C17H10F3N3OS: C, 56.51; H, 2.79; N, 11.63; S, 8.87. Found:
C, 56.45; H, 2.65; N, 11.54; S, 8.75. 2-(3-(2-Furyl)-5-
hydroxy-5-tri¯uoromethylpyrazolin-1-yl)-4-phenyl) thia-
zole (4e) (0.5 g, 42%), as yellow crystals, mp 146±
148 8C. 1H NMR ((CD3)2SO) d: 3.60 (d, 1H,
J ˆ 18:6 Hz, pyrazole 4-H), 3.93 (d, 1H, J ˆ 18:6 Hz,
pyrazole 4-H), 6.70 (m, 1H, furyl 4-H), 7.07 (d, 1H,
J ˆ 3:3 Hz, furyl 3-H), 7.31 (dd, 1H, J ˆ 8:4 Hz, phenyl
4-H), 7.42 (dd, 2H, J ˆ 8:4 Hz, phenyl 3-H and 5-H), 7.55
(s, 1H, thiazole), 7.91 (m, 1H, furyl 5-H), 7.92 (d, 2H,
J ˆ 8:4 Hz, phenyl 2-H and 6-H), 8.31 (s, 1H, OH); 13C
NMR ((CD3)2SO) d: 44.7 (pyrazole 4-C), 92.4 (q,
JCÀF ˆ 33:2 Hz, pyrazole 5-C), 106.8 (thiazole 5-C),
112.3 (furyl 4-C), 114.1 (furyl 3-C), 123.1 (q,
JCÀF ˆ 284:7 Hz, CF3), 125.7 (phenyl 3-C and 5-C),
127.7 (phenyl 4-C), 128.6 (phenyl 2-C and 6-C), 134.4
(phenyl 1-C), 142.9 (furyl 2-C), 145.2 (pyrazole 3-C),
145.7 (furyl 5-C), 150.9 (thiazole 4-C), 162.0 (thiazole 2-
C); 19F NMR (CDCl3) d: 80.9 (s, CF3). MS (EI) m/z: 379
‡
(CDCl3) d: 98.8 (s, CF3). MS (EI) m/z: 395/397 [M]
‡
‡
(100/40), 376/378 [M À F] (5/2), 366/368 [M À CHO]
(33/14). Calcd. for C17H9ClF3N3OS: C, 51.59; H, 2.29; Cl,
8.96; N, 10.62; S, 8.10. Found: C, 51.86; H, 2.16; Cl, 8.85;
N, 10.48; S, 8.03. 2-(3-(2-Furyl)-5-hydroxy-5-tri¯uoro-
methylpyrazolin-1-yl)-4-(4-chlorophenyl) thiazole (4d)
1
(0.4 g, 36%), as white crystals, mp 142±144 8C. H NMR
((CD3)2SO) d: 3.61 (d, 1H, J ˆ 18:7 Hz, pyrazole 4-H), 3.94
(d, 1H, J ˆ 18:7 Hz, pyrazole 4-H), 6.70 (m, 1H, furyl 4-H),
7.07 (d, 1H, J ˆ 3:4 Hz, furyl 3-H), 7.48 (d, 2H, J ˆ 8:4 Hz,
phenyl 2-H and 6-H), 7.61 (s, 1H, thiazole 5-H), 7.92 (m,
1H, furyl 5-H), 7.94 (d, 2H, J ˆ 8:4 Hz, phenyl 3-H and 5-
H), 8.30 (s, 1H, OH); 13C NMR ((CD3)2SO) d: 44.7 (pyr-
azole 4-C), 92.3 (q, JCÀF ˆ 33:5 Hz, pyrazole 5-C), 107.5
(thiazole 5-C), 112.2 (furyl 4-C), 114.1 (furyl 3-C), 123.0 (q,
JCÀF ˆ 284:7 Hz, CF3), 127.4 (phenyl 3-C and 5-C), 128.5
(phenyl 2-C and 6-C), 132.1 (phenyl 4-C), 133.3 (phenyl 1-
C), 143.0 (furyl 2-C), 145.1 (pyrazole 3-C), 145.1 (pyrazole
3-C), 145.7 (furyl 5-C), 149.7 (thiazole 4-C), 163.0 (thiazole
2-C); 19F NMR (CDCl3) d: 80.9 (s, CF3). MS (EI) m/z: 413/
‡
‡
‡
[M] (81), 361 [M À H2O] (11), 311 [M À CF3] (100).
Anal. Calcd. for C17H12F3N3O2S: C, 53.82; H, 3.19; N,
11.08; S, 8.45. Found: C, 53.77; H, 3.06; N, 11.04; S,
8.36.
‡
‡
‡
415 [M] (84/34), 395/397 [M À H2O] (7/4), 344/346 [M
3.1.6. 2-(5-(2-Furyl)-3-trifluoromethylpyrazol-1-yl)-
4-ethoxycarbonylthiazole (3f) and 2-(5-hydroxy-3-
(2-furyl)-5-trifluoromethylpyrazolin-1-yl)-
À CF3] (100/41). Anal. Calcd. for C17H11ClF3N3O2S: C,
49.34; H, 2.68; Cl, 8.57; N, 10.15; S, 7.75. Found: C, 49.25;
H, 2.49; Cl, 8.54; N, 10.03; S, 7.63.
4-ethoxycarbonylthiazole (4f)
Following the general procedure 1, three products 3f, 4f
and 5f in a ratio 7.7:7.8:1 as determined by the 19F NMR
spectral data were obtained (the ratio 5-CF3/3-CF3 is
1.15:1). Compounds 3f and 4f were separated using a
mixture of dichloromethane and hexane (1:2). The ®rst
fraction contained 3f (Rf 0.5) and the second was 4f (Rf
0.45). Compound 5f was obtained by the method, described
in general procedure 2. 2-(5-(2-Furyl)-3-tri¯uoromethylpyr-
azol-1-yl)-4-ethoxycarbonylthiazole (3f) (0.25 g, 22%), as
3.1.5. 2-(5-(2-Furyl)-3-trifluoromethylpyrazol-1-yl)-4-
phenylthiazole (3e) and 2-(3-(2-furyl)-5-hydroxy-5-
trifluoromethylpyrazolin-1-yl)-4-phenyl) thiazole (4e)
Following the general procedure 1, three products 3e, 4e
and 5e in a ratio 3.4:3.2:1 as determined by the 19F NMR
spectral data were obtained (the ratio 5-CF3/3-CF3 is
1.25:1). The mixture of 3e and 4e was chromatographically
separated, using dichloromethane±hexane (1:2) as the elu-
ent. The ®rst fraction contained 3e, Rf 0.5, the second
contained 4e, Rf 0.25. Compound 5e was obtained by the
method, described in general procedure 2. 2-(5-(2-Furyl)-3-
tri¯uoromethylpyrazol-1-yl)-4-phenylthiazole (3e) (0.3 g,
1
white crystals, mp 108±110 8C. H NMR ((CD3)2SO) d:
1.34 (t, 3H, J ˆ 7:1 Hz, Et), 4.34 (q, 2H, J ˆ 7:1 Hz, Et),
6.70 (dd, 1H, J ˆ 3:5 Hz, furyl 4-H), 7.40 (s, 1H, pyrazole 4-
H), 7.68 (d, 1H, J ˆ 3:5 Hz, furyl 3-H), 7.92 (d, 1H,

190
A.B. Denisova et al. / Journal of Fluorine Chemistry 115 (2002) 183±192
J ˆ 1:7 Hz, furyl 5-H), 8.57 (s, 1H, thiazole 5-H); 13C NMR
((CD3)2SO) d: 14.1 (Me), 61.1 (OCH2), 105.8 (pyrazole 4-
C), 112.1 (furyl 4-C), 114.7 (furyl 3-C), 120.5 (q,
JCÀF ˆ 284:0 Hz, CF3), 129.5 (thiazole 5-C), 137.1 (pyr-
azole 5-C), 141.4 (furyl 2-C), 142.9 (thiazole 4-C), 143.5
(q, J ˆ 38:4 Hz, pyrazole 3-C), 145.4 (furyl 5-C), 159.0
(thiazole 2-C), 160.0 (CO); 19F NMR (CDCl3) d: 98.7
3.2.2. 2-(3-(2-Thienyl)-5-trifluoromethylpyrazol-1-yl)-
4-phenylthiazole (5b)
Following the general procedure 2, the compound 5b
(0.26 g, 90%) was obtained as white crystals, mp 176±
178 8C. 1H NMR ((CD3)2SO) d: 7.22 (dd, 1H,
J ˆ 5:0 Hz, thienyl 4-H), 7.39 (m,1H, phenyl 4-H), 7.50
(dd, 2H, J ˆ 7:3 Hz, phenyl 3-H and 5-H), 7.72 (dd, 1H,
J5À4 ˆ 5:0 Hz, J5À3 ˆ 1:1 Hz, thienyl 5-H), 7.80 (dd, 1H,
J3À4 ˆ 3:6 Hz, J3À5 ˆ 1:2 Hz, thienyl 3-H), 7.86 (s, 1H,
pyrazole 4-H), 7.98 (d, 2H, J ˆ 7:3 Hz, phenyl 2-H and 6-
H), 8.10 (s, 1H, thiazole 5-H); 13C NMR ((CD3)2SO) d:
109.3 (pyrazole 4-C), 112.0 (thiazole 5-C), 118.4 (q,
JCÀF ˆ 284:2 Hz, CF3), 124.6 (phenyl 3-C and 5-C),
127.0 (phenyl 4-C), 127.1 (thienyl 4-C), 127.2 (thienyl 3-
C), 127.5 (thienyl 5-C), 128.0 (phenyl 2-C and 6-C), 130.8
(q, J ˆ 42:0 Hz, pyrazole 5-C), 131.3 (pyrazole 3-C), 132.3
(phenyl 1-C), 147.3 (thienyl 2-C), 150.4 (thiazole 4-C),
157.0 (thiazole 2-C); 19F NMR (CDCl3) d: 102.1 (s,
‡
‡
(s, CF3). MS (EI) m/z: 357 [M] (100), 338 [M À F]
‡
‡
(9), 329 [M À Et] (27), 312 [M À OEt] (26). Anal. Calcd.
for C14H10F3N3O3S: C, 47.06; H, 2.82; N, 11.76; S,
8.97%. Found: C, 46.95; H, 2.69; N, 11.68; S, 8.90. 2-
(5-Hydroxy-3-(2-furyl)-5-tri¯uoromethylpyrazolin-1-yl)-4-
ethoxycarbonylthiazole (4f) (0.55 g, 46%), as yellow
crystals, mp 68±70 8C. 1H NMR ((CD3)2SO) d: 1.32 (t,
3H, J ˆ 7:1 Hz, Et), 3.59 (d, 1H, J ˆ 18:7 Hz, pyrazole 4-
H), 3.92 (d, 1H, J ˆ 18:7 Hz, pyrazole 4-H), 4.27 (q, 2H,
J ˆ 7:1 Hz, Et), 6.69 (dd, 1H, J ˆ 3:4 Hz, furyl 4-H), 7.08
(d, 1H, J ˆ 3:4 Hz, furyl 3-H), 7.92 (d, 1H, J ˆ 1:4 Hz,
furyl 5-H), 7.98 (s, 1H, thiazole 5-H), 8.38 (s, 1H, OH);
13C NMR ((CD3)2SO) d: 14.1 (Me), 44.6 (pyrazole 4-C),
60.4 (OCH2), 92.3 (q, JCÀF ˆ 34:2 Hz, pyrazole 5-C),
112.1 (furyl 4-C), 114.4 (furyl 3-C), 122.4 (thiazole 5-C),
122.9 (q, JCÀF ˆ 284:8 Hz, CF3), 143.2 (furyl 2-C),
143.5 (thiazole 4-C), 145.0 (pyrazole 3-C), 145.9
(furyl 5-C), 160.7 (CO), 163.0 (thiazole 2-C); 19F NMR
‡
CF3). MS (EI) m/z: 377 [M] (100). Anal. Calcd. for
C17H10F3N3S2: C, 54.10; H, 2.67; N, 11.13; S, 16.99. Found:
C, 53.95; H, 2.61; N, 11.00; S, 16.87.
3.2.3. 2-(3-(2-Thienyl)-5-trifluoromethylpyrazol-1-yl)-
4-ethoxycarbonylthiazole (5c)
Following the general procedure 2, the compound 5c
(0.24 g, 83%) was obtained as white crystals, mp 175±
‡
(CDCl3) d: 80.9 (s, CF3). MS (EI) m/z: 375 [M] (88), 357
‡
‡
‡
1
[M À H2O] (7), 330 [M À OEt] (12), 306 [M À CF3]
177 8C. H NMR ((CD3)2SO) d: 1.31 (t, 3H, J ˆ 7:0 Hz,
(100). Anal. Calcd. for C14H12F3N3O4S: C, 44.80; H, 3.22;
N, 11.20; S, 8.54. Found: C, 44.72; H, 3.10; N, 11.02; S,
8.38.
Et), 4.33 (q, 2H, J ˆ 7:0 Hz, Et), 7.22 (dd, 1H, J ˆ 4:5 Hz,
thienyl 4-H), 7.72 (d, 1H, J ˆ 4:6 Hz, thienyl 5-H), 7.80 (d,
1H, J ˆ 3:1 Hz, thienyl 3-H), 7.87 (s, 1H, pyrazole 4-H),
8.46 (s, 1H, thiazole 5-H); 13C NMR ((CD3)2SO) d: 14.1
(Me), 61.2 (OCH2), 110.5 (pyrazole 4-C), 118.9 (q,
JCÀF ˆ 284:0 Hz, CF3), 128.1 (thienyl 4-C), 128.2 (thienyl
3-C), 128.2 (thienyl 5-C), 128.2 (thiazole 5-C), 132.1 (pyr-
azole 3-C), 132.2 (q, J ˆ 42:0 Hz, pyrazole 5-C), 143.3
(thiazole 4-C), 148.6 (thienyl 2-C), 158.3 (thiazole 2-C),
159.9 (CO); 19F NMR (CDCl3) d: 102.1 (s, CF3). MS (EI) m/
3.2. General procedure 2: dehydration of 4a±f to 5a±f
in acetic anhydride
3.2.1. 2-(3-(2-Thienyl)-5-trifluoromethylpyrazol-1-yl)-4-
(4-chlorophenyl)thiazole (5a)
Compound 4a (0.3 g, 0.7 mmol) in acetic anhydride (5±
7 cm3) was re¯uxed for 3 h. The solvent was removed and
the residue was crystallized from ethanol. 5a (0.25 g, 87%)
‡
‡
‡
‡
z: 373 [M] (100), 354 [M À F] (4), 344 [M À Et] (3), 328
‡
[M À OEt] (18), 301 [M À COOEt] (32). Anal. Calcd. for
C14H10F3N3O2S2: C, 45.04; H, 2.70; N, 11.25; S, 17.17.
Found: C, 44.97; H, 2.67; N, 11.34; S, 17.00.
1
was obtained as white crystals, mp 165±167 8C. H NMR
((CD3)2SO) d: 7.22 (dd, 1H, J ˆ 5:0 Hz, thienyl 4-H), 7.51
(d, 2H, J ˆ 8:5 Hz, phenyl 2-H and 6-H), 7.71 (d, 1H,
J ˆ 5:0 Hz, thienyl 5-H), 7.79 (d, 1H, J ˆ 3:6 Hz, thienyl
3-H), 7.86 (s, 1H, pyrazole 4-H), 7.87 (d, 2H, J ˆ 8:5 Hz,
phenyl 3-H and 5-H), 8.15 (s, 1H, thiazole 5-H); 13C NMR
((CD3)2SO) d: 110.4 (pyrazole 4-C), 113.7 (thiazole 5-C),
119.0 (q, JCÀF ˆ 268:8 Hz, CF3), 127.3 (phenyl 3-C and 5-
C), 127.3 (phenyl 4-C), 128.0 (thienyl 4-C), 128.1 (thienyl 3-
C), 128.2 (thienyl 5-C), 129.0 (phenyl 2-C and 6-C), 131.5
(q, J ˆ 40:0 Hz, pyrazole 5-C), 132.2 (pyrazole 3-C), 133.0
(phenyl 1-C), 148.4 (thienyl 2-C), 150.1 (thiazole 4-C),
158.2 (thiazole 2-C); 19F NMR (CDCl3) d: 102.1 (s,
3.2.4. 2-(3-(2-Furyl)-5-trifluoromethylpyrazol-1-yl)-4-
(4-chlorophenyl)thiazole (5d)
Following the general procedure 2, the compound 5d
(0.25 g, 87%) was obtained as pink crystals, mp 147±
149 8C. 1H NMR ((CD3)2SO) d: 6.70 (dd, 1H, J ˆ
3:4 Hz, furyl 4-H), 7.16 (d, 1H, J ˆ 3:4 Hz, furyl 3-H),
7.56 (d, 2H, J ˆ 8:5 Hz, phenyl 2-H and 6-H), 7.71 (s, 1H,
pyrazole 4-H), 7.88 (d, 1H, J ˆ 1:2 Hz, furyl 5-H), 7.97 (d,
2H, J ˆ 8:5 Hz, phenyl 3-H and 5-H), 8.15 (s, 1H, thiazole
5-H); 13C NMR ((CD3)2SO) d: 110.2 (pyrazole 4-C), 110.5
(furyl 4-C), 112.0 (furyl 3-C), 113.8 (thiazole 5-C), 119.1 (q,
JCÀF ˆ 270:1 Hz, CF3), 127.3 (phenyl 3-C and 5-C), 128.9
(phenyl 2-C and 6-C), 131.6 (q, J ˆ 40:0 Hz, pyrazole 5-C),
132.1 (phenyl 4-C), 133.0 (phenyl 1-C), 144.5 (furyl 5-C),
‡
CF3). MS (EI) m/z: 411/413 [M] (100/43), 342/344 [M
‡
À CF3] (3/1). Calcd. for C17H9ClF3N3S2: C, 49.58; H,
2.20; Cl, 8.61; N, 10.20; S, 15.57. Found: C, 49.45; H, 2.05;
Cl, 8.55; N, 10.02; S, 15.46.

A.B. Denisova et al. / Journal of Fluorine Chemistry 115 (2002) 183±192
191
144.8 (pyrazole 3-C), 145.0 (furyl 2-C), 150.1 (thiazole
4-C), 158.3 (thiazole 2-C); 19F NMR (CDCl3) d: 102.1
(s, CF3). MS (EI) m/z: 395/397 [M] (100/41), 376/378
[M À F] (3/1), 366/368 [M À CHO] (23/10). Calcd. for
C17H9ClF3N3OS: C, 51.59; H, 2.29; Cl, 8.96; N, 10.62; S,
8.10. Found: C, 51.89; H, 2.15; Cl, 8.75; N, 10.49; S, 8.00.
ratio of 9:13.5:26.5:1. as determined by the 19F NMR
spectrum. Column chromatography, using hexane±ethyl
acetate (10:1), separated the mixture of 6a and 4a only.
7a is not stable and transforms to 4a on silica gel. Compound
3a was not obtained by this method because of low con-
centration. The ®rst fraction contained 4a (60%) Rf 0.4,
identical to the product obtained according to procedure 1.
The second fraction contained 6a, Rf 0.25. 4,4,4-tri¯uoro-1-
(2-thienyl)-1,3-butanedione-3-(N-(4-(4-chlorophenyl)-1,3-
thiazol-2-yl)hydrazone (6a) (0.23 g, 16%) was obtained as
orange crystals, mp 55±57 8C. 1H NMR ((CD3)2SO) d: 4.54
(s, 2H, CH2), 7.31 (dd, 1H, J ˆ 4:8 Hz, thienyl 4-H), 7.45 (d,
2H, J ˆ 8:6 Hz, phenyl 2-H and 6-H), 7.46 (s, 1H, thiazolyl
5-H), 7.85 (d, 2H, J ˆ 8:6 Hz, phenyl 3-H and 5-H), 8.08 (d,
1H, J ˆ 4:9 Hz, thienyl 5-H), 8.09 (d, 1H, J ˆ 3:9 Hz,
thienyl 3-H), 12.31 (bs, 1H, NH); 13C NMR ((CD3)2SO) d:
36.7 (CH2), 106.4 (thiazole 5-C), 121.1 (q, J ˆ 273:1 Hz,
CF3), 128.8 (thienyl 4-C), 132.2 (thienyl 2-C), 134.5 (thienyl
3-C), 135.3 (thienyl 5-C), 142.2 (thiazole 4-C), 161.5 (thia-
zole 2-C), 185.3 (CO); 19F NMR (CDCl3) d: 92.5 (s, CF3).
‡
‡
‡
3.2.5. 2-(3-(2-Furyl)-5-trifluoromethylpyrazol-1-yl)-
4-phenylthiazole (5e)
Following the general procedure 2, the compound 5e (0.25,
1
87%). was obtained as white crystals, mp 162±164 8C. H
NMR ((CD3)2SO) d: 6.69 (m, 1H, furyl 4-H), 7.16 (d, 1H,
J ˆ 3:0 Hz, furyl 3-H), 7.38 (m, 1H, phenyl 4-H), 7.47 (dd,
2H, J ˆ 7:2 Hz, phenyl 3-H and 5-H), 7.70 (s, 1H, pyrazole 4-
H), 7.88 (m, 1H, furyl 5-H), 7.96 (d, 2H, J ˆ 7:2 Hz, phenyl 2-
H and 6-H), 8.09 (s, 1H, thiazole 5-H); 13C NMR ((CD3)2SO)
d: 110.2 (pyrazole 4-C), 110.6 (furyl 4-C), 112.1 (furyl 3-C),
113.1 (thiazole 5-C), 119.2 (q, JCÀF ˆ 268:6 Hz, CF3), 125.7
(phenyl 3-C and 5-C), 128.5 (phenyl 4-C), 128.9 (phenyl 2-C
and 6-C), 131.7 (q, J ˆ 41:5 Hz, pyrazole 5-C), 133.3 (phenyl
1-C), 144.6 (furyl 5-C), 144.8 (pyrazole 3-C), 145.1 (furyl 2-
C), 151.4 (thiazole 4-C), 158.2 (thiazole 2-C); 19F NMR
‡
‡
MS (EI) m/z: 429/431 [M] (31/15), 411/413 [M À H2O]
‡
(14/8), 360/362 [M À CF3] (11/4). Anal. Calcd. for
C17H11ClF3N3OS2: C, 47.50; H, 2.58; Cl, 8.41; N, 9.78; S,
14.92. Found: C, 47.31; H, 2.50; Cl, 8.31; N, 9.65; S, 14.83.
‡
(CDCl3) d: 102.1 (s, CF3). MS (EI) m/z: 361 [M] (100),
‡
‡
342 [M À F] (3), 332 [M À CHO] (25). Anal. Calcd. for
C17H10F3N3OS: C, 56.51; H, 2.79; N, 11.63; S, 8.87. Found:
C, 56.47; H, 2.69; N, 11.58; S, 8.79.
3.3.2. Compound 4c and ethyl-2-((3-oxo-3-(2-thienyl)-
1-(trifluoromethyl)propylidene)hydrazono)-1,3-thiazole-
4-carboxylate (6c)
3.2.6. 2-(3-(2-Furyl)-5-trifluoromethylpyrazol-1-yl)-
4-ethoxycarbonylthiazole (5f)
A mixture of 1c (1 g, 5.34 mmol) and 2a (1.2 g, 5.40 mmol)
in ethanol (40 cm3) was re¯uxed during 7 h. The crystalline
solid that separated out on cooling, was collected, washed
with a little ethanol, dried and recrystallized from ethanol to
give hydrazone 6c as yellow crystals. The ®ltrate mainly
contained a mixture of 4c and 6c (TLC) and was not further
investigated. Ethyl-2-((3-oxo-3-(2-thienyl)-1-(tri¯uoro-
methyl)propylidene)hydrazono)-1,3-thiazole-4-carboxylate
Following the general procedure 2, the compound 5f
(0.24 g, 84%) was obtained as white crystals, mp 182±
1
184 8C. H NMR ((CD3)2SO) d: 1.32 (t, 3H, J ˆ 7:1 Hz,
Et), 4.32 (q, 2H, J ˆ 7:1 Hz, Et), 6.69 (dd, 1H, J ˆ 3:5 Hz,
furyl 4-H), 7.17 (d, 1H, J3À4 ˆ 3:5 Hz, J3À5 ˆ 0:6 Hz, furyl
3-H), 7.71 (s, 1H, pyrazole 4-H), 7.88 (d, 1H, J ˆ 1:7 Hz,
furyl 5-H), 8.46 (s, 1H, thiazole 5-H); 13C NMR ((CD3)2SO)
d: 14.1 (Me), 61.0 (OCH2), 110.3 (pyrazole 4-C), 110.8 (furyl
4-C), 112.1 (furyl 3-C), 118.9 (q, JCÀF ˆ 269:6 Hz, CF3),
128.2 (thiazole 5-C), 131.8 (q, J ˆ 41:0 Hz, pyrazole 5-C),
143.3 (thiazole 4-C), 144.7 (furyl 5-C), 144.9 (pyrazole 3-C),
145.0 (furyl 2-C), 158.4 (thiazole 2-C), 160.0 (CO); 19F NMR
1
(6c) (1.1 g (52%), mp 77±75 8C. H NMR ((CD3)2SO) d:
1.32 (t, J ˆ 7:0 Hz, 3H, Me), 4.23 (q, J ˆ 7:0 Hz, 2H,
OCH2), 4.40 (s, 2H, CH2), 7.23 (dd, 1H, J ˆ 4:9 Hz, thienyl
4-H), 7.72 (s, 1H, thiazolyl 5-H), 7.93 (d, 1H, J ˆ 5:0 Hz,
thienyl 5-H), 7.98 (d, 1H, J ˆ 3:8 Hz, thienyl 3-H), 12.45
(bs, 1H, NH); 13C NMR ((CD3)2SO) d: 14.0 (Me), 36.5
(CH2), 60.2 (OCH2), 120.8 (thiazole 5-C), 120.9 (q,
J ˆ 272:9 Hz, CF3), 128.8 (thienyl 4-C), 134.5 (thienyl 3-
C), 135.3 (thienyl 5-C), 142.1 (thienyl 2-C), 142.8 (thiazole
4-C), 160.7 (thiazole 2-C), 167.8 (CO), 185.0 (CO); 19F
‡
(CDCl3) d: 102.0 (s, CF3). MS (EI) m/z: 357 [M] (100), 338
‡
‡
‡
[M À F] (3), 329 [M À Et] (5), 312 [M À OEt] (22). Anal.
Calcd. for C14H10F3N3O3S: C, 47.06; H, 2.82; N, 11.76; S,
8.97%. Found: C, 46.97; H, 2.73; N, 11.70; S, 8.91.
‡
3.3. General procedure 3: reaction of 1a±c and 2a,b in the
absence of hydrochloric acid
NMR (CDCl3) d: 92.5 (s, CF3). MS (EI) m/z: 391 [M] (11),
373 [M À H2O] (3), 358 [M À CHF2] (5), 322 [M À CF3] (8).
Anal. Calcd. for C14H12F3N3O3S2: C, 42.96; H, 3.09; N,
10.74; S, 16.38. Found: C, 43.05; H, 2.98; N, 10.65; S, 16.42.
3.3.1. Compound 4a and 4,4,4-trifluoro-1-(2-thienyl)-1,
3-butanedione-3-(N-(4-(4-chlorophenyl)-1,3-thiazol-2-
yl)hydrazone (6a)
A mixture of 1a (0.2 g, 0.89 mmol) and 2a (0.21 g,
0.95 mmol) in methanol (15 cm3) was re¯uxed during
10 h. The solvent was completely removed. The residue
indicated the formation of four products 6a, 7a, 4a and 3a in
3.3.3. Compound 4f and ethyl-2-((3-oxo-3-(2-furyl)-
1-(trifluoromethyl)propylidene)hydrazono)-1,
3-thiazole-carboxylate (6f)
A mixture of 1c (0.4 g, 2.14 mmol) and 2b (0.46 g,
2.23 mmol) in methanol (20 cm3) was re¯uxed during

192
A.B. Denisova et al. / Journal of Fluorine Chemistry 115 (2002) 183±192
5 h. The crystalline solid that separated out on cooling, was
collected and dried to give 5-hydroxypyrazoline 4f as white
crystals, yield 0.3 g (37%), mp 68±70 8C. The ®ltrate was
completely evaporated and was separated by column chro-
matography, using dichloromethane as the eluent. The ®rst
fraction contained 4f, Rf 0.5, the second afforded 6f, Rf 0.25.
Ethyl-2-((3-oxo-3-(2-furyl)-1-(tri¯uoromethyl)propylidene)-
hydrazono)-1,3-thiazole-carboxylate (6f) (0.13 g, 16%),
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1
mp 52±54 8C was obtained as orange crystals. H NMR
((CD3)2SO) d: 1.30 (t, J ˆ 7:1 Hz, 3H, Me), 4.20 (q,
J ˆ 7:1 Hz, 2H, OCH2), 4.34 (s, 2H, CH2), 6.79 (d, 1H,
J ˆ 3:4 Hz, furyl 4-H), 7.56 (d, 1H, J ˆ 3:1 Hz, furyl 3-H),
7.88 (d, 1H, J ˆ 1:8 Hz, furyl 5-H), 8.06 (s, 1H, thiazole
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‡
5-H), 12.15 (bs, 1H, NH). MS (EI) m/z: 375 [M] (64), 357
[M À H2O] (5), 330 [M À OEt] (11), 306 [M À CF3] (100).
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11.20; S, 8.54. Found: C, 44.72; H, 3.10; N, 11.02; S,
8.38.
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