Synthesis of 2,2,2-trifluoroethyl 1H-pyrazole carboxylates: Insight into the mechanism of trichloromethyl group hydrolysis

Article abstract of DOI:10.1016/j.jfluchem.2016.05.009

This paper reports one-pot synthesis of 2,2,2-trifluoroethyl 1H-pyrazole-5(3)-carboxylates via cyclocondensation of 1,1,1-trichloro-4-alkoxy-3-alken-2-ones [Cl₃CC(O)C(R²) = C(R¹)OMe, where R¹ = H, CH₃

Full text of DOI:10.1016/j.jfluchem.2016.05.009

Accepted Manuscript
Title: Synthesis of 2,2,2-trifluoroethyl 1H-pyrazole
carboxylates: insight into the mechanism of trichloromethyl
group hydrolysis
Author: Helena A. Gonc¸alves Bruna A. Pereira Wystan K.O.
Teixeira Sidnei Moura Darlene C. Flores Alex F.C. Flores
PII:
S0022-1139(16)30121-X
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.05.009
FLUOR 8779
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Received date:
Revised date:
Accepted date:
8-4-2016
14-5-2016
17-5-2016
Please cite this article as: Helena A.Gonc¸alves, Bruna A.Pereira, Wystan K.O.Teixeira,
Sidnei Moura, Darlene C.Flores, Alex F.C.Flores, Synthesis of 2,2,2-trifluoroethyl 1H-
pyrazole carboxylates: insight into the mechanism of trichloromethyl group hydrolysis,
Journal of Fluorine Chemistry http://dx.doi.org/10.1016/j.jfluchem.2016.05.009
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1
Synthesis of 2,2,2-trifluoroethyl 1H-pyrazole carboxylates: insight into the mechanism of
trichloromethyl group hydrolysis
Helena A. Gonçalves1, Bruna A. Pereira1, Wystan K. O. Teixeira1, Sidnei Moura2, Darlene C.
Flores1, Alex F. C. Flores1,*
1Escola de Química e Alimentos, Universidade Federal do Rio Grande, 96203 900
Rio Grande, RS, Brazil
2 Instituto de Biotecnologia, Universidade de Caxias do Sul, 95070–560 Caxias do Sul, RS, Brazil
Graphical Abstract

2
Synthesis of novel 2,2,2-trifluoroethyl 1H-pyrazol-5(3)-carboxylates from cyclocondensation
between hydrazine hydrochloride and 1,1,1-trichloro-4-alkoxy-3-alken-2-ones and trichloromethyl-
1,3-diketones in TFE.
Highlights
 Use of green trifluoroethanol;
 Easy diversification of products from trichloromethyl-substituted precursors;
 The route proposed allows to obtain novel products with trifluoroethyl chain;
 The products obtained are all unpublished and with high potential biological activity.
Abstract – This paper reports one-pot synthesis of 2,2,2-trifluoroethyl 1H-pyrazole-5(3)-
carboxylates via cyclocondensation of 1,1,1-trichloro-4-alkoxy-3-alken-2-ones
[Cl3CC(O)C(R2)=C(R1)OMe, where R1 = H, CH3, n-octyl, n-nonyl, n-undecyl, n-undecyl, n-
tridecyl, -(CH2)2Ph, 4-ClC6H4, 4-BrC6H4 and R2 = H] and 1,1,1-trichloro-2,4-alkanediones, 1-aryl-
4,4,4-trichloro-1,3-butanediones [Cl3CC(O)CHR2C(O)R1, where R1 = H, CH3, -(CH2)2Ph, Ph, 4-
,
FC6H4 4-BrC6H4, R2 = H, R1 = Ph and R2 = CH3 and R1, R2 = cyclo-(CH2)5-] with hydrazine
hydrochloride in 2,2,2-trifluoroethanol (TFE). Considering the low nucleophilicity of TFE in
relation to methanol or ethanol, the results provide evidence for the mechanism of hydrolysis of the
trichloromethyl group attached to the 1H-pyrazol ring.
Keywords: 2,2,2-trifluoroethyl 1H-pyrazole-5(3)-carboxylates; 2,2,2- trifluoroethanol; 1H-
pyrazoles; 1,1,1-trichloromethyl-4-alkoxy-3-alken-2-ones
1. Introduction
The synthesis of CF3-containing compounds is largely done because they have enhanced biological
activity and can be used as pharmaceuticals and agricultural chemicals, in addition to their role in
the development of new technological materials [1]. The geometrical similarities between the
methyl and trifluoromethyl groups are well known, but compounds in the latter group modify the
physicochemical profiles of chemicals, increasing their lipophilicity and metabolic stability [2]. In
addition, fluorinated solvents have attracted increasing interest in the context of green synthesis,
having been introduced as alternative green reaction media because of their unique chemical and
physical properties; for example, they exhibit significant regiochemistry control, allowing facile
recovery of solvents by distillation [3].

3
1H-pyrazole rings are versatile moieties present in many synthetic physiologically active
substances, including commercial crop broad-spectrum fungicides, the herbicide Fluazolate, and the
anti-inflammatory COX-2 inhibitor Celecoxib [4]. Owing to their versatile bioactivity, a large
amount of research has focused on these nuclei [5].
On the other hand, we have studied the synthesis of 1,1,1-trichloro-4-methoxy-3-alken-2-ones and
trichloromethyl-1,3-diketones as building blocks for the production of a diversity of heterocycles,
including 1H-pyrazole-carboxylate derivatives [6]. This paper reports the results of [3 + 2]
cyclocondensation of a series of 1,1,1-trichloro-4-methoxy-3-alken-2-ones (1) and 1,1,1-trichloro-
2,4-alkanediones (2) with hydrazine in environmental friendliness 2,2,2-trifluoroethanol (TFE), a
synthetic approach to producing new 2,2,2-trifluoroethyl 1H-pyrazole-carboxylates (3).
2. Results and Discussion
A series of 1,1,1-trichloro-4-methoxy-3-alken-2-ones 1 and trichloromethyl-1,3-diketones 2 were
obtained via trichloroacetylation of the respective enol ether or acetal derivative [6, 7].
Initially the reaction between 1h and NH2NH2.HCl in 10 mL TFE was conducted at 50°C for 12 h.
Then TFE was distilled off and the solid residue was characterized by 1H NMR as a mixture of two
products, 2,2,2-trifluoroethyl 3-phenethyl-1H-pyrazole-5-carboxylate (3h) and methyl 3-phenethyl-
5-pyrazole carboxylate (4h) (Figure 1). To find the best reaction conditions, considering the yield
and product purity of 3h, we tested different reaction conditions, varying the temperature, reaction
time, and amount of TFE. The [3 + 2] cyclocondensation was performed in an alcohol solvent
according to a previously described method, leading initially to the aromatic 5(3)-trichloromethyl-
1H-pyrazoles; thereafter, the trichloromethyl group was hydrolyzed, leading to the 1H-pyrazole-
5(3)-carboxylates [6a]. We propose that the key intermediate in this mechanism is a carboxylic acid
chloride, which is attacked by nucleophilic solvent (Scheme 1). Then, using TFE as the solvent, the
nucleophilic attack occurs preferentially from methanol that forms in situ after the
cyclocondensation of the 1,1,1-trichloro-4-methoxy-4-phenethyl-3-hexen-2-one (1h). When the
proportion of TFE was increased in the reaction medium from 10 to 25 mL, or when a more
concentrated 5 mL TFE reaction solution was used, yields and the mixture rate remained in the
same range, as shown in Table 1. The formation only of the product derivative of the alcohol
generated in situ from the dielectrophilic substrate probably does not occur due to the 100ºC
reaction temperature, at which both methanol or ethanol are in the highest concentration in the
vapor phase.
Attempts to replace hydrazine hydrochloride with inexpensive hydrazine sulfate were unsuccessful,
because even under reflux of TFE, it did not dissolve and did not react with dielectrophilic
trichloromethyl-substituted substrates [8].
The reaction conditions shown in entry 5 of Table 1 were extended to cyclocondensations between
series 1a-i, 1m, n, and hydrazine hydrochloride in TFE solvent to afford an almost equimolar
mixture of two products, which were identified as 2,2,2-trifluoroethyl 1H-pyrazole-5(3)-
carboxylates 3a-i, 3m, n, and respective ethyl or methyl 1H-pyrazole-5(3)-carboxylates 4a-i, 4m, n
(Scheme 2). The ratio of these two products in each reaction was measured by 1H NMR
spectroscopy of the crude reaction mixture (Table 1). The formation of products 3 and 4 was
confirmed on the basis of their 1H, 13C, 19F and LC-MS/MS spectra (Supplementary Information).

The strategy to circumvent the formation of nucleophilic alcohol in the reaction medium was
to use the previously developed trichloromethyl-β-diketones as 1,3-dielectrophilic precursors
in the cyclocondensation process. We have previously demonstrated the synthesis of
trichloroacetyl-cycloalkanones and 4,4,4-trichloro-1-aryl-1,3-butanediones[9].Then 1,1,1-
trichloro-6-phenyl-2,4-hexanedione (2h) was synthesized via acid hydrolysis of the 1,1,1-
trichloro-4-methoxy-6-phenyl-3-hexen-2-one (1h), and cyclocondensation was conducted as
described in entry 5 of Table 1. After the reaction, the residual white solid was identified as
pure 2,2,2-trifluoroethyl 3-phenethyl-1H-pyrazole-5-carboxylate (3h) (Fig. 2). This reaction
was extended to the series of trichloromethyl-1,3-diketones 2a, 2b, 2j, 2k, 2l, 2n, and 2o,
leading to the respective 2,2,2-trifluoroethyl 1H-pyrazole-5-carboxylates in good yields
(Scheme 3).
All isolated products were identified by NMR spectroscopy and LC-MS/MS data. The 1H
NMR spectra for 1H-pyrazole-5(3)-carboxylates 3 showed a general feature, displaying the
signals related to methylene from the 2,2,2-trifluoroethyl chain at 4.6–4.9 ppm and the H-4
from the pyrazole ring at 6.5–7.5 ppm. The 13C NMR spectra showed the characteristic
signals for each derivative series. The quartet related to the CF3 group was displayed at about
δ 125 ppm with JCF 277 Hz, that related to 2,2,2-trifluoroethyl methylene was at about δ 60
ppm with 3JCF 36 Hz, and that related to C=O from the carboxyl group was at about δ 160
ppm.
3. Conclusion
We developed an efficient method to synthesize 2,2,2-trifluoroethyl 1H-pyrazol-5(3)-
carboxylates with good yields and purity. The results demonstrate the efficiency and
versatility of the precursors 1,1,1-trichloro-4-alkoxy-3-alken-2-ones and trichloromethyl--
diketones for 1H-pyrazol-5(3)-carboxylate synthesis, and furthermore provide data that
endorse the proposed mechanism of hydrolysis of the trichloromethyl group attached to the
1H-pyrazole ring of carboxylic ester, with confirmation of a step that depends on the
nucleophilicity of the alcohol solvent.
4. Experimental
1H and 13C NMR spectra were collected at 305 K on a Bruker DPX 400 spectrometer (1H at
400.13 MHz, 13C at 100.62 MHz) using a 5 mm dual probe. Chemical shifts (δ) are quoted in
ppm from tetramethylsilane (TMS), and coupling constants (J) are given in Hz. 19F NMR
spectra were collected at 376.5 MHz on a Bruker Ascend Avance III 400 spectrometer using a
5 mm dual probe. The ESI mass spectra were obtained on an Agilent 6460 Triple Quadrupole
connected to a 1200 series LC and equipped with a solvent degasser, binary pump, column
oven, auto-sampler, and an ESI source. The Agilent QQQ 6460 tandem mass spectrometer
was operated in positive jet stream electrospray ionization (ESI) mode. Nitrogen was used as
the nebulizer, turbo (heater) gas, curtain gas, and collision-activated dissociation gas. The
capillary voltage was set at +3500 V and the nozzle voltage was at +500 V. The ion source
gas temperature was 300°C with a flow rate of 5 L/min. The jet stream sheath gas
temperature was 250°C with a flow rate of 11 L/min. All samples were infused into the ESI
source at a 5 μL/min flow rate. Data were acquired in positive MS total ion scan mode (mass
scan range m/z 50–650) and in positive MS/MS product ion scan mode. The mass spectra
recorded were evaluated using the Qualitative Analysis software from Agilent Technologies.

4.1. General procedure for 2,2,2-trifluoroethyl 1H-pyrazol-5-carboxylates
A solution of 1,1,1-trichloro-2,4-alkanedione or 4,4,4-trichloro-1-aryl-1,3-butanedione 2 (3
mmol) and NH2NH2.HCl (3.1 mmol) in 5 mL TFE was stirred at 100°C until complete
dissolution, and the resulting mixture was stirred for 16 h. TFE was removed and residue was
dissolved in CH2Cl2 (30 mL); the organic solution was washed with water (1 × 30 mL) and
dried with Na2SO4. The solvent was evaporated, resulting in product 3. Products were
analyzed without further purification. Spectroscopic data are shown in the Supplementary
Information.
2,2,2-Trifluoroethyl 1H-pyrazol-5(3)-carboxylate (3a) was obtained (74%) as a yellowish
white solid (CH2Cl2). It decomposes above 135°C. 1H NMR (CD3CN): δ 4.81 (q,3JHF 8.8 Hz,
2H, CH2), 6.91 (d, 3JHH 2.4, 1H, H-4), 7.74 (d, 1H, 3JHH 2.4 Hz, 1H, H-3); 13C
NMR(CD3CN): δ 60.1 (q, 2JCF 36.1 Hz, CH2), 108.3 (C-4), 123.5 (q, JCF 276 Hz, CF3), 131.5
(C-3), 140.8 (C-5), 160.3 (C=O); 19F NMR (CDCl3) δ ppm: –73.5 (t, 3JFH 7.5 Hz).
C6H5F3N2O2 calcd. mass 194.0303 g.mol-1. Found: 195.0340 g.mol-1.
2,2,2-Trifluoroethyl 3(5)-methyl-1H-pyrazol-5(3)-carboxylate (3b) was obtained (81%) as a
yellowish white solid (CH2Cl2). It decomposes above 150°C. 1H NMR (CDCl3): δ 2.30 (s,
3H), 4.64 (q,3JHF 8.4 Hz, 2H, CH2), 6.56 (s, 1H, H-4); 13C NMR(CDCl3): δ 10.4 (CH3), 60.1
(q, 2JCF 37.2 Hz, CH2), 107.4 (C-4), 122.8 (q, JCF 277 Hz, CF3), 131.5 (C-3), 140.8 (C-5),
160.3 (C=O); 19F NMR (CDCl3) δ ppm: –73.7 (t, 3JFH 7.5 Hz). C7H7F3N2O2 calcd. mass
208.0460 g.mol-1. Found: 209.0519 g.mol-1.
2,2,2-Trifluoroethyl 3(5)-octyl-1H-pyrazol-5(3)-carboxylate (3c) was obtained (30%) as a
yellow oil. 1H NMR (CDCl3): δ 0.87 (t, 3JHH 6,8 Hz 3H, CH3), 1.29 (m, 10H), 1.62 (m, 2H),
2.69 (m, 2H), 4.67 (q,3JHF 8.4 Hz, 2H, CH2), 6.62 (s, 1H, H-4); 13C NMR(CDCl3): δ 13.9
(CH3), 22.5, 25.6, 28.9, 29.1, 31.7 (CH2), 60.1 (q, 2JCF 36.2 Hz, CH2), 106.7 (C-4), 122.9 (q,
JCF 277.5 Hz, CF3), 140.7 (C-3), 147.6 (C-5), 160.5 (C=O); 19F NMR (CDCl3) δ ppm: –73.6
(t, 3JFH 7.5 Hz). C14H21F3N2O2 calcd. mass 306.1555 g.mol-1. Found 307.1632.mol-1.
2,2,2-Trifluoroethyl 3(5)-nonyl-1H-pyrazol-5(3)-carboxylate (3d) was obtained (33%) as a
yellow oil. 1H NMR (CDCl3): δ 0.89 (t, 3JHH 6,8 Hz 3H, CH3), 1.31 (m, 10H), 1.64 (m, 2H),
2.69 (m, 2H), 4.67 (q,3JHF 8.4 Hz, 2H, CH2), 6.63 (s, 1H, H-4); 13C NMR(CDCl3): δ 13.8
(CH3), 22.5, 25.7, 28.9, 29.2, 29.3, 31.7 (CH2), 60.1 (q, 2JCF 36.2 Hz, CH2), 106.7 (C-4),
122.9 (q, JCF 277.2 Hz, CF3), 141.2 (C-3), 148.1 (C-5), 160.3 (C=O); 19F NMR (CDCl3) δ
ppm: –73.6 (t, 3JFH 7.5 Hz). C15H23F3N2O2 calcd. mass 320.1712 g.mol-1. Found
321.1632.mol-1.
2,2,2-Trifluoroethyl 3(5)-decyl-1H-pyrazol-5(3)-carboxylate (3e) was obtained (22%) as a
yellowish oil. 1H NMR (CDCl3): δ 0.87 (t, 3JHH 6,8 Hz 3H, CH3), 1.26 (m, 14H), 1.63 (m,
2H), 2.69 (m, 2H), 4.65 (q,3JHF 8.4 Hz, 2H, CH2), 6.60 (s, 1H, H-4); 13C NMR(CDCl3): δ
13.8 (CH3), 22.5, 25.6, 28.9, 29.2, 29.3, 29.4, 31.7 (CH2), 60.3 (q, 2JCF 37 Hz, CH2), 106.6 (C-
4), 123.0 (q, JCF 278 Hz, CF3), 140.4 (C-3), 147.3 (C-5), 160.3 (C=O); 19F NMR (CDCl3) δ
ppm: –73.6 (t, 3JFH 7.5 Hz). C16H25F3N2O2 calcd. mass 334.1868 g.mol-1. Found 335.1936
g.mol-1.
2,2,2-Trifluoroethyl 3(5)-undecyl-1H-pyrazol-5(3)-carboxylate (3f) was obtained (41.2%) as
a yellowish oil. 1H NMR (CDCl3): δ 0.89 (t, 3JHH 6,8 Hz 3H, CH3), 1.29 (m, 14H), 1.66 (m,

2H), 2.70 (m, 2H), 4.68 (q,3JHF 8.4 Hz, 2H, CH2), 6.64 (s, 1H, H-4); 13C NMR(CDCl3): δ
13.8 (CH3), 22.5, 25.6, 28.9, 29.2, 29.3, 29.4, 31.7 (CH2), 60.3 (q, 2JCF 37 Hz, CH2), 106.8 (C-
4), 123.0 (q, JCF 277 Hz, CF3), 140.3 (C-3), 147.7 (C-5), 160.2 (C=O); 19F NMR (CDCl3) δ
ppm: –73.6 (t, 3JFH 7.5 Hz). C17H27F3N2O2 calcd. mass 348.2025 g.mol-1. Found 349.2085
g.mol-1.
2,2,2-Trifluoroethyl 3(5)-tridecyl-1H-pyrazol-5(3)-carboxylate (3g) was obtained (41.2%) as
a yellowish oil. 1H NMR (CDCl3): δ 0.89 (t, 3JHH 6,8 Hz 3H, CH3), 1.29 (m, 20H), 1.66 (m,
2H), 2.70 (m, 2H), 4.68 (q,3JHF 8.4 Hz, 2H, CH2), 6.65 (s, 1H, H-4); 13C NMR(CDCl3): δ
13.8 (CH3), 22.5, 25.6, 28.9, 29.2, 29.3, 29.4, 31.7 (CH2), 60.3 (q, 2JCF 37 Hz, CH2), 106.8 (C-
4), 123.0 (q, JCF 277 Hz, CF3), 140.2 (C-3), 147.5 (C-5), 160.2 (C=O); 19F NMR (CDCl3) δ
ppm: –73.6 (t, 3JFH 7.5 Hz). C19H31F3N2O2 calcd. mass 376.2338 g.mol-1. Found 377.2408
g.mol-1.
2,2,2-Trifluoroethyl 3(5)-phenethyl-1H-pyrazol-5(3)-carboxylate (3h) was obtained (97%) as
a white solid, m.p. 119–120°C. 1H NMR (CDCl3): δ 2.97 (m, 2H, CH2), 3.07 (m, 2H, CH2),
4.63 (q,3JHF 8.4 Hz, 2H, CH2), 6.67 (s, 1H, H-4), 7.18 (m, 2H, Ph), 7.23 (m, 1H, Ph), 7.32 (m,
2H, Ph); 13C NMR(CDCl3): δ 27.5 (CH2), 35.3 (CH2), 60.4 (q, 2JCF 37 Hz, CH2), 107.2 (C-4),
122.9 (q, JCF 277 Hz, CF3), 126.4, 128.3, 128.5, 140.4 (Ph), 140.5 (C-3), 146.6 (C-5), 160.3
(C=O); 19F NMR (CDCl3) δ ppm:–73.6 (t, 3JFH 7.5 Hz). C19H31F3N2O2 calcd. mass 298.0929
g.mol-1. Found 299.0991 g.mol-1.
3-(5(3)(2,2,2-trifluoroethoxycarbonyl)-1H-pyrazol-3(5)-yl)-propanoic acid (3i) was obtained
(51%) as a white solid. 1H NMR (DMSO-d6): δ 2.58 (m, 2H, CH2), 2.86 (m, 2H, CH2), 4.88
(q,3JHF 8.8 Hz, 2H, CH2), 6.61 (s, 1H, H-4); 13C NMR(DMSO-d6): δ 21.2 (CH2), 33.3 (CH2),
60.1 (q, 2JCF 36 Hz, CH2), 106.9 (C-4), 123.9 (q, JCF 278 Hz, CF3), 140.5 (C-3), 145.7 (C-5),
160.5 (C=O), 173.7 (C=O); 19F NMR (CDCl3) δ ppm:–73.6 (t, 3JFH 7.5 Hz). C9H9F3N2O2
calcd. mass 266.0514 g.mol-1. Found 267.0575 g.mol-1.
2,2,2-trifluoroethyl 2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxylate (3j) was
obtained (87%) as a white solid, m.p. 180–182°C. 1H NMR (CDCl3): δ 1.68 (m, 4H, 2CH2),
1.85 (m, 2H, CH2), 2.78 (m, 2H, CH2), 2.93 (m, 2H, CH2), 4.66 (q,3JHF 8.4 Hz, 2H, CH2) 13C
NMR(CDCl3): δ 24.2, 26.9, 27.6, 28.1, 31.7 (CH2), 60.1 (q, 2JCF 37 Hz, CH2), 123.0 (q, JCF
278 Hz, CF3), 125.2 (C-4), 134.2 (C-3), 149.7 (C-5), 160.1 (C=O); 19F NMR (CDCl3) δ
ppm:–75.2 (t, 3JFH 9.4 Hz). C11H13F3N2O2 calcd. mass 262.0929 g.mol-1. Found 263.1000
g.mol-1.
2,2,2-Trifluoroethyl 3(5)-phenyl-1H-pyrazol-5(3)-carboxylate (3k) was obtained (92%) as a
white solid, m.p. 96–97°C. 1H NMR (CDCl3): δ 4.59 (q,3JHF 8.4 Hz, 2H, CH2), 7.1 (s, 1H, H-
4), 7.41 (m, 3H, Ph), 7.71 (m, 2H, Ph); 13C NMR(CDCl3): δ 60.6 (q, 2JCF 37 Hz, CH2), 106.5
(C-4), 122.8 (q, JCF 277 Hz, CF3), 125.7, 128.9, 129.0, 129.5 (Ph), 139.1 (C-3), 148.1 (C-5),

158.2 (C=O); 19F NMR (CDCl3) δ ppm: –73.5 (t, 3JFH 7.5 Hz). C12H9F3N2O2 calcd. mass
270.0616 g.mol-1. Found 271.0683 g.mol-1.
2,2,2-Trifluoroethyl 3(5)-(4-fluorophenyl)-1H-pyrazol-5(3)-carboxylate (3l) was obtained
(94%) as a white solid, m.p. 96–97°C. 1H NMR (CDCl3): δ 4.69 (q,3JHF 8.4 Hz, 2H, CH2),
7.03 (s, 1H, H-4), 7.10 (t, 2H, Ph), 7.78 (m, 2H, Ph); 13C NMR(CDCl3): δ 60.5 (q, 2JCF 37 Hz,
CH2), 105.6 (C-4), 116.0 (d,3JCF 22 Hz, Ph), 122.9 (q, JCF 277 Hz, CF3), 125.5 (Ph), 127.8
(d,3JCF 2 Hz, Ph), 139.7 (C-3), 146.3 (C-5), 159.7 (C=O), 163.1 (d, JCF 248 Hz, Ph); 19F NMR
(CDCl3) δ ppm: –73.6 (t, 3JFH 7.5 Hz, CF3), -112.0 (m, p-F). C12H8F4N2O2 calcd. mass
288.0522 g.mol-1. Found 289.0591 g.mol-1.
2,2,2-Trifluoroethyl 3(5)-(4-chlorophenyl)-1H-pyrazol-5(3)-carboxylate (3m) was obtained
(51%) as a brown solid. 1H NMR (DMSO-d6): δ 4.95 (q,3JHF 9.2 Hz, 2H, CH2), 7.29 (s, 1H,
H-4), 7.46 (m, 2H, Ph), 7.85 (m, 2H, Ph); 13C NMR(DMSO-d6): δ 60.3 (q, 2JCF 35 Hz, CH2),
106.5 (C-4), 123.8 (q, JCF 278 Hz, CF3), 127.7, 128.8, 129.4, 133.6 (Ph), 139.8 (C-3), 145.7
(C-5), 159.8 (C=O); 19F NMR (CDCl3) δ ppm: –73.6 (t, 3JFH 7.5 Hz). C12H8ClF3N2O2 calcd.
mass 304.0226 g.mol-1. Found 305.0300 g.mol-1.
2,2,2-Trifluoroethyl 3(5)-(4-bromophenyl)-1H-pyrazol-5(3)-carboxylate (3n) was obtained
(89%) as a brown solid, m.p. 138–140°C. 1H NMR (DMSO-d6): δ 4.95 (q,3JHF 9.2 Hz, 2H,
CH2), 7.28 (s, 1H, H-4), 7.60 (m, 2H, Ph), 7.78 (m, 2H, Ph); 13C NMR(DMSO-d6): δ 60.3 (q,
2JCF 35 Hz, CH2), 106.5 (C-4), 122.1 (Ph), 123.9 (q, JCF 277 Hz, CF3), 127.9, 129.2, 132.3
(Ph), 139.8 (C-3), 145.8 (C-5), 159.8 (C=O); 19F NMR (CDCl3) δ ppm:–73.6 (t, 3JFH 7.5 Hz).
C12H8BrF3N2O2 calcd. mass 304.0226 g.mol-1. Found 305.0300 g.mol-1.
2,2,2-Trifluoroethyl 4-methyl-3(5)-(phenyl)-1H-pyrazol-5(3)-carboxylate (3o) was obtained
(89%) as a brown solid, m.p. 138–140°C. 1H NMR (DMSO-d6): δ 4.95 (q,3JHF 9.2 Hz, 2H,
CH2), 7.28 (s, 1H, H-4), 7.60 (m, 2H, Ph), 7.78 (m, 2H, Ph); 13C NMR(DMSO-d6): δ 9.5
(CH3), 60.1 (q, 2JCF 37 Hz, CH2), 118.0 (C-4), 122.9 (q, JCF 277 Hz, CF3), 127.6, 128.3,
128.7, 129.9 (Ph), 136.9 (C-3), 145.0 (C-5), 159.9 (C=O); 19F NMR (CDCl3) δ ppm:–72.6 (t,
3JFH 7.5 Hz). C13H11F3N2O2 calcd. mass 284.0788 g.mol-1. Found 285.0846 g.mol-1.
Acknowledgments
The authors are grateful for financial support from Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq, universal grant 6577818477962764-01), Fundação de
Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, PqG grant 1016236), and
Programa de Apoio à Publicação da Produção Acadêmica/PROPESP/FURG/2015.
Fellowships from CAPES (H.A. Gonçalves, W.K.O. Teixeira, and B.A. Pereira) are also
acknowledged.

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Figure 1. 1H NMR spectrum of the cyclocondensation product obtained from 1h and
NH2NH2.HCl.

Figure 2. 1H NMR spectrum of the cyclocondensation product obtained from 2h and
NH2NH2.HCl.

Scheme 1 . Mechanism proposed to [CCC + NN] cyclocondensation followed of
trichloromethyl
hydrolysis for 1H-pyrazole-5(3)-carboxylates 3 or 4.

Scheme 2. Synthesis of mixtures of 2,2,2-trifluoroethyl 1H-pyrazole-5(3)-carboxylate (3) and
(ethyl) methyl 1H-pyrazole-5(3)-carboxylate (4).

Scheme 3. Synthesis of the 2,2,2-trifluoroethyl 1H-pyrazole-5(3)-carboxylate (3).

Table 1. Yields, isomer ratio, and reaction conditions for cyclocondensation between 1h and
NH2NH2.HX
Entry
HX
Temperature (°C)
solvent volume (mL)
time (h)
16
yield (%)
a
1
2
HCl
HCl
25
25
5
-
-a
15
20
24
24
84
(41:59)
3
4
HCl
HCl
HCl
50
15
5
12
16
81
(42:58)
100
100
97
(41:59)
5
6
-a
H2SO4
H2SO4
100
100
5
24
24
-a
7
15
a
Recovery of starting reagents.

Table 2. Yields and ratio 3:4 obtained for cyclocondensation between 1a-i, 1m, n, and
NH2NH2.HCl in 5 mL TFE
Yield
(%)
Ratio
Precursor
Ra
3:4b
H
75
79
64
69
67
71
67
97
93
86
92
47:53
51:49
45:55
48:52
33:67
58:42
55:45
41:59
55:45
59: 41
34:66
1a
1b
1c
1d
1e
1f
CH3
n-octyl
n-nonyl
n-decyl
n-undecyl
n-tridecyl
Ph(CH2)2
HO2C(CH2)2
4-ClC6H4
4-BrC6H4
1g
1h
1i
1m
1n
a R in 1H-pyrazol-5carboxylate; b from 1H NMR integral of H-4 signals.