New synthetic access to 3-fluoroalkyl-5-pyrazolecarboxylates and carboxylic acids

Article abstract of DOI:10.1016/j.jfluchem.2018.07.010

A novel process for preparing 3-fluoroalkyl-5-pyrazolecarboxylates and carboxylic acids is hereby presented. Easily accesible α-fluorinated ketimines were condensed with oxalyl monochloride derivatives, and the obtained vinamides underwent acid-catalyzed cyclization with substituted hydrazines. This highly efficient protocol can also be used for non-fluorinated C-3 and C-5 substituents.

Full text of DOI:10.1016/j.jfluchem.2018.07.010

Accepted Manuscript
Title: New synthetic access to
3
-fluoroalkyl-5-pyrazolecarboxylates and carboxylic acids
Authors: Alberto G o´ mez Herrera, Etienne Schmitt, Armen
Panossian, Jean-Pierre Vors, Sergii Pazenok, Fr e´ d e´ ric R.
Leroux
PII:
S0022-1139(18)30272-0
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2018.07.010
FLUOR 9199
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
3-7-2018
23-7-2018
26-7-2018
Please cite this article as: Herrera AG, Schmitt E, Panossian A, Vors J-
Pierre, Pazenok S, Leroux FR, New synthetic access to 3-fluoroalkyl-5-
pyrazolecarboxylates and carboxylic acids, Journal of Fluorine Chemistry (2018),
https://doi.org/10.1016/j.jfluchem.2018.07.010
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New synthetic access to 3-fluoroalkyl-5-pyrazolecarboxylates and
carboxylic acids
a
a
a
b
Alberto Gómez Herrera, Etienne Schmitt, Armen Panossian, Jean-Pierre Vors, Sergii
c
a
Pazenok and Frédéric R. Leroux*
a. Université de Strasbourg, Université de Haute-Alsace, CNRS, UMR 7042-LIMA, ECPM, 25 Rue
Becquerel, 67087 Strasbourg, France. E-mail: frederic.leroux@unistra.fr (+33 3 68 85 26 40)
b. Bayer S.A.S, 14 Impasse Pierre Baizet, BP99163, 69263 Lyon Cedex 09, France.
c. Bayer AG, Alfred-Nobel-Strasse 50, 40789 Monheim, Germany.
Graphical abstract
The synthesis of 3-fluoroalkyl-5-pyrazolecarboxylic acids was achieved by means of an
optimised 3-step sequence from fluoroalkyl methylketones and alkyl oxalyl chlorides.
Highlights

Convenient alternative to the scarce known methods to prepare 3-fluoroalkyl-5-
pyrazolecarboxylates.


Efficient and atom-economical synthesis of up to 18 compounds.
Novel access to fluorinated and non-fluorinated vinamides with no precedents in the
literature.


Highly regioselective cyclization for the synthesis of 3,5-disubstituted pyrazoles.
Easy setups, economical reagents and versatile tolerance to various functionalities.
Abstract
A novel process for preparing 3-fluoroalkyl-5-pyrazolecarboxylates and carboxylic acids is
hereby presented. Easily accesible -fluorinated ketimines were condensed with oxalyl
monochloride derivatives, and the obtained vinamides underwent acid-catalyzed cyclization
with substituted hydrazines. This highly efficient protocol can also be used for non-fluorinated
C-3 and C-5 substituents.

Keywords
•
Fluorinated pyrazole • 3,5-disubstitution • Vinamide • Cyclization
1
. Introduction
Pyrazoles conform a family of heterocyclic compounds with an important significance in
chemistry, having been extensively reviewed by the scientific community [1]. Among the vast
variety of related derivatives, (polyfluoroalkyl)pyrazolecarboxylic acids can certainly be
highlighted as a group of molecules with high synthetic value as building blocks in the
construction of bioactive molecules. This scaffold can be nowadays found in the structure of
compounds with various roles, such as fungicides (Bixafen) [2], acaricides (Tebufenpyrad
analogues) [3] or antivirals (AS-136A) [4]. The importance of this motif for the final properties
of these and other active ingredients renders the study for new and more efficient synthetic
methods highly interesting for the scientific community.
Figure 1. Examples of polyfluorinated pyrazolecarboxylic acid derivatives with bioactive
properties.
Up to date, a variety of methods for the preparation of polyfluoroalkylated
pyrazolecarboxylate species can be found in the literature, commonly proceeding through the
reaction of appropriately substituted dicarbonyl compounds with hydrazine derivatives [5,6,7].
Among this vast literature, however, only a few reports for the preparation of 3-fluoroalkyl-5-
pyrazolecarboxylates are available [7d,8], which is somehow surprising considering their
outstanding nature and properties (common presence in biologically active chemicals [9],
suitability for C-4 functionalisation...) [10]. These compounds are commonly prepared via the
[
3+2] cycloaddition of nitrilimines and propiolic esters [6m,8a,8d-f], or the cyclocondensation
of α,β-unsaturated dicarbonyl compounds and hydrazines [8c]. The first strategy has been
predominantly chosen for this synthesis, and even reports on flow synthesis conditions are
available (Jamison and co-workers, Scheme 1) [8e]. However, the described methodologies still
present inconveniences, such as long reaction times, moderate selectivities and a limited
number of substrates due to their price and stability (e.g. -fluoroamines).

Scheme 1. Some methodologies for the synthesis of 3-fluoroalkyl-5-pyrazolecarboxylates and
proposed approach.
In response to this need for more optimal routes, our most recent work in the assembly of
fluorinated heterocycles was considered. Encouraged by the recent work of Pazenok and Lui
with perfluoroalkyl anhydrides [8c], a new methodology employing Fluoroalkyl Amino
Reagents (FARs) was developed and afforded access to 3,5-bis(fluoroalkyl)pyrazoles (Scheme
1
) [11], resulting in a novel, efficient and industrially scalable alternative for the introduction of
F-containing motifs in pyrazoles. However, the introduction of a C-5 carboxylate functionality
was not investigated at the time. In order to explore this synthetic gap, and following an
analogous approach to the aforementioned one, it is proposed that perfluoroalkyl vinamides
appropriately substituted on the C-end by a carboxylate function, could afford the desired 3-
polyfluoroalkyl-5-pyrazolecarboxylates after cyclisation in the presence of monosubstituted
hydrazines (Scheme 1). These vinamides could be accessed through simple condensation of -
fluoroalkylated ketimines with oxalic acid derivatives under basic conditions. All reagents are
commercially available and fairly economical, and the pretty straightforward reaction setups
could prove being competitive for the preparation of these targets.
2
. Results and discussion
To validate the proposed synthetic scheme, the accessibility to the required vinamides was
first assessed. The preparation of the necessary N-benzylketimines was carried out by adapting
a literature procedure which reacts fluorinated methyl ketones and amines in the presence of
activated 4Å Molecular Sieves [12]. Using this protocol, three N-benzyl fluoroalkyl
methylketones (2a-c) were successfully isolated as stable upon storage liquids in excellent
yields (Scheme 2; for detailed experimental information, see the "Experimental" section).

Reaction conditions: 1 (1.00-2.93 equiv.), Bn-NH
1 °C, 6-72 h.
2
(1.00 equiv.), 4Å MS (1.00 g per mmol of 1),
2
Scheme 2. Synthesis of starting ketimines (2)
The reaction of the prepared ketimines with acyl electrophiles was next studied, employing an
analogous procedure to that used in the case of FARs [11]. Substrates 2a-c were reacted with
alkyl oxalyl chlorides in the presence of pyridine as base; gratifyingly, under these conditions,
2
a and 2b substrates could be successfully converted to their corresponding vinamides (3,
Table 1). The main side product in the reaction was confirmed as the N-acylation species (3',
Table 1), with the ratio 3:3' being strongly dependant on the substrate and reaction conditions
(
for the complete experimental optimisation, see the "Experimental" section). A pre-stirring
time with pyridine of 15 minutes was generally employed for optimal results [13], while longer
times led to higher percentages of 3'. While CH Cl was proven to be a suitable solvent for the
2
2
reaction, the use of THF allowed for the two-fold reduction of the reaction times, thus
increasing the selectivity towards 3. Interestingly, during the solvent scope it was
acknowledged that isopropyl acetate (lately included in a privileged selection of desirable
green solvents for synthesis) [14], afforded similar reactivity and selectivity to THF, highlighting
the interest of this route for its application in industrial scale. In the case of 2c, despite many
attempts towards the isolation of the major species observed by 19F NMR monitoring, no
expected product could be isolated [15].
Table 1. Synthesis of vinamides (3)a
Yield
Entry
R
F
R1
Solvent
t (h)
Product
3:3' b
c
(%)
1
2
3
a
CHF
2
Et
Me
Et
CH
CH
THF
2
Cl
Cl
2
2
18
18
72
3a
3b
3c
61:39
81:19
---
64
49
0
CF
3
2
d
C
F
2 5
See the "Experimental" section for a detailed optimisation of reaction
b
conditions. Product ratio obtained in the crude reaction mixture according to
1
c
d
H NMR integration ratio. Isolated yield of 3. Decomposition observed.
Investigating the reaction conditions for the cyclisation of these vinamide intermediates was
the next step of the present work. In a similar fashion to previous work [8c], the use of
monosubstituted hydrazines under acidic conditions allowed the smooth conversion of
substrates 3a and 3b into their corresponding 3-(polyfluoroalkyl)-5-pyrazolecarboxylates (4,
Table 2). Both methyl- and phenylhydrazine were used as cyclization partners, and the
products were cleanly isolated in yields of up to 81% (for the complete experimental
information, see the "Experimental" section). In all tested examples, the 3-fluoroalkyl-5-
carboxylate was the major isolated compound, thus highlighting the good selectivity of this
method. While most compounds were directly obtained as pyrazoles, 4d could only be isolated
after dehydrating the 5-hydroxypyrazoline intermediate in the presence of a pyridine/SOCl
mixture, reflecting difficult OH elimination from the carbon attached to the strong electron
2

withdrawing CF -group. This species could not be detected in the other products, where
3
spontaneous dehydration occurred either during the reaction or the silica gel purification.
Table 2. Acid-promoted cyclization of vinamides 3.a
Yield
R1
R2
o
Entry
R
F
Product
T ( C)
t (h)
b
(%)
1
2
3
4
a
CHF
CF
CHF
CF
2
Et
Me
Et
Me
Me
Ph
4a
4b
4c
4d
21
85
85
85
1
1
16
16
63
(99)
81
c
3
2
3
Me
Ph
64
Reaction conditions: 3 (1.00 equiv.), substituted hydrazine (1.57 equiv.),
b
c 19
H
2
SO
4
(51 mol%), CH
3
CN (0.4 M), 21-85 °C, 1-16 h. Isolated yields.
F
NMR yield (using fluorobenzene as internal standard).
With these esters in hand, simple hydrolysis could be performed in order to obtain the related
carboxylic acids. Although acidic conditions can also be used for this step, basic hydrolysis
using NaOH in EtOH at 21 °C proved to be a suitable method for the quantitative conversion of
all prepared esters into their corresponding pyrazolecarboxylic acids within 1 h (5, Scheme 3).
Reaction conditions: 4 (1.00 equiv.), NaOH (2.01 equiv.), EtOH, 21 °C, 1 h.
Scheme 3. Hydrolysis of 3-fluoroalkyl-5-pyrazolecarboxylates (5)
To further evaluate the utility of this synthetic route, it was suggested that variations of the
employed reagents could allow the introduction of new C-3 and C-5 functionalities in the final
pyrazoles, expanding its applicability. Two different examples were studied to assess this
statement. First, the possibility to introduce other C-3 functionalities was tested by replacing
polyfluorinated methyl ketones with acetophenone as starting material. After the isolation of
the corresponding ketimine 2d in 98% yield after 5 days at 21 °C in CH
2
Cl as solvent, this
2
compound was further subjected to the optimised conditions for vinamide synthesis using THF
as solvent. To our delight, the corresponding phenyl-substituted analogue 3d was formed and
could be isolated in 74% yield after standard workup techniques (Scheme 4). As with previous
substrates, the main side species was the related N-acylation product (3d'), with all attempts
to suppress its formation being unsuccessful. This compound was nevertheless isolated and
fully characterised for further reference. Finally, the cyclisation of 3d under acidic conditions
was also possible, being complete after 24 h at 85 °C using phenylhydrazine, and obtaining the

corresponding product 4e in 80% isolated yield (Scheme 4). This ester could be indeed
quantitatively hydrolysed using the previously described conditions, and its related carboxylic
acid 5d could be cleanly isolated.
Scheme 4. Synthesis of non-fluorinated heterocycles: 3-phenyl-5-pyrazolecarboxylate 4e and
carboxylic acid 5d.
Alternatively, exchanging the carbonyl electrophile employed in the condensation step was
also evaluated as a way to provide access to a broader range of C-5 functionalities. Indeed,
when the alkyl oxalyl monochloride derivatives were replaced with 2,2,2-trichloroacetyl
chloride [16], the use of the optimised conditions for vinamide synthesis using THF as solvent
proved being similarly effective. Full conversion of 2a into a species identified as the
corresponding vinamide 3e was observed (Scheme 5), isolating this compound in 79% yield.
Next, and upon treatment with phenyl hydrazine at 80 °C for 24 h, 3e was successfully
transformed into the CCl -functionalised pyrazole 4f in 70% yield. Both steps proceeded
3
efficiently in terms of reactivity, again with a significant preference for the 3-fluoroalkyl
species. This provides an example of the exploitability of this approach, considering the
significant variety of accessible acyl chloride derivatives in the market, and could definitely be
a powerful synthetic tool for the preparation of 5-substituted pyrazoles.
Scheme 5. Synthesis of non-carboxylated pyrazoles: 3-fluoroalkyl-5-trichloromethyl pyrazole
4
f.
3
. Conclusions
In conclusion, a new and facile methodology for the synthesis of 3-fluoroalkyl-5-
pyrazolecarboxylates and carboxylic acids is hereby disclosed. This 3-step reaction sequence
displays high efficiency using simple reagents and can be highlighted as a very convenient
alternative to other known methods for the preparation of these scaffolds. Moreover, non-
fluorinated substituents in either C-3 or C-5 position of the pyrazole ring are also well
tolerated, increasing its applicability in organic synthesis.
4
. Experimental
4
.1. General methods
Solvents were purified and dried following standard procedures, and stored over 4Å Molecular
Sieves upon convenience. Technical grade solvents for extraction and chromatography
(cyclohexane, dichloromethane, n-pentane, diethyl ether, toluene, and ethyl acetate) were
used as received, without further purification. All reagents were purchased from standard
commercial suppliers and used without further purification. All reactions were carried out in
air, unless stated otherwise. Purification by flash column chromatography was performed

using silica gel 60 (40-63 m, 230-400 mesh, ASTM). H, 13C-{ H} and F-{ H} Nuclear Magnetic
1
1
19
1
Resonance (NMR) spectra were recorded on Bruker Avance 300 or 400 MHz spectrometers,
using the residual solvent peak as reference (CDCl
3
: δ
H
= 7.26 ppm, δ
C
= 77.16 ppm ; d6-DMSO:
δ
H
= 2.50 ppm, δ = 39.52 ppm). NOESY (Nuclear Overhauser Effect Spectroscopy) spectra were
C
recorded on a Bruker Avance 500 MHz spectrometer. Chemical shifts are reported in parts per
million (ppm). The following abbreviations are used in the characterization details: s = singlet, s
br = broad singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet. High Resolution Mass
Spectrometry (HRMS, accuracy ≤ 15 ppm) and elemental analyses were performed by the
Analytical Facility at the University of Strasbourg.
4
.2. General procedure for the synthesis of imines 2a-d
To a mixture of the corresponding fluoroalkyl methylketone (1.00 mol, 1.00 equiv.) in CH
2
Cl or
2
toluene (0.5 mL), benzylamine (107 g, 1.00 mol, 1.00 equiv.) was slowly added at 10 °C, and
the reaction mixture was stirred at the corresponding temperature and time. The solvent was
removed under vacuum to yield the corresponding (fluoroalkyl-2-ylidene)benzylamines.
N-(1,1-difluoropropan-2-ylidene)benzylamine (2a)
Pale oil (88% yield).
1
H NMR (400 MHz, CDCl3, 298K): δ (ppm) = 7.41-7.29 (m, 5H, CHAr), 5.99 (t, 1H, 2JH-H = 55.6 Hz,
CHF
2
), 4.60 (s, 2H, CH
2
N) , 2.00 (s, 3H, CH
C-{ H} NMR (100 MHz, CDCl , 298K): δ (ppm) = 163.1 (t, 1C, JC-F = 28.5 Hz, C=N), 138.7 (s, 1C,
CCH ),
), 128.7 (s, 2C, CHAr), 127.8 (s, 2C, CHAr), 127.2 (s, 1C, CHAr), 115.7 (t, 1JC-F = 243 Hz, CHF
5.2 (s, 1C, CH ), 11.3 (s, 1C, CH ).
F NMR (376 MHz, CDCl3, 298K): δ (ppm) = -120.6 (tt, 2F, JF-H = 56 Hz, 4JF-H = 3 Hz, CHF
3
).
1
3
1
2
3
2
2
5
2
3
19
2
2
).
N-(1,1,1-Trifluoropropan-2-ylidene)benzylamine (2b)
Colourless oil (99% yield).
1
H NMR (400 MHz, CDCl3, 298K): δ (ppm) = 7.37-7.30 (m, 5H, CHAr), 4.67 (s, 2H, CH N), 2.12 (s,
2
3
H, CH
3
).
1
3
1
, 298K): δ (ppm) = 157.1 (q, 1C, 2JC-F = 33.5 Hz, C=N), 138.0 (s, 1C,
),
C-{ H} NMR (100 MHz, CDCl
3
C
Ar), 128.7 (s, 2C, CHAr), 127.7 (s, 2C, CHAr), 127.3 (s, 2C, CHAr), 119.9 (q, 1C, 1JC-F = 278 Hz, CF
5.2 (s, 1C, NCH ), 13.0 (s, 1C, CH ).
F NMR (376 MHz, CDCl3, 298K): δ (ppm) = -74.6 (t, 3F, JF-H = 1.6 Hz, CF
3
5
2
3
19
4
3
).
N-(3,3,4,4,4-Pentafluorobutan-2-ylidene)benzylamine (2c)
Pale yellow oil (99% yield) (1:99, Z:E).
1
H NMR (400 MHz, CDCl3, 298K): δ (ppm) = 7.29-7.26 (m, 2H, CHAr), 7.25-7.18 (m, 3H, CHAr) 4.61
(
s, 2H, CH
C-{ H} NMR (125 MHz, CDCl
Ar), 128.7 (s, 2C, CHAr), 127.4 (s, 2C, CHAr), 127.2 (s, 1C, CAr), 118.9 (qt, 1C, 1JC-F = 286.4 Hz, JC-F
2
), 2.03 (s, 3H, CH
3
).
1
3
1
, 298K): δ (ppm) = 158.3 (t, 1C, 2JC-F = 26.7 Hz, C=N), 138.2 (s, 1C,
3
2
C
3
1
=
5 Hz, CF
C, CH ).
F NMR (376 MHz, CDCl3, 298K): δ (ppm) = -81.3 (s, 3F, CF
2
CF
3
), 110.4 (tq, 1C, 1JC-F = 255.5 Hz, 2JC-F = 36.3 Hz, CF
2
CF
3 2
), 55.6 (s, 1C, CH N), 13.3 (s,
3
1
9
3
), -118.2 (s, 2F, CF
2
).

N- (1-Phenylethylidene)benzylamine (2d)
Brown oil (98% yield) (8:92, Z:E).
1
H NMR (400 MHz, CDCl3, 298K): δ (ppm) = 7.90-7.85 (m, 2H, CHAr), 7.52-7.33 (m, 8H, CHAr),
4
.75 (s, 2H, CH
C-{ H} NMR (100 MHz, CDCl
2
), 2.34 (s, 3H, CH
, 298K): δ (ppm) = 166.1 (s, 1C, C=N), 141.2 (s, 1C, C(N)CAr), 140.7
), 129.7 (s, 1C, CHAr), 128.5 (s, 2C, CHAr), 128.3 (s, 2C, CHAr), 127.8 (s, 2C, CHAr), 126.9
s, 2C, CHAr), 126.7 (s, 1C, CHAr), 55.82 (s, 1C, CH ), 16.0, (s, 1C, CH ).
3
).
13
1
3
(s, 1C, CCH
2
(
2
3
4
.3. General procedure for the synthesis of vinamides 3a-d
A solution of the ketimine (1.00 equiv.) in the appropriate solvent (approx. 2M) was cooled to -
0 °C. Pyridine (1.05 equiv.) was then added, and the mixture was stirred at -20 °C for 15
2
minutes (in the case of the use of THF as solvent, no additional stirring time was required at
this stage). A solution of ethyl oxalyl chloride (1.03 equiv.) in the solvent (1.00-1.50 M) was
then added dropwise. The mixture was left to evolve from -20 °C to 21 °C under stirring over a
period of 7-18 h. The reaction mixture was diluted with CH
2
Cl and filtered through cotton, and
2
the resulting filtrate was concentrated to dryness under vacuum. The crude residue was
purified by flash chromatography to yield the desired compound.
Ethyl 4-(benzylamino)-5,5-difluoro-2-oxopent-3-enoate (3a)
2
CH Cl
2
as solvent, 18 h. Purification by flash chromatography (Cyclohexane:AcOEt, 100:0 to
8
5:15). Orange oil (61% yield).
1
H NMR (400 MHz, CDCl3, 298K): δ (ppm) = 10.91 (s br, NH), 7.39-7.28 (m, 5H, Phenyl), 6.18 (t,
4
CHF
2
, JH-H = 53 Hz), 6.17 (s, CHCO), 4.66 (d, CH
2
NH), 4.31 (q, OCH
, 298K): δ (ppm) = 180.2 (s, 1C, C(O)COOEt), 162.6 (s, 1C,
), 136.2 (s, 1C, CPh), 129.2(s, 2C, CHPh), 128.3(s, 2C,
), 91.4 (t, 1C, 3JC-F = 7 Hz, CHCO), 62.2 (s,
CH ).
F NMR (376 MHz, CDCl3, 298K): δ (ppm) = -118.9 (d, 2F, JH-F = 53 Hz, CHF
Anal. calcd for C14 NO : C, 59.36; H, 5.34; F, 13.41; N, 4.94; O, 16.94. Found: C, 59.16; H,
.36; N, 4.95.
2
), 1.36 (t, OCH
2
3
CH ).
13
1
C-{ H} NMR (100 MHz, CDCl
3
2
C(O)OEt), 156.8 (t, 1C, JH-F = 22 Hz, CCHF
2
CHPh), 127.3 (s, 1C, CHPh), 111.4 (t, 1JH-F = 245 Hz, CHF
C, OCH ), 48.2 10 (s, 1C, CH NH), 14.1 (s, 1C, OCH
2
1
2
2
2
3
19
2
2
).
15
H F
2
3
5
Methyl 4-(benzylamino)-5,5,5-trifluoro-2-oxopent-3-enoate (3b)
CH Cl as solvent, 18 h. Purification by flash chromatography (Cyclohexane:AcOEt, 100:0 to
0:10). Colourless oil (49% yield).
2
2
9
1
H NMR (400 MHz, CDCl3, 298K): δ (ppm) = 11.02 (s br, NH), 7.40-7.28 (m, 5H, Ph), 6.40 (s, 1H,
NH), 3.87 (s, 3H, COOCH ).
, 298K): δ (ppm) = 180.3 (s, 1C, CHCO), 162.7 (s, 1C, COOMe),
), 135.8 (s, 1C, CPh), 129.3 (s, 2C, CHPh), 128.5 (s, 2C, CHPh),
CHCO), 4.64 (d, 2H, CH
2
3
13
1
C-{ H} NMR (100 MHz, CDCl
52.6 (q, 1C, JC-F = 32.5 Hz, CCF
3
2
1
1
3
1
3
27.4 (s, 1C, CHPh), 119.6 (q, 1C, JC-F = 278 Hz, CF
), 49.0 (s, 1C, CH NH).
F NMR (376 MHz, CDCl3, 298K): δ (ppm) = -66.6 (s, 3F, CF
HRMS (ESI) - calcd for C13 NNaO [M+Na]: 310.0661. Found: 310.0635.
3
), 90.4 (q, 1C, JC-F = 5 Hz, CHCO), 53.1 (s, 1C,
COOCH
3
2
19
3
).
H
F
12 3
3

Ethyl 4-(benzylamino)-2-oxo-4-phenylbut-3-enoate (3d)
THF as solvent, 7 h. Purification by column chromatography (pentane:AcOEt, 80:20 to 70:30).
Orange oil (86% yield) (mixture of Z:E isomers, ratio not determined).
1
H NMR (400 MHz, CDCl3, 298K): δ (ppm) = 11.83 (s br, 1H, NH), 7.54-7.07 (m, 10H, CHAr), 5.98
3
3
(
s, 1H, CHCO), 4.48 (d, 2H, JH-H = 6.4 Hz, CH
J
2 2
NH), 4.30 (q, 2H, JH-H = 7.1 Hz, OCH ), 1.36 (t, 3H,
3
H-H = 7.1 Hz, OCH
C-{ H} NMR (100 MHz, CDCl
2
CH ).
3
13
1
3
, 298K): δ (ppm) = 177.3 (s, 1C, C=O), 169.7 (s, 1C, C(O)OEt),
1
(
(
64.1 CPhvinyl), 137.3 (s, 1C, CPh), 134.2 (s, 1C, CPh), 130.4 (s, 1C, CHPh), 129.0 (s, 2C, CHPh), 128.9
s, 2C, CHPh), 127.9 (s, 1C, CHPh) , 127.7 (s, 2C, CHPh), 127.0 (s, 2C, CHPh), 95.0 (s, 1C, CHCO), 61.8
s, 1C, OCH ), 49.0 (s, 1C, CH NH), 14.3 (s, 1C, OCH CH ).
Na [M+Na]: 332.1257. Found: 332.1232.
2
2
2
3
HRMS (ESI) - calcd for C19
H
19NO
3
Ethyl 2-(benzyl(1-phenylvinyl)amino)-2-oxoacetate (3d')
Isolated as a side species from the synthesis of 3d. Viscous orange oil.
1
H NMR (400 MHz, CDCl3, 298K): δ (ppm) = 7.48-7.40 (m, 5H, CHAr), 7.30-7.27 (m, 3H, CHAr),
7
2
.19-7.17 (m, 2H, CHAr), 5.32 (s, 1H, CH2,vinyl), 4.90 (s, 1H, CH2,vinyl), 4.61 (s, 2H, CH
2
Ph), 4.19 (q,
3
3
H, JH-H = 7.2 Hz, CH
2
CH
3
), 1.17 (t, 3H, JH-H = 7.1 Hz, CH
, 298K): δ (ppm) = 162.8 (s, 1C, C=O), 162.3 (s, 1C, COOMe),
), 135.8 (s, 1C, CAr), 134.6 (s, 1C, CAr), 129.7 (s, 1C, CHAr), 129.3 (s, 2C, CHAr
28.9 (s, 2C, CHAr), 128.6 (s, 2C, CHAr), 127.9 (s, 1C, CHAr), 127.5 (s, 2C, CHAr), 114.7 (s, 1C,
CH ), 48.4 (s, 1C, CH N), 13.8 (s, 1C, CH CH ).
HRMS (ESI) - calcd for C19 Na [M+Na]: 332.1257. Found: 332.1255.
2
CH
3
).
1
3
1
C-{ H} NMR (100 MHz, CDCl
3
1
1
45.5 (s, 1C, NCCH
2
)
CH2,vinyl), 62.0 (s, 1C, CH
2
3
2
2
3
H
19NO
3
4
.4. Procedures for the synthesis of pyrazoles 4a-f.
Ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-carboxylate (4a): To a solution of ethyl 4-
(
(
benzylamino)-5,5-difluoro-2-oxopent-3-enoate (3a, 363 mg, 1.78 mmol, 1.00 equiv.) in CH
4.00 mL) was added methylhydrazine (129 mg, 2.79 mmol, 1.57 equiv.), followed by
3
CN
concentrated H
stirred at 21 °C for 1 h and was then diluted with CH
concentrated to dryness under vacuum. The crude product was purified by flash
chromatography (pentane:Et O, 100:0 to 60:40), and afforded ethyl 3-(difluoromethyl)-1-
methyl-1H-pyrazole-5-carboxylate (4a) as a colourless oil (230 mg, 63%).
2
SO
4
(0.05 mL, 0.91 mmol, 0.51 equiv.) under argon. The reaction mixture was
2
2
Cl (5.00 mL), filtered through cotton and
2
1
H NMR (400 MHz, CDCl3, 298K): δ (ppm) = 7.04 (t, 1H, JH-H = 1 Hz, 4-CH), 6.66 (t, 1H, 2JH-F = 55
Hz, CHF ), 4.36 (q, 2H, OCH ), 4.19 (s, 3H, CH ), 1.38 (t, 3H, OCH CH ).
C-{ H} NMR (100 MHz, CDCl , 298K): δ (ppm) = 159.4 (s, 1C, C=O), 145.1 (t, 1C, JC-F = 29.8 Hz,
CCHF ), 108.7 (s, 1C, 4-CH), 61.5 (s, 1C,
), 134.0 (s, 1C, CCOOEt), 110.8 (t, 1C, 1JC-F = 234 Hz, CHF
OCH ), 40.1 (s, 1C, NCH ), 14.3 (s, 1C, OCH CH ).
F NMR (376 MHz, CDCl3, 298K): δ (ppm) = -112.1 (d, 2F, JH-F = 55 Hz, CHF
HRMS (ESI) - calcd for C [M+H]: 205.0783. Found: 205.0782.
4
2
2
3
2
3
13
1
2
3
2
2
2
3
2
3
19
2
2
).
8
H
11
F
2
N
O
2 2

Methyl 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (4b): To a solution of methyl
-(benzylamino)-5,5,5-trifluoro-2-oxopent-3-enoate (3b, 150 mg, 0.47 mmol, 1.00 equiv.) in
CH CN (1.00 mL) was added methylhydrazine (34.2 mg, 0.74 mmol, 1.57 equiv.), followed by
concentrated H SO (13.0 L, 0.24 mmol, 0.51 equiv.) under argon. The reaction mixture was
stirred at 90 °C for 1 h and was then removed from the oil bath for 5 min. Pyridine (305 μL,
.77 mmol, 8.02 equiv.) was added, followed by SOCl (70.0 μL, 0.97 mmol, 2.05 equiv.). The
4
3
2
4
3
2
mixture was stirred for 30 minutes, and analyzed by NMR using fluorobenzene as an internal
standard. Methyl 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (4b) was detected
but not isolated. 19F NMR yield >99%.
Ethyl 3-(difluoromethyl)-1-phenyl-1H-pyrazole-5-carboxylate (4c): To a solution of ethyl 4-
(
(
benzylamino)-5,5-difluoro-2-oxopent-3-enoate (3a, 420 mg, 1.44 mmol, 1 equiv.) in CH
3.00 mL) was added phenylhydrazine (0.22 mL, 2.26 mmol, 1.57 equiv.), followed by
3
CN
concentrated H
refluxed for 16 h. CH
2
SO
4
(40.2 L, 0.73 mmol, 0.51 equiv.) under argon. The reaction mixture was
Cl (15.0 mL) was added, the mixture filtered and concentrated in vacuo.
2
2
The crude product was purified by flash chromatography (cyclohexane:AcOEt, 100:0 to 98:2) to
give ethyl 3-(difluoromethyl)-1-phenyl-1H-pyrazole-5-carboxylate (4c) as an orange oil (310
mg, 81% yield).
1
H NMR (400 MHz, CDCl3, 298K): δ (ppm) = 7.50-7.41 (m, 5H, CHPh), 7.24 (s, 1H, 4-CH), 6.76 (t,
2
1
H, JH-F = 54.9 Hz, CHF
2 2
), 4.26 (q, 2H, OCH ), 1.26 (t, 3H, OCH
2
CH ).
3
13
1
2
C-{ H} NMR (100 MHz, CDCl3, 298K): δ (ppm) = 158.4 (s, 1C, C=O), 146.8 (t, 1C, JC-F = 30 Hz,
CCHF
s, 2C, CPh), 110.7 (t, 1C, 1JC-F = 234 Hz, CHF
OCH CH ).
F NMR (376 MHz, CDCl3, 298K): δ (ppm) = -112.2 (d, 2F, 2JF-H = 54.6 Hz, CHF
HRMS (ESI) - calcd for C13 [M+H]: 267.0940. Found: 267.0918.
2
), 139.8 (s, 1C, NCPh), 135.0 (s, 1C, CCOOEt), 129.2 (s, 2C, CHPh), 128.7 (s, 1C, CHPh), 126.0
(
2
), 109.6 (s, 1C, 4-CH), 61.6 (s, 1C, OCH ), 13.9 (s, 1C,
2
2
3
1
9
2
,).
H
13 2 2
F N O
2
Methyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (4d): To a solution of methyl
-(benzylamino)-5,5,5-trifluoro-2-oxopent-3-enoate (3b, 500 mg, 1.74 mmol, 1 equiv.) in
CH CN (5.00 mL) was added phenylhydrazine (0.27 mL, 2.73 mmol, 1.57 equiv.), followed by
concentrated H SO (49.0 L, 0.89 mmol, 0.51 equiv.) under argon. The reaction mixture was
refluxed for 16 h. CH Cl (20.0 mL) was added, the mixture was refluxed for 2 days and cooled
to room temperature. Pyridine (1.10 mL, 13.6 mmol, 7.81 equiv.) was added, followed by slow
addition of SOCl (410 mg, 0.25 mL, 3.45 mmol, 1.98 equiv.) via syringe. The mixture was
stirred for 30 min, then filtered and concentrated in vacuo. The crude was purified by flash
chromatography (pentane:Et O, 100:0 to 95:5), to give methyl 1-phenyl-3-(trifluoromethyl)-
H-pyrazole-5-carboxylate (4d) as a red solid (370 mg, ca. 80wt.% = 300 mg, 64% yield), which
4
3
2
4
2
2
2
2
1
was not further purified.
HRMS (ESI) - calcd for C12
H
10
F
3
N
2
O [M+H]: 271.0689. Found: 271.0697.
2

Ethyl 1,3-diphenyl-1H-pyrazole-5-carboxylate (4e): To a solution of ethyl 4-(benzylamino)-2-
oxo-4-phenylbut-3-enoate (3d, 250 mg, 0.81 mmol, 1.00 equiv.) in CH CN (2.00 mL) was added
phenylhydrazine (0.13 mL, 1.27 mmol, 1.57 equiv.), followed by concentrated H SO (23.0 L,
.41 mmol, 0.51 equiv.) under argon. The reaction mixture was stirred at 80 for 24 h, and was
then diluted with CH Cl (5.00 mL), filtered through Celite® (washing the Celite® pad with 2 x 3
mL CH Cl ). The filtrate was then evaporated under vacuum. The crude was purified by flash
3
2
4
0
2
2
2
2
chromatography (pentane:AcOEt, 9:1 to 8:2), to give ethyl 1,3-diphenyl-1H-pyrazole-5-
carboxylate (4d) as a pale orange oil (191 mg, 81% yield).
1
H NMR (400 MHz, CDCl3, 298K): δ (ppm) = 7.36-7.28 (m, 8H, CHPh), 7.23-7.20 (m, 2H, CHAr),
.04 (s, 1H, CHpyr), 4.46 (q, 2H, 3JH-H = 7.1 Hz, OCH
3
CH ).
7
2
), 1.42 (t, 3H, JH-H = 7.1 Hz, OCH
2
3
13
1
C-{ H} NMR (100 MHz, CDCl3, 298K): δ (ppm) = 162.6 (s, 1C, C=O), 144.8 (s, 1C, 3-C), 144.5 (s,
C, CpyrC(Ph)), 139.7 (s, 1C, NCPh), 129.7 (s, 1C, CCOOEt), 129.1 (s, 2C, CHPh), 128.9 (s, 2C, CHPh),
28.8 (s, 1C, CHPh), 128.7 (s, 2C, CHPh), 128.5 (s, 1C, CHPh), 125.9 (s, 2C, CHPh), 110.1 (s, 1C, 4-
1
1
2
CH), 61.3 (s, 1C, OCH ), 14.6 (s, 1C, OCH
2
CH ).
3
3
(
-(Difluoromethyl)-1-phenyl-5-(trichloromethyl)-1H-pyrazole (4f): To a solution of 4-
benzylamino)-1,1,1-trichloro-5,5-difluoropent-3-ene-2-one (3ab, 154 mg, 0.47 mmol, 1.00
equiv.) in CH CN (1.50 mL) was added phenylhydrazine (75.0 L, 0.74 mmol, 1.57 equiv.),
followed by concentrated H
3
2
SO
4
(13.0 L, 0.24 mmol, 0.50 equiv.) under argon and under
°
vigorous stirring. The reaction mixture was stirred at 80 C for 24 h and was then diluted with
CH
was purified by flash chromatography (pentane:AcOEt, 98:2 to 96:4), to give 3-
difluoromethyl)-1-phenyl-5-(trichloromethyl)-1H-pyrazole (4f) as an orange solid (102 mg,
2
Cl (5.00 mL), filtered through Celite® and evaporated under vacuum. The crude product
2
(
7
1
0%).
H NMR (400 MHz, CDCl3, 298K, TMS): δ (ppm) = 7.56-7.47 (m, 5H, CHAr), 7.11 (br s, 1H, CHpyr),
2
6
.70 (t, 1H, JH-F = 54.4 MHz, CHF
2
).
1
3
1
), 145.3 (t, 1C, 2JC-F
C-{ H} NMR (100 MHz, CDCl3
,
298K, TMS): δ (ppm) = 146.2 (s, 1C, C-CCl =
3
3
1
0.0 MHz, Cpyr), 139.4 (s, 1C, NCPh), 130.3 (s, 1C, CHAr), 128.9 (s, 2C, CHAr), 128.4 (s, 2C, CHAr),
2
10.7 (t, 1C, JC-F = 234 MHz, CHF
F NMR (376 MHz, CDCl3, 298K, TMS): δ (ppm) = -112.3 (d, 2F, JF-H = 54.4 MHz, CHF
2
), 106.3 (s, 1C, CHpyr), 86.2 (s, 1C, C-CCl
3
).
1
9
2
2
).
HRMS (ESI) - calcd for C11
H
8
Cl
3 2
F
O [M+H]: 310.9716. Found: 310.9710.
2
4
.5. General procedure for the synthesis of pyrazoles 5a-d.
A mixture of the corresponding pyrazolecarboxylate (4, 1.00 equiv., 0.6-0.8 M) and NaOH (2.01
equiv., 2N) in EtOH was stirred at 21 °C for 1 h. The mixture was treated with 1N HCl until pH 2-
3
, and was then extracted with CH
and dried over Na SO , filtered and concentrated in vacuo, to yield the desired product after
trituration with the appropriate solvent.
2
Cl . The combined organic layers were washed with brine
2
2
4
3
-(Difluoromethyl)-1-methyl-1H-pyrazole-5-carboxylic acid (5a)
Following the general procedure, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-carboxylate
4a, 185 mg, 0.906 mmol, 1.00 equiv.) afforded 3-(difluoromethyl)-1-methyl-1H-pyrazole-5-
(
carboxylic acid (5a) after trituration with pentane, as a white solid (160 mg, >99% yield).
M.p: 179.8 to 180.2 °C.

1
2
1
H NMR (400 MHz, d6-DMSO
,
298K): δ (ppm) = 13.7 (s br, COOH), 7.02 (s, 1H, 4-CH), 7.01 (t,
J
H-F = 54.4 Hz, CHF
2
), 4.11 (s, 3H, NCH ).
3
3
1
2
C-{ H} NMR (100 MHz, d6-DMSO, 298K): δ (ppm) = 160.1 (s, 1C, C=O), 144.0 (t, 1C, JC-F = 28.5
1
Hz, CCHF
C, NCH
2
), 134.6 (s, 1C, CCOOH), 110.9 (t, 1C, JC-F = 232 Hz, CHF
2
), 108.4 (s, 1C, 4-CH), 39.7 (s,
1
3
).
F NMR (376 MHz, d6-DMSO
HRMS (ESI) - calcd for C
1
9
298K): δ (ppm) = -111.6 (d, 2F, 2JF-H = 54.5 Hz, CHF
[M+H]: 205.0783. Found: 205.0782.
,
2
).
H F
8 11 2
N
O
2 2
3
-(Difluoromethyl)-1-phenyl-1H-pyrazole-5-carboxylic acid (5b):
Following the general procedure, ethyl 3-(difluoromethyl)-1-phenyl-1H-pyrazole-5-carboxylate
4a, 160 mg, 0.601 mmol, 1 equiv.) was hydrolyzed for 1 h, affording 3-(difluoromethyl)-1-
(
phenyl-1H-pyrazole-5-carboxylic acid (5e) after trituration in pentane, as a brown solid (142
mg, >99% yield).
M.p: 132.7 to 133.5 °C.
1
H NMR (400 MHz, d6-DMSO
,
298K): δ (ppm) = 13.6 (s, 1H, COOH), 7.50 (m, 5H, CHPh), 7.25 (s,
2
1
H, 4-CH), 7.13 (t, 1H, JH-F = 54 Hz, CHF
2
).
13
1
2
C-{ H} NMR (100 MHz, d6-DMSO
,
298K): δ (ppm) = 159.3 (s, 1C, COOH), 146.0 (t, 1C, JC-F = 29
Hz, CCHF
25.9 (s, 2C, CHPh), 110.9 (t, 1C, 1JC-F = 233 Hz, CHF
2
), 139.7 (s, 1C, NCPh), 135.9 (s, 1C, CCOOH), 128.9 (s, 2C, CHPh), 128.7 (s, 1C, CHPh),
1
2
), 109.5 (s, 1C, 4-CH).
1
9
2
F NMR (376 MHz, d6-DMSO
Anal. calcd for C11
,
298K): δ (ppm) = -112.2 (d, 2F, JF-H = 53.7 Hz, CHF
: C, 55.47; H, 3.39; F, 15.95; N, 11.76; O, 13.43. Found: C, 55.97; H,
2
) ppm.
8
H F
2
N
2
O
2
3
.54; N, 11.61.
1
-Phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (5c): Following the general
procedure, methyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (4b, 170 mg, 0.503
mmol, 1 equiv.) afforded 1-phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (5f) as a
brown solid (128 mg, >99% yield).
M.p: 155 - 165 °C (degradation observed).
1
H NMR (400 MHz, d6-DMSO 298K): δ (ppm) = 13.8 (s br, COOH), 7.55-7.53 (m, 5H, CHPh), 7.50
,
(
s, 1H, 4-CH).
13
1
298K): δ (ppm) = 158.9 (s, 1C, COOH), 141.0 (q, 1C, 2JC-F = 38
C-{ H} NMR (100 MHz, d6-DMSO
Hz, CCF ), 139.4 (s, 1C, NCPh), 136.4 10 (s, 1C, CCOOH), 129.3 (s, 2C, CHPh), 128.7 (s, 1C, CHPh),
26.0 (s, 2C, CHPh), 120.9 (q, 1C, 1JC-F = 269 Hz, CF
), 110.1 (s, 1C, 4-CH).
298K): δ (ppm) = -60.9 (s, 3F, CF ).
[M+H]: 257.0532. Found: 257.0536.
,
3
1
3
1
9
F NMR (376 MHz, d6-DMSO
HRMS (ESI) - calcd for C11
,
3
H
F
8 3
N
O
2 2
1
,3-Diphenyl-1H-pyrazole-5-carboxylic acid (5d): Following the general procedure, ethyl 1,3-
diphenyl-1H-pyrazole-5-carboxylate (4d, 116 mg, 0.397 mmol, 1.00 equiv.) afforded 1,3-
diphenyl-1H-pyrazole-5-carboxylic acid (5d) after trituration with pentane, as an orange solid
(
103 mg, >99% yield).
1
H NMR (400 MHz, CDCl3, 298K): δ (ppm) = 7.37-7.29 (m, 8H, CHPh), 7.23-7.21 (m, 2H, CHAr),
7
.09 (s, 1H, CHpyr).
1
3
1
C-{ H} NMR (100 MHz, CDCl3, 298K): δ (ppm) = 165.3 (s, 1C, C=O), 145.4 (s, 1C, 3-C), 143.4 (s,
1
1
C, CpyrC(Ph)), 139.4 (s, 1C, NCPh), 129.4 (s, 1C, CCOOEt), 129.2 (s, 2C, CHPh), 129.1 (s, 2C, CHPh),
28.9 (s, 1C, CHPh), 128.8 (s, 2C, CHPh), 128.7 (s, 1C, CPh), 125.7 (s, 2C, CHPh), 110.3 (s, 1C, 4-CH).

HRMS (ESI) - calcd for C16
H
12
N
2
NaO [M+Na]: 287.0791. Found: 287.0793.
2
Acknowledgements
Funding: This work was supported by Bayer S.A.S. (project grants to E.S. and A.G.H), the Centre
National de la Recherche Scientifique (CNRS), the University of Strasbourg and The French
Fluorine Network (GIS Fluor).
Notes and references
[
7
1] S. Fustero, M. Sánchez-Roselló, P. Barrio, A. Simón-Fuentes, Chem. Rev. 111 (2011) 6984-
034.
[2] For some selected examples, see: (a) R. Dunkel, H. Rieck, H.-L. Elbe, U. Wachendorff-
Neumann and K.-H. Kuck, WO 070 705, 2003; (b) T. Tsuchiya, P. Wasnaire, S. Hoffman, P.
Cristau, T. Seitz, J. Kluth, S. Hillebrand, J. Benting, D. Portz and U. Wachendorff-Neumann
(Bayer Cropscience AG), WO 025 557, 2012.
[3] For some selected examples, see: (a) R. Román, A. Navarro, D. Wodka, M. Alvim-Gaston, S.
Husain, N. Franklin, A. Simón-Fuentes, S. Fustero, Org. Proc. Res. Dev. 18 (2014) 1027-1036; (b)
D. Marcic, Exp. Appl. Acarol. 36 (2005) 177-185.
[
4] For some selected examples, see: (a) H.-G. Schwarz, R. Velten, A. Hense, S. Maechling, S.
Werner, B. Alig, E.-M. Franken, A. Voerste and U. Görgens (Bayer Cropscience AG), US 124 660,
011; (b) J. X. Qiao, X. Cheng, J. M. Smallher, R. A. Galemmo, S. Drummond, J. P. Pinto, D. L.
2
Cheney, K. He, P. C. Wong, J. M. Luettgen, R. M. Knabb, R. R. Wexler, P. Y. S. Lam, Bioorg. Med.
Chem. Lett. 17 (2007) 1432-1437.
[5] For a summary on various methodologies for the synthesis of these compounds, see: V.
Nenajdenko, in Fluorine in Heterocyclic Chemistry Volume 1: 5-Membered Heterocycles and
Macrocycles, Springer, 2014, pp. 289-303.
[6] For some selected examples on the synthesis of fluorinated 3,4-disubstituted pyrazoles,
see: (a) R. Lantzsch, W. Joerges and S. Pazenok (Bayer Cropscience AG), WO 042 468, 2005; (b)
S. Pazenok, N. Lui and A. Neeff (Bayer Cropscience AG), WO 022 777, 2008; (c) S. Pazenok
(
(
Bayer Cropscience AG), WO 112 157, 2009; (d) S. Pazenok, N. Lui, J.-D. Heinrich and T. Wollner
Bayer Cropscience AG), WO 106 230, 2009; (e) M. Okamoto, H. Imura and N. Takada (Central
Glass Company, Limited), US Pat. 0 107 347, 2014; (f) J. Jaunzems, M. Braun, Org. Proc. Res.
Dev. 18 (2014) 1055-1059; (g) Z. Wang and A. Wang (Kingchem LLC), WO 120 397, 2014; (h) E.
Schmitt, S. Bouvet, B. Pégot, A. Panossian, J.-P. Vors, S. Pazenok, E. Magnier, F. R. Leroux, Org.
Lett. 19 (2017) 4960-4963; (i) I. I. Gerus, M. X. Mironetz, I. S. Kondratov, A. V. Bezdudny, Y. V.
Dmytriv, O. V. Shishkin, V. S. Starova, O. A. Zaporozhets, A. A. Tolmachev, P. K. Mykhailiuk, J.
Org. Chem. 77 (2012) 47−56.
[7] For some selected examples on the synthesis of fluorinated 4,5-disubstituted pyrazoles,
see: (a) S. Tajammal, A. E. Tipping, J. Fluorine Chem. 47 (1990) 45-51; (b) L. Wang and R. B.
Sheth (Syngenta Participations AG), WO 019 950, 2012; (c) G. Beaton, C. F. Tucci, B. S. Ravula,
R. C. Shah and H. Liu (Epigen Biosciences, Inc), WO 145 873, 2014; (d) J. Britton, T. F. Jamison,
Eur. J. Org. Chem. (2017) 6566-6574.

[8] (a) F. Li, J. Nie, L. Sun, Y. Zheng, J.-A. Ma, Angew. Chem. Int. Ed. 52 (2013) 6255–6258; (b) R.
S. Foster, H. Adams, H. Jakobi, J. P. A. Harrity, J. Org. Chem. 78 (2013) 4049−4064; (c) S.
Pazenok and N. Lui (Bayer Cropscience AG), WO 189 138, 2015; (d) P. K. Mykhailiuk, Beilstein J.
Org. Chem. 11 (2015) 16-24; (e) J. Britton, T. F. Jamison, Angew. Chem. Int. Ed. 56 (2017) 8823-
8
827.
9] For some selected examples, see: (a) P. Cristau, S. Hoffmann, J. Kluth, T. Tsuchiya, P.
Wasnaire, J. Benting, U. Wachendorff-Neumann (Bayer CropScience AG), WO 144 586, 2011;
b) P. Muthuppalaniappan, S. Viswanadha, G. S. Merikapudi, S. K. Vakkalanka (Icozen
[
(
Therapeutics Pvt. Ltd., Rhizen Pharmaceuticals S.A.), WO 042 797, 2011; (c) R. J. Pasteris, M. A.
Hanagan, R. Shapiro (Du Pont De Nemours and Co.), WO 013 622, 2008; (d) J. M. Fevig, J.
Cacciola, C. G. Clark, P. Y. S. Lam, D. J. P. Pinto, J. R. Pruitt, M. L. Quan, K. A. Rossi (Bristol-Myers
Squibb Pharma Company), US Pat. 6 413 980, 1999.
[10] For some examples of the metalation/functionalization sequence at the C-4 position
leading to 3,4,5-trisubstituted pyrazoles, see: a) M. Schlosser, J.-N. Volle, F. Leroux, K. Schenk,
Eur. J. Org. Chem. (2002) 2913–2920; b) C. Despotopoulou, L. Klier, P. Knochel, Org. Lett.
(2009) 11, 23326-23329; (c) V. J. Blank, S. Bordas, V. Cotesta, H. Guagnano, A. Rueeger, R.
Vaupel (Novartis AG), US Pat. 0 349 990, 2014; (d) E. Schmitt, A. Panossian, J.-P. Vors, C. Funke,
N. Lui, S. Pazenok, F. R. Leroux, Chem. Eur. J. 22 (2016) 11239-11244.
[
2
11] (a) S. Pazenok, N. Lui, C. Funke, W. Etzel, A. Neeff (Bayer Cropscience AG), WO 144 578,
015; (b) S. Pazenok, J.-P. Vors, F. R. Leroux, E. Schmitt (Bayer AG), WO 207 167, 2016.
[
12] S. Perrone, F. Rosato, A. Salomone, L. Troisi, Tetrahedron 69 (2013) 3878-3884.
[
13] The pre-stirring time with pyridine was directly linked with the amount of substrate
employed, as no pre-stirring time was required for optimal synthesis at quantities of < 0.20
mmol.
[
14] For a few selected classification charts about its properties within the context of green
solvents, see: (a) C. Jiménez-González, A. D. Curzons, D. J. C. Constable, V. L. Cunningham,
Clean Techn Environ Policy 7 (2005) 42–50; (b) B. W. Cue, J. Zhang, Green Chem. Lett. Rev. 2
(2009) 193-211.
[
15] Complex mixture of fluorinated products was formed and all attempts to isolate pure
product failed.
[
16] The utility of the CCl
3
group relates to its use as a CF - or COOH precursor, therefore
3
providing an alternative pathway to the preparation of C-5 trifluoromethylpyrazoles or
carboxylates. For a reported example on these transformations on pyrazoles, see: (a) H.
Hayashi, H. Sonoda, K. Goto, K. Fukumura, J. Naruse, H. Oikawa, T. Nagata, T. Shimaoka, T.
Yasutake, H. Umetani, T. Kitashima (Mitsui Chemicals, Inc.), US Pat. 6 417 361, 2002; (b) S.
Pazenok, N. Lui, H. Blaschke (Bayer CropScience AG), WO 112 178, 2010; (c) S. Pazenok, N. Lui
(Bayer CropScience AG), WO 009 551, 2011.