A new synthesis and process development of bis(fluoroalkyl)pyrazoles as novel agrophores

Article abstract of DOI:10.1021/op500102h

The synthesis of 3,5-bis(fluoroalkyl)-pyrazoles as novel agrophores is described. Commercially available fluoroacetoacetates are treated with BF ₃-activated TFEDMA affording in a straightforward one-pot sequence pyrazole carboxylates in good yields and with excellent regioselectivity. The carboxylate intermediates have been converted into the corresponding pyrazolic acids and submitted to decarboxylation, affording valuable building blocks for the design of novel bioactive ingredients. The found process is suitable for scale up and preparation of compounds in kilogram quantity.

Full text of DOI:10.1021/op500102h

Article
pubs.acs.org/OPRD
A New Synthesis and Process Development of
Bis(fluoroalkyl)pyrazoles As Novel Agrophores
Florence Giornal,† Gregory Landelle,† Norbert Lui,‡ Jean-Pierre Vors,§ Sergiy Pazenok,‡
́
and Frederic R. Leroux*,†
́
́
†CNRS-Universite
́
de Strasbourg, UMR 7509, SynCat, 25 Rue Becquerel, 67087 Strasbourg Cedex 02, France
‡Bayer CropScience AG, Alfred-Nobel-Strasse 50, 40789 Monheim, Germany
§Bayer S.A.S, 14 Impasse Pierre Baizet, BP99163, 69263 Lyon Cedex 09, France
S
* Supporting Information
ABSTRACT: The synthesis of 3,5-bis(fluoroalkyl)-pyrazoles as novel agrophores is described. Commercially available
fluoroacetoacetates are treated with BF3-activated TFEDMA affording in a straightforward one-pot sequence pyrazole
carboxylates in good yields and with excellent regioselectivity. The carboxylate intermediates have been converted into the
corresponding pyrazolic acids and submitted to decarboxylation, affording valuable building blocks for the design of novel
bioactive ingredients. The found process is suitable for scale up and preparation of compounds in kilogram quantity.
of one haloalkyl substituent has only poorly been developed:
only two references can be found in the literature. Indeed, the
resulting products are generally very volatile, thus very difficult
to isolate. 5-Methyl-1-phenyl-3-(trifluoromethyl)-1H-pyrazole-
4-carboxylic acid was transformed into 5-methyl-1-phenyl-3-
trifluoromethyl pyrazole by reaction with copper powder in
quinoline,11 but the yield merely reached 32%. Maggio et al.
described the decarboxylation of 5-amino-1-phenyl-3-(trifluor-
omethyl)-1H-pyrazole-4-carboxylic acid by heating it neat at its
melting point for 1 h with a low yield of 30%.12 No method was
reported for the decarboxylation of a 4-pyrazole carboxylic acids
bearing more than one haloalkyl substituent. Guillou et al.
describe a copper-catalyzed protodecarboxylation on pyrazoles
using Cu2O in the presence of 1,10-phenanthroline and cesium
carbonate.13 The reaction is carried out in DMF and under
harsh conditions (microwave irradiation for 2 h at 200 °C).
Metal-catalyzed protodecarboxylation reactions are described
by Goossen et al. using copper and silver catalysts.14 These
reactions have been performed on aromatic and heteroaromatic
carboxylic acids; however, no substrates having bis(haloalkyl)-
substituents have been reported as they could significantly
influence the reaction in a negative way.
Herein we report a scalable and operationally convenient
method that does not have the aforementioned disadvantages
and hence provides a route for the regioselective preparation of
3,5-bis(fluoroalkyl)pyrazoles. Starting from commercially avail-
able fluoroacetoacetates and by using TFEDMA as a
convenient (CF2H)C-transfer reagent, a straightforward one-
pot sequence affords highly substituted pyrazoles in good yields
and excellent regioselectivity (>97:3). Furthermore, these
carboxylate intermediates have been converted into the
INTRODUCTION
■
Fluorine introduction into lead structures allows optimizing the
physicochemical and biological properties of agricultural
products.1 A significant increase of the number of fluorinated
active ingredients has been observed over the last decades,2 and
a recent survey estimated that as many as 18% of the pesticides
on the market were fluorinated compounds.3 Among the vast
array of fluorine-containing functionalities the synthesis of
fluoroalkyl pyrazoles has attracted considerable interest during
the last decades.4 Indeed, their potential enhanced biological
properties make them very attractive for the preparation of
pharmaceutical and agrochemical ingredients. In particular, 3,5-
bis(haloalkyl)pyrazole derivatives,5 polyfluoroalkyl pyrazolyl
carboxylic acid derivatives and 3,5-bis(fluoroalkyl)pyrazoles
are important building blocks for the preparation of crop
protection chemicals.6
Nevertheless, the preparation of pyrazoles bearing two
fluorinated groups remains scarcely depicted in the literatu-
re.5n,7
Pyrazole carboxylic acid derivatives are typically prepared by
reacting acrylic acid derivatives having two leaving groups with
hydrazines.8 In turn, 2,2-dihaloacyl-3-aminoacrylic esters can be
obtained by reacting acid halides with dialkylaminoacrylic
esters.9 3-Dihalomethylpyrazole-4-carboxylic acid derivatives
are obtained when α,α-difluoroamines are reacted in the
presence of Lewis acids with acrylic acid derivatives and
subsequent reaction with alkyl hydrazines.10
3,5-Bis(fluoroalkyl)pyrazoles are prepared by reacting
bisperfluoroalkyl diketones (e.g., 1,1,1,5,5,5-hexafluoroacetyla-
cetone) with hydrazines, the yields being only 27−40%.7a The
synthesis, isolation and purification of the polyfluoroalkyl
diketones are very complex since the compounds are generally
very volatile and highly toxic.
Special Issue: Fluorine Chemistry 14
Received: March 24, 2014
Another access towards 3,5-bis(fluoroalkyl)pyrazoles might
be based on the decarboxylation reactions of 4-pyrazole
carboxylic acids. However, this kind of reaction in the presence
© XXXX American Chemical Society
A
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Scheme 1. Utilization of FAR for the synthesis of a key intermediate (3) of Bixafen
corresponding pyrazolic acids, valuable building blocks for the
design of novel bioactive ingredients.
Table 1. Reaction of activated TFEDMA with β-keto esters
and hydrazines
RESULTS AND DISCUSSION
■
Synthesis of Bis(perfluoroalkyl)pyrazole Carboxy-
lates. α,α-Fluoroalkyl amino reagents (FAR) have been so
far employed for the selective fluorination of alcohols and
activated carbonyls.15 Tetrafluoroethyl dimethylamine (TFED-
MA, 1), prepared at low cost from tetrafluoroethylene and thus
a reagent of choice for industrial applications, reacts as a
difluoroacetyl-transfer reagent after activation with a Lewis
acid.16 Some of us showed its use in the preparation of
difluoromethyl pyrazoles. Activation with BF3−OEt2 followed
by reaction with dimethylamino acrylate afforded the
intermediate 2 which undergoes cyclization with methyl
hydrazine towards mono(fluoroalkyl)pyrazole 3 in a 92:8
regioselectivity (Scheme 1).10
a
entry
Rf
R
cmpd
yield (%)
1
CF3
CH3
H
4a
73
75
67
53
69
56
43
30
75
67
85
33
72
72
53
b
2
4b
3
Ph
4c
c
4
tBu
CH3
H
4d
5
CF2H
C2F5
4e
b
6
4f
7
Ph
4g
c
8
tBu
CH3
H
4h
During the present process research and development study,
TFEDMA (1) was activated with one equivalent of BF3(OEt2)
in dichloromethane or acetonitrile at 20 °C affording an
intermediate iminium salt A, which has been submitted to the
reaction with various β-keto esters. When ethyl trifluoroace-
toacetate was added in the presence of pyridine as organic base,
the desired 3-(difluoromethyl)-5-(trifluoromethyl)pyrazole 4a
was obtained in a fair 63% yield. In contrast, inorganic bases
such as Cs2CO3 and KF led to no reaction or very poor yields.
The addition of azaphilic Lewis acids like iron(III), titanium-
(IV) and copper(II) chlorides, ytterbium(III) and copper(II)
triflates showed no beneficial influence on the outcome of the
reaction.
Various commercially available ethyl difluoro-, trifluoro- and
pentafluoroethyl acetoacetates, as well as ethyl chlorodifluor-
oacetoacetate, synthesized by Claisen condensation,17 were
submitted to the reaction with activated TFEDMA and cyclized
with different hydrazines (Table 1).18
Moderate to good yields were obtained for 3,5-bis-
(fluoroalkyl)pyrazoles 4a−o depending on the fluoroalkyl
group at the β-keto ester and the hydrazine. Ethyl
trifluoroacetoacetate led to yields ranging between 53% and
75%. In all cases 3,5-bis(fluoroalkyl)pyrazoles 4 were formed as
single regioisomers.
9
4i
b
10
11
12
13
14
15
4j
Ph
4k
c
tBu
CH3
H
4l
CF2Cl
4m
b
4n
Ph
4o
a
b
Isolated yield. Hydrazine hydrate was used for the cyclo-
c
condensation step. tBuNHNH2·HCl was used for the cyclo-
condensation step.
aqueous sodium hydroxide in ethanol at 20 °C. These
conditions provided the desired carboxylic acids in very high
yields (Table 2). All saponification yields were almost
quantitative, and all the obtained products are crystalline and
did not need any further purification, which makes this method
very practical and adaptable to scale-up.
In spite of numerous efforts, the saponification of the free N-
H pyrazoles (4b, 4f, 4j, 4n) did not occur, and in every case the
starting material was completely recovered. Therefore, tert-
butyl pyrazoles were employed as an access towards the desired
free NH-derivatives, since the N-tBu group can be readily
deprotected under strong acidic conditions. Developing an
access to 3,5-difluoroalkyl pyrazoles having a free nitrogen atom
is a very important aspect as this provides further options for
functionalisation of the pyrazole nitrogen on demand.
Saponification of Bis(perfluoroalkyl)pyrazole Carbox-
ylates. The saponification of the ester group in these products
would allow access to attractive difluoromethyl pyrazole-
carboxamides. Thus, the carboxyesters 4 were reacted with
B
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Table 2. Saponification of 3,5-bis(fluoroalkyl)pyrazoles 4
Scheme 2. Access to N-H pyrazoles
a
entry
Rf
R
cmpd
yield (%)
1
CF3
CH3
Ph
5a
5c
5d
5e
5g
5h
5i
98
94
94
97
98
97
97
98
99
80
99
CONCLUSION
■
2
We developed and optimized a scalable route for the synthesis
of unsymmetrical 3,5-bis(fluoroalkyl)-pyrazoles. Our process
utilizes commercially available β-keto esters and hydrazines
using TFEDMA as a (CF2H)C transfer reagent. Experiments
have been done even in 100 g quantity without any scale up
problems related to exothermicity or stirring problems. This
robust and operationally convenient process is therefore
suitable for scalability. An important class of pyrazole-
carboxamides after optimized saponification conditions starting
from pyrazolic acids becomes accessible. The decarboxylation
leads then to 4-unsubstituted and thus functionalizable pyrazole
scaffolds as promising agrophores.
3
tBu
CH3
Ph
4
CF2H
C2F5
5
6
tBu
CH3
Ph
7
8
5k
5l
9
tBu
CH3
Ph
10
11
CF2Cl
5m
5o
a
Isolated yield.
Decarboxylation of Bis(perfluoroalkyl)pyrazole Car-
EXPERIMENTAL SECTION
■
boxylic Acids. The obtention of the free 4-position could lead
to worthwhile synthons functionalizable by means of
halogenation reactions19 or organometallic reagents.20 How-
ever, the decarboxylation of these compounds, expected to
occur readily due to the presence of two electron-withdrawing
groups in the pyrazole moiety, revealed being a challenging
task. After numerous unsuccessful attempts employing classical
methods such as heating to its melting point, Krapcho
conditions and use of transition metals, the decarboxylation
was performed with a copper(I) oxide/phenanthroline catalytic
system in NMP/quinoline (3:1) as solvent, as recently reported
by Goossen et al.21 The pyrazolic acids were stirred in this
solvent mixture with 5 mol % of Cu2O and 10 mol % of
phenanthroline at 160 °C for 14 h. The above approach finally
offers an efficient way to obtain the desired products in
moderate to good yields (Table 3).22
General. All air- and moisture-sensitive manipulations were
conducted under inert gas atmosphere. All substrates, reagents,
and solvents were used from suppliers without further
purification. In some samples, all the solvent could not be
removed due to volatility issues. In those cases, yields have been
calculated according to NMR ratios.
General Procedure for the Preparation of Pyrazole
Carboxylates 4a−o. BF3(OEt2) (0.1 mol, 1 equiv) was added
to a solution of TFEDMA (0.1 mol, 1 equiv) in dry CH2Cl2
(100 mL) under argon in a Teflon flask. The solution was
stirred for 15 min at 20 °C, and CH2Cl2 was removed under
reduced pressure. The solid was taken up in dry CH3CN (150
mL). In another Teflon flask, the fluoroacetoacetate (0.1 mmol,
1 equiv) was added to a solution of pyridine (0,3 mol, 3 equiv)
in dry CH3CN (100 mL) and stirred at 20 °C for 15 min. At
−30 °C, the content of the first flask was added dropwise, and
the reaction mixture was stirred at −30 °C for 2 h and allowed
to reach 20 °C over 14 h. The desired hydrazine (0.15 mol, 1.5
equiv) was added dropwise at 20 °C, and the reaction mixture
was stirred for 12 h at 30 °C. The solution was concentrated
under reduced pressure and taken up in methyl tert-butylether
(200 mL). The organic phase was washed with HCl 1 M (3 ×
50 mL) and brine (50 mL), dried over sodium sulfate, and
evaporated at atmospheric pressure. The crude material was
purified by crystallization from a toluene/methylcyclohexane
mixture or by column chromatography (pentane/Et2O
mixture) on silica gel to afford the expected 3,5-bis-
(fluoroalkyl)pyrazole carboxylate.
Product 5l was deprotected during decarboxylation, but the
other free N-H-pyrazoles can be obtained by deprotection of
the tert-butyl derivative, as exemplified for 6d. Heating to reflux
in TFA for 14 h in the presence of anisole afforded the desired
compound 7a (Scheme 2).
Table 3. Decarboxylation of 3,5-bis(fluoroalkyl)pyrazoles 5
a
entry
Rf
R
cmpd
yield (%)
Ethyl 1-Methyl-3-difluoromethyl-5-trifluoromethyl-1H-
pyrazole-4-carboxylate (4a). Yellow oil; 73%; 1H NMR
1
2
3
4
5
6
7
8
9
CF3
CH3
Ph
6a
6c
6d
6e
6g
6h
6i
50
84
83
78
87
64
63
88
2
(CDCl3, 300 MHz, 25 °C): δ = 7.00 (t, JH−F = 54 Hz, 1H,
CHF2), 4.37 (q, J = 7.2 Hz, 2H, CH2), 4.12 (s, 3H, N−CH3),
tBu
CH3
Ph
1.37 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (CDCl3, 75 MHz, 25
CF2H
C2F5
2
°C): δ = 160.2 (CO), 145.7 (t, JC−F = 25.6 Hz, CIVarom),
133.2 (q, 2JC−F = 40.3 Hz, CIVarom), 119.0 (q, JC−F = 271.2 Hz,
CF3), 114.4 (CIVarom), 109.0 (t, JC−F = 237.9 Hz, CHF2), 61.9
tBu
CH3
Ph
4
(CH2), 40.8 (q, JC−F = 3.2 Hz, N−CH3), 13.8 (CH3) ; 19F
6k
6l
b
NMR (CDCl3, 282 MHz, 25 °C): δ = −57.6 (CF3), −116.4
(CHF2) ; elemental analysis: calcd (%) C 39.72, H 3.33, N
10.29; found C 39.03, H 3.33, N 10.26.
tBu
46
a
b
Isolated yield. Yield for the isolated N-H pyrazole.
C
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Ethyl 3-Difluoromethyl-5-trifluoromethyl-1H-pyrazole-4-
carboxylate (4b). Colorless solid; 75%; mp 63−64 °C; H
Ethyl 1-Phenyl-3,5-bis(difluoromethyl)-1H-pyrazole-4-car-
boxylate (4g). Colorless solid; 43%; mp 54−55 °C; H NMR
1
1
(CDCl3, 300 MHz, 25 °C): δ = 7.57−7.51 (m, 5H, N-Ph), 7.44
(t, JH−F = 52.5 Hz, 1H, CHF2), 7.13 (t, JH−F = 53.7 Hz, 1H,
CHF2), 4.43 (q, J = 7.1 Hz, 2H, CH2), 1.43 (t, J = 7.1 Hz, 3H,
CH3) ; 13C NMR (CDCl3, 75 MHz, 25 °C): δ = 161.2 (CO),
NMR (CDCl3, 300 MHz, 25 °C): δ = 11.07 (br s, 1H, NH),
7.22 (t, JH−F = 53.5 Hz, 1H, CHF2), 4.39 (q, J = 6.9 Hz, 2H,
CH2), 1.38 (t, J = 6.9 Hz, 3H, CH3) ; 13C NMR (CDCl3, 75
2
MHz, 25 °C): δ = 160.4 (CO), 142.2 (t, JC−F = 18.3 Hz,
2
CIVarom), 142.2 (q, 2JC−F = 32.0 Hz, CIVarom), 119.7 (q, JC−F
=
146.6 (t, JC−F = 25.3 Hz, CIVarom), 139.0 (N−CIV Phenyl),
138.9 (t, 2JC−F = 24.8 Hz, CIVarom), 130.1 (CH Phenyl), 129.1
(CH Phenyl), 125.9 (CH Phenyl), 113.8 (CIVarom), 109.4 (t,
268.1 Hz, CF3), 111.7 (CIVarom), 107.4 (t, JC−F = 237.5 Hz,
CHF2), 62.0 (CH2), 13.7 (CH3) ; 19F NMR (CDCl3, 282 MHz,
25 °C): δ = −62.5 (CF3), −117.1 (d, JF−H = 53.5 Hz, CHF2) ;
elemental analysis: calcd (%) C 37.22, H 2.73, N 10.85; found
C 37.27, H 2.91, N 10.61.
J
C−F = 238.2 Hz, CF2H), 106.9 (t, JC−F = 238.4 Hz, CHF2), 61.8
(CH2), 14.0 (CH3) ; 19F NMR (CDCl3, 282 MHz, 25 °C): δ =
−114.3 (d, JF−H = 52.5 Hz, CHF2), −117.7 (d, JF−H = 53.7 Hz,
CHF2) ; HRMS (ESI positive) for C14H12F4N2NaO2 [M +
Na]: calcd339.073; found 339.075.
Ethyl 1-Phenyl-3-difluoromethyl-5-trifluoromethyl-1H-pyr-
azole-4-carboxylate (4c). Colorless solid; 67%; mp 58−59 °C;
1H NMR (CDCl3, 300 MHz, 25 °C): δ = 7.55−7.42 (m, 5H,
N-Ph), 7.05 (t, JH−F = 53.7 Hz, 1H, CHF2), 4.42 (q, J = 7.1 Hz,
2H, CH2), 1.40 (t, J = 7.1 Hz, 3H, CH3) ; 13C NMR (CDCl3,
Ethyl 1-tert-Butyl-3,5-bis(difluoromethyl)-1H-pyrazole-4-
1
carboxylate (4h). Orange oil; 30%; H NMR (CDCl3, 300
MHz, 25 °C): δ = 7.71 (t, JH−F = 52.9 Hz, 1H, CHF2), 6.97 (t,
J
H−F = 54.0 Hz, 1H, CHF2), 4.37 (q, J = 7.1 Hz, 2H, CH2), 1.71
2
75 MHz, 25 °C): δ = 160.3 (CO), 146.7 (t, JC−F = 26.2 Hz,
(s, 9H, tBu), 1.39 (t, J = 7.1 Hz, 3H, CH3) ; 13C NMR (CDCl3,
2
CIVarom), 138.8 (N−CIV Phenyl), 133.8 (q, JC−F = 40.1 Hz,
2
75 MHz, 25 °C): δ = 161.9 (CO), 143.4 (t, JC−F = 25.5 Hz,
CIVarom), 137.9 (t, JC−F = 24.8 Hz, CIVarom), 114.5
2
CIVarom), 130.4 (CH Phenyl), 129.3 (CH Phenyl), 125.9 (CH
Phenyl), 118.6 (q, JC−F = 271.9 Hz, CF3), 115.0 (CIVarom),
109.2 (t, JC−F = 238.4 Hz, CHF2), 62.0 (CH2), 13.8 (CH3) ; 19F
NMR (CDCl3, 282 MHz, 25 °C): δ = −56.8 (CF3), −117.3
(CHF2) ; elemental analysis: calcd (%) C 50.31, H 3.32, N
8.38; found C 50.34, H 3.40, N 8.51.
(CIVarom), 109.9 (t, JC−F = 237.3 Hz, CHF2), 106.8 (t, JC−F
= 238.3 Hz, CHF2), 65.3 (N−CIV tBu), 61.5 (CH2), 30.0 (t,
5JC−F = 3.4 Hz, tBu CH3), 14.0 (CH3) ; 19F NMR (CDCl3, 282
MHz, 25 °C): δ = −111.5 (CHF2), −116.0 (CHF2) ; HRMS
(ESI positive) for C12H16F4N2NaO2 [M + Na]: calcd 319.104;
found 319.104.
Ethyl 1-tert-Butyl-3-difluoromethyl-5-trifluoromethyl-1H-
pyrazole-4-carboxylate (4d). Yellow oil; 53%; 1H NMR
(CDCl3, 300 MHz, 25 °C): δ = 6.80 (t, JH−F = 54.0 Hz, 1H,
CHF2), 4.37 (q, J = 7.1 Hz, 2H, CH2), 1.70 (s, 9H, tBu), 1.36
(t, J = 7.1 Hz, 3H, CH3) ; 13C NMR (CDCl3, 75 MHz, 25 °C):
δ = 161.5 (CO), 141.9 (t, 2JC−F = 27.8 Hz, CIVarom), 131.5 (q,
2JC−F = 40.6 Hz, CIVarom), 119.3 (q, JC−F = 270.7 Hz, CF3),
116.9 (CIVarom), 109.9 (t, JC−F = 236.7 Hz, CHF2), 66.0 (N−
Ethyl 1-Methyl-3-difluoromethyl-5-pentafluoroethyl-1H-
pyrazole-4-carboxylate (4i). Colorless oil; 75%; 1H NMR
2
(CDCl3, 300 MHz, 25 °C): δ = 7.00 (t, JH−F = 53.9 Hz, 1H,
CHF2), 4.35 (q, J = 7.1 Hz, 2H, CH2), 4.10 (t, 5JH−F = 2.2 Hz,
3H, N−CH3), 1.35 (t, J = 7.1 Hz, 3H, CH3) ; 13C NMR
2
(CDCl3, 75 MHz, 25 °C): δ = 160.2 (CO), 146.1 (t, JC−F
=
2
25.6 Hz, CIVarom), 131.1 (t, JC−F = 29.6 Hz, CIVarom), 118.6
(qt, JC−F = 287.1 Hz, JC−F = 37.7 Hz, CF2CF3), 116.3
(CIVarom), 109.98 (tq, JC−F = 192.0 Hz, JC−F = 41.7 Hz,
1
2
5
CIV tBu), 62.0 (CH2), 29.9 (q, JC−F = 2.4 Hz, tBu CH3), 13.8
1
2
(CH3) ; 19F NMR (CDCl3, 282 MHz, 25 °C): δ = −53.3
(CF3), −114.4 (d, JF−H = 54.0 Hz, CHF2) ; HRMS (ESI
positive) for C12H15F5N2NaO2 [M + Na]: calcd 337.095; found
337.097.
CF2CF3), 109.1 (t, JC−F = 238.1 Hz, CHF2), 61.9 (CH2), 41.0
4
(t, JC−F = 4.3 Hz, N−CH3), 13.8 (CH3) ; 19F NMR (CDCl3,
282 MHz, 25 °C): δ = −83.7 (CF2CF3), −109.5 (CF2CF3),
−116.8 (d, JF−H = 53.9 Hz, CHF2) ; HRMS (ESI positive) for
C10H9F7N2NaO2 [M + Na]: calcd345.044; found 345.046.
Ethyl 3-Difluoromethyl-5-pentafluoroethyl-1H-pyrazole-4-
Ethyl 1-Methyl-3,5-bis(difluoromethyl)-1H-pyrazole-4-car-
1
boxylate (4e). Colorless solid; 69%; mp 53−54 °C; H NMR
(CDCl3, 300 MHz, 25 °C): δ = 7.48 (t, JH−F = 52.6 Hz, 1H,
CHF2), 7.04 (t, JH−F = 53.8 Hz, 1H, CHF2), 4.38 (q, J = 7.1 Hz,
2H, CH2), 4.12 (s, 3H, N−CH3), 1.39 (t, J = 7.2 Hz, 3H, CH3)
1
carboxylate (4j). Colorless oil; 67%; H NMR (CDCl3, 300
MHz, 25 °C): δ = 12.69 (br s, 1H, N−H), 7.26 (t, JH−F = 53.5
Hz, 1H, CHF2), 4.40 (q, J = 7.1 Hz, 2H, CH2), 1.39 (t, J = 7.1
Hz, 3H, CH3) ; 13C NMR (CDCl3, 75 MHz, 25 °C): δ = 160.6
;
13C NMR (CDCl3, 75 MHz, 25 °C): δ = 161.1 (CO), 145.3
2
2
(t, JC−F = 24.9 Hz, CIVarom), 138.2 (t, JC−F = 24.1 Hz,
CIVarom), 112.9 (m, CIVarom), 109.1 (t, JC−F = 237.6 Hz,
CHF2), 107.2 (t, JC−F = 236.3 Hz, CHF2), 61.5 (CH2), 39.6 (t,
4JC−F = 3.1 Hz, N−CH3), 13.9 (CH3) ; 19F NMR (CDCl3, 282
MHz, 25 °C): δ = −117.00 (d, JF−H = 53.8 Hz, CHF2),
−117.04 (d, JF−H = 52.6 Hz, CHF2) ; elemental analysis: calcd
(%) C 42.53, H 3.97, N 11.02; found C 42.50, H 4.05, N 11.18.
Ethyl 3,5-Bis(difluoromethyl)-1H-pyrazole-4-carboxylate
2
2
(CO), 141.8 (t, JC−F = 25.9 Hz, CIVarom), 141.1 (t, JC−F
=
1
2
31.7 Hz, CIVarom), 118.7 (qt, JC−F = 286.6 Hz, JC−F = 36.3
1
Hz, CF2CF3), 113.2 (CIVarom), 110.1 (tq, JC−F = 252.9 Hz,
2JC−F = 39.5 Hz, CF2CF3), 107.5 (t, JC−F = 238.8 Hz, CHF2),
62.0 (CH2), 13.6 (CH3) ; 19F NMR (CDCl3, 282 MHz, 25
°C): δ = −83.2 (CF2CF3), −110.1 (CF2CF3), −117.2 (d, JF−H
= 53.5 Hz, CHF2) ; HRMS (ESI positive) for C9H7F7N2NaO2
[M + Na]: calcd 331.029; found 331.031.
1
(4f). Colorless solid; 56%; mp 88−89 °C; H NMR (CDCl3,
Ethyl 1-Phenyl-3-difluoromethyl-5-pentafluoroethyl-1H-
300 MHz, 25 °C): δ = 7.15 (t, JH−F = 53.6 Hz, 2H, CHF2), 4.39
(q, J = 7.1 Hz, 2H, CH2), 1.39 (t, J = 7.1 Hz, 3H, CH3) ; 13C
NMR (CDCl3, 75 MHz, 25 °C): δ = 161.1 (CO), 143.8 (t,
pyrazole-4-carboxylate (4k). Beige solid; 85%; mp 93−94
1
°C; H NMR (CDCl3, 300 MHz, 25 °C): δ = 7.58−7.35 (m,
5H, N-Ph), 7.04 (t, JH−F = 53.8 Hz, 1H, CHF2), 4.40 (q, J = 7.1
2JC−F = 23.1 Hz, CIVarom), 111.6 (CIVarom), 108.2 (t, JC−F
=
Hz, 2H, CH2), 1.38 (t, J = 7.2 Hz, 3H, CH3) ; 13C NMR
238.4 Hz, CHF2), 61.7 (CH2), 13.9 (CH3) ; 19F NMR (CDCl3,
282 MHz, 25 °C): δ = −117.3 (d, JF−H = 53.6 Hz, CHF2) ;
HRMS (ESI positive) for C8H8F4N2NaO2 [M + Na]: calcd
263.041; found 263.043.
2
(CDCl3, 75 MHz, 25 °C): δ = 165.8 (CO), 147.6 (t, JC−F
=
=
2
25.8 Hz, CIVarom), 138.7 (N−CIV Phenyl), 135.1 (q, JC−F
40.4 Hz, CIVarom), 130.6 (CH Phenyl), 129.4 (CH Phenyl),
1
2
125.9 (CH Phenyl), 118.4 (qt, JC−F = 287.5 Hz, JC−F = 37.5
D
dx.doi.org/10.1021/op500102h | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
1
Hz, CF2CF3), 116.4 (CIVarom), 109.6 (tq, JC−F = 255.3 Hz,
reaction. The solvents were evaporated, and the crude solid
obtained was taken up in water (10 mL). The aqueous layer
was extracted with Et2O (10 mL) and acidified to pH = 1 with
1 M HCl before being extracted with ethyl acetate (3 × 10
mL). The combined organic layers were dried over Na2SO4 and
evaporated under reduced pressure to afford pure pyrazole-4-
carboxylic acid 5.
2JC−F = 41.6 Hz, CF2CF3), 109.4 (t, JC−F = 238.6 Hz, CHF2),
62.1 (CH2), 13.7 (CH3) ; 19F NMR (CDCl3, 282 MHz, 25
°C): δ = −83.6 (CF2CF3), −107.1 (CF2CF3), −117.3 (CHF2) ;
elemental analysis: calcd (%) C 46.88, H 2.88, N 7.29; found
(%) C 46.84, H 3.00, N 7.11.
Ethyl 1-tert-Butyl-3-difluoromethyl-5-pentafluoroethyl-
1H-pyrazole-4-carboxylate (4l). Colorless oil; 33%; H NMR
1
1-Methyl-3-difluoromethyl-5-trifluoromethyl-1H-pyrazole-
4-carboxylic Acid (5a). Yellow solid; 98%; mp 116−117 °C;
1H NMR (CDCl3, 300 MHz, 25 °C): δ = 7.08 (t, JH−F = 53.5
Hz, 1H, CHF2), 4.16 (s, 3H, N−CH3) ; 13C NMR (CDCl3, 75
(CDCl3, 300 MHz, 25 °C): δ = 6.83 (t, JH−F = 54.1 Hz, 1H,
CHF2), 4.35 (q, J = 7.1 Hz, 2H, CH2), 1.69 (s, 9H, tBu), 1.34
(t, J = 7.2 Hz, 3H, CH3) ; 13C NMR (CDCl3, 75 MHz, 25 °C):
δ = 161.2 (CO), 142.8 (t, 2JC−F = 27.3 Hz, CIVarom), 130.0 (q,
2
MHz, 25 °C): δ = 165.5 (CO), 146.7 (t, JC−F = 18.8 Hz,
2JC−F = 31.0 Hz, CIVarom), 118.6 (qt, 1JC−F = 287.8 Hz, 2JC−F
=
CIVarom), 134.4 (q, 2JC−F = 30.8 Hz, CIVarom), 118.8 (q, JC−F
=
1
38.3 Hz, CF2CF3), 118.5 (CIVarom), 110.8 (tq, JC−F = 258.1
202.5 Hz, CF3), 112.9 (CIVarom), 108.7 (t, JC−F = 177.0 Hz,
2
4
CHF2), 41.1 (q, JC−F = 2.3 Hz, N−CH3) ; 19F NMR (CDCl3,
Hz, JC−F = 41.0 Hz, CF2CF3), 110.0 (t, JC−F = 237.2 Hz,
CHF2), 67.6 (N−CIV tBu), 62.0 (CH2), 30.5 (t, 5JC−F = 3.6 Hz,
CH3 tBu), 13.7 (CH3) ; 19F NMR (CDCl3, 282 MHz, 25 °C):
δ = −80.7 (CF2CF3), −100.8 (CF2CF3), −115.5 (d, JF−H = 54.1
Hz, CHF2) ; HRMS (ESI positive) for C13H15F7N2NaO2 [M +
Na]: calcd 387.091; found 387.091.
282 MHz, 25 °C): δ = −57.9 (CF3), −117.3 (d, JF−H = 53.5 Hz,
CHF2) ; elemental analysis: calcd (%) C 34.44, H 2.06, N
11.48; found (%) C 34.44, H 2.19, N 11.13.
1-Phenyl-3-difluoromethyl-5-trifluoromethyl-1H-pyrazole-
4-carboxylic Acid (5c). Colorless solid; 94%; mp 154−155 °C;
1H NMR (CDCl3, 300 MHz, 25 °C): δ = 11.53 (br s, 1H,
COOH), 7.58−7.44 (m, 5H, N-Phenyl), 7.15 (t, JH−F = 53.5
Hz, 1H, CHF2) ; 13C NMR (CDCl3, 75 MHz, 25 °C): δ =
Ethyl 1-Methyl-3-difluoromethyl-5-chlorodifluoromethyl-
1H-pyrazole-4-carboxylate (4m). Colorless oil; 72%; 1H
NMR (CDCl3, 300 MHz, 25 °C): δ = 6.97 (t, JH−F = 53.9
Hz, 1H, CHF2), 4.37 (q, J = 7.1 Hz, 2H, CH2), 4.10 (t, 5JH−F
=
2
165.8 (CO), 147.6 (t, JC−F = 25.8 Hz, CIVarom), 138.7 (N−
2.2 Hz, 3H, N−CH3), 1.38 (t, J = 7.1 Hz, 3H, CH3) ; 13C NMR
2
CIV Phenyl), 135.1 (q, JC−F = 40.4 Hz, CIVarom), 130.6 (CH
2
(CDCl3, 75 MHz, 25 °C): δ = 160.3 (CO), 145.3 (t, JC−F
=
Phenyl), 129.4 (CH Phenyl), 125.9 (CH Phenyl), 118.4 (q,
2
25.7 Hz, CIVarom), 137.5 (t, JC−F = 33.3 Hz, CIVarom), 119.9
J
C−F = 272.3 Hz, CF3), 114.3 (CIVarom), 108.9 (t, JC−F = 239.0
(t, JC−F = 288.8 Hz, CF2Cl), 112.7 (CIVarom), 109.1 (t, JC−F
=
Hz, CHF2) ; 19F NMR (CDCl3, 282 MHz, 25 °C): δ = −56.8
(CF3), −117.8 (CHF2) ; elemental analysis: calcd (%) C 47.07,
H 2.30, N 9.15; found C 47.24, H 2.40, N 8.89.
4
237.8 Hz, CHF2), 61.8 (CH2), 40.6 (t, JC−F = 4.6 Hz, N−
CH3), 13.7 (CH3) ; 19F NMR (CDCl3, 282 MHz, 25 °C): δ =
−47.9 (CF2Cl), −116.7 (d, JF−H = 53.9 Hz, CHF2) ; HRMS
(ESI positive) for C9H9ClF4N2NaO2 [M + Na]: calcd 311.018;
found 311.018.
Ethyl 3-Difluoromethyl-5-chlorodifluoromethyl-1H-pyra-
zole-4-carboxylate (4n). Colorless solid; 72%; mp 78−79
°C; 1H NMR (CDCl3, 300 MHz, 25 °C): δ = 11.62 (br s, 1H,
NH), 7.25 (t, JH−F = 53.5 Hz, 2H, CHF2), 4.41 (q, J = 7.1 Hz,
2H, CH2), 1.41 (t, J = 7.1 Hz, 3H, CH3) ; 13C NMR (CDCl3,
75 MHz, 25 °C): δ = 160.6 (CO), 146.3 (t, JC−F = 32.3 Hz,
CIVarom), 142.7 (t, JC−F = 29.3 Hz, CHF2), 121.3 (t, JC−F
287.3 Hz, CF2Cl), 110.8 (CIVarom), 109.1 (t, JC−F = 240.2 Hz,
CHF2), 62.0 (CH2), 13.6 (CH3) ; 19F NMR (CDCl3, 282 MHz,
25 °C): δ = −49.6 (CF2Cl), −116.8 (d, JF−H = 53.5 Hz, CHF2)
; elemental analysis: calcd (%) C 35.00, H 2.57, N 10.20; found
C 35.22, H 2.67, N 9.95.
1-tert-Butyl-3-difluoromethyl-5-trifluoromethyl-1H-pyra-
zole-4-carboxylic Acid (5d). Yellow solid; 94%; mp 126−127
1
°C; H NMR (CDCl3, 300 MHz, 25 °C): δ = 6.92 (t, JH−F
=
53.8 Hz, 1H, CHF2), 1.74 (s, 9H, tBu) ; 13C NMR (CDCl3, 75
2
MHz, 25 °C): δ = 166.8 (CO), 142.9 (t, JC−F = 26.9 Hz,
CIVarom), 132.9 (q, 2JC−F = 41.1 Hz, CIVarom), 119.1 (q, JC−F
=
271.1 Hz, CF3), 115.1 (CIVarom), 109.5 (t, JC−F = 237.5 Hz,
CHF2), 66.7 (N−CIV tBu), 29.9 (q, 5JC−F = 2.5 Hz, CH3 tBu) ;
19F NMR (CDCl3, 282 MHz, 25 °C): δ = −54.0 (CF3), −116.0
(CHF2) ; HRMS (ESI negative) for C10H10F5N2O2 [M-H]:
calcd 285.066; found 285.067.
2
2
=
1-Methyl-3,5-bis(difluoromethyl)-1H-pyrazole-4-carbox-
ylic acid (5e). Colorless solid; 97%; mp 131−132 °C; 1H NMR
(CDCl3, 300 MHz, 25 °C): δ = 12.16 (br s, 1H, COOH), 7.48
(t, JH−F = 52.4 Hz, 1H, CHF2), 7.08 (t, JH−F = 53.6 Hz, 1H,
CHF2), 4.16 (s, 3H, N−CH3) ; 13C NMR (CDCl3, 75 MHz, 25
Ethyl 1-Phenyl-3-difluoromethyl-5-chlorodifluoromethyl-
1H-pyrazole-4-carboxylate (4o). Colorless solid; 53%; mp
70−71 °C; 1H NMR (CDCl3, 300 MHz, 25 °C): δ = 7.55−7.45
(m, 5H, N-Ph), 7.03 (t, JH−F = 53.7 Hz, 1H, CHF2), 4.42 (q, J =
2
°C): δ = 166.9 (CO), 146.4 (t, JC−F = 25.1 Hz, CIVarom),
139.2 (t, 2JC−F = 24.4 Hz, CIVarom), 111.5 (CIVarom), 108.8 (t,
7.1 Hz, 2H, CH2), 1.41 (t, J = 7.2 Hz, 3H, CH3) ; 13C NMR
J
C−F = 238.1 Hz, CHF2), 106.9 (t, JC−F = 237.0 Hz, CHF2), 39.9
(t, 4JC−F = 3.1 Hz, N−CH3) ; 19F NMR (CDCl3, 282 MHz, 25
2
(CDCl3, 75 MHz, 25 °C): δ = 160.5 (CO), 146.5 (t, JC−F
26.3 Hz, CIVarom), 138.9 (N−CIV Phenyl), 138.3 (t, JC−F
=
=
2
°C): δ = −117.1 (d, JF−H = 52.6 Hz, CHF2), −117.3 (d, JF−H
53.7 Hz, CHF2) ; elemental analysis: calcd (%) C 37.18, H
2.67, N 12.39; found C 37.19, H 2.84, N 12.00.
=
32.7 Hz, CIVarom), 130.3 (CH Phenyl), 129.2 (CH Phenyl),
126.2 (CH Phenyl), 119.5 (t, JC−F = 290.0 Hz, CF2Cl), 115.6
(CIVarom), 109.3 (t, JC−F = 238.4 Hz, CHF2), 62.0 (CH2), 13.9
(CH3) ; 19F NMR (CDCl3, 282 MHz, 25 °C): δ = −46.6
(CF2Cl), −117.3 (CHF2) ; elemental analysis: calcd (%) C
47.95, H 3.16, N 7.99; found (%) C 47.86, H 3.20, N 7.73.
General Procedure for the Saponification of Pyrazole
Carboxylates 4a−o. To a pyrazole-4-carboxylate 4 (1.8
mmol, 1 equiv) in ethanol (3 mL) was slowly added an 8 M
aqueous solution of NaOH (0.70 mL, 3 equiv). The reaction
mixture was stirred at 20 °C for 3 h until completion of the
1-Phenyl-3,5-bis(difluoromethyl)-1H-pyrazole-4-carboxylic
1
Acid (5g). Colorless solid; 98%; mp 169−170 °C; H NMR
(CDCl3, 300 MHz, 25 °C): δ = 7.59−7.49 (m, 5H, N-Phenyl),
7.43 (t, JH−F = 52.3 Hz, 1H, CHF2), 7.16 (t, JH−F = 53.5 Hz, 1H,
CHF2) ; 13C NMR (CDCl3, 75 MHz, 25 °C): δ = 166.3 (CO),
2
2
147.4 (t, JC−F = 25.5 Hz, CIVarom), 139.8 (t, JC−F = 24.9 Hz,
CIVarom), 138.8 (N−CIV Phenyl), 130.3 (CH Phenyl), 129.2
3
(CH Phenyl), 125.9 (CH Phenyl), 112.3 (t, JC−F = 3.5 Hz,
CIVarom), 109.0 (t, JC−F = 238.7 Hz, CHF2), 106.6 (t, JC−F
=
E
dx.doi.org/10.1021/op500102h | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
239.2 Hz, CHF2) ; 19F NMR (CDCl3, 282 MHz, 25 °C): δ =
−113.4 (CHF2), −117.0 (CHF2) ; elemental analysis: calcd
(%) C 50.01, H 2.80, N 9.72; found C 50.28, H 3.04, N 9.59.
1-tert-Butyl-3,5-bis(difluoromethyl)-1H-pyrazole-4-carbox-
CF2Cl), 111.15 (CIVarom), 108.8 (t, JC−F = 238.4 Hz, CHF2),
4
41.0 (t, JC−F = 4.9 Hz, N−CH3) ; 19F NMR (CDCl3, 282
MHz, 25 °C): δ = −48.1 (CF2Cl), −117.2 (d, JF−H = 53.6 Hz,
CHF2) ; elemental analysis: calcd (%) C 32.27, H 1.93, N
10.75; found C 32.53, H 2.13, N 10.38.
1
ylic Acid (5h). Pink solid; 97%; mp 159−160 °C; H NMR
(CDCl3, 300 MHz, 25 °C): δ = 7.72 (t, JH−F = 52.7 Hz, 1H,
CHF2), 7.06 (t, JH−F = 53.7 Hz, 1H, CHF2), 1.75 (s, 9H, tBu) ;
13C NMR (CDCl3, 75 MHz, 25 °C): δ = 167.3 (CO), 144.5 (t,
1-Phenyl-3-difluoromethyl-5-chlorodifluoromethyl-1H-
pyrazole-4-carboxylic Acid (5o). Colorless solid; 99%; mp
155−156 °C; 1H NMR (CDCl3, 300 MHz, 25 °C): δ = 7.57−
7.47 (m, 5H, N-Phenyl), 7.12 (t, JH−F = 53.5 Hz, 1H, CHF2) ;
13C NMR (CDCl3, 75 MHz, 25 °C): δ = 165.9 (CO), 147.4 (t,
2JC−F = 25.8 Hz, CIVarom), 139.8 (t, 2JC−F = 33.0 Hz, CIVarom),
138.9 (N−CIV Phenyl), 130.5 (CH Phenyl), 129.3 (CH
Phenyl), 126.2 (CH Phenyl), 119.2 (t, JC−F = 290.6 Hz,
CF2Cl), 112.1 (CIVarom), 108.9 (t, JC−F = 239.0 Hz, CHF2) ;
19F NMR (CDCl3, 282 MHz, 25 °C): δ = −46.9 (CF2Cl),
−117.8 (CHF2) ; elemental analysis: calcd (%) C 44.67, H
2.19, N 8.68; found C 44.83, H 2.34, N 8.32.
General Procedure for the Decarboxylation of
Pyrazole Carboxylic Acids 5. The carboxylic acid 5 (2.1 g,
8.6 mmol, 1 equiv), Cu2O (65 mg, 0.45 mmol, 5 mol %), and
1,10-phenanthroline hydrate (176 mg, 0.90 mmol, 10 mol %),
NMP (15 mL), quinoline (5 mL), and H2O (2 drops) were
heated at 160 °C for 14 h. The reaction mixture was then
diluted with Et2O (30 mL) and water (30 mL). The organic
layer was washed with 1 M HCl (4 × 30 mL) and brine (30
mL), and dried over Na2SO4, and the solvent was distilled off
through a Vigreux column at atmospheric pressure. The crude
material obtained was purified by distillation under reduced
pressure.
2
2JC−F = 25.3 Hz, CIVarom), 138.8 (q, JC−F = 25.1 Hz,
CIVarom), 113.0 (CIVarom), 109.4 (t, JC−F = 237.7 Hz, CF2H),
106.5 (t, JC−F = 238.8 Hz, CHF2), 65.9 (N−CIV tBu), 30.0 (t,
5JC−F = 3.5 Hz, CH3 tBu) ; 19F NMR (CDCl3, 282 MHz, 25
°C): δ = −112.5 (CHF2), −117.4 (CHF2) ; HRMS (ESI
negative) for C10H11F4N2O2 [M-H]: calcd 267.076; found
267.076.
1-Methyl-3-difluoromethyl-5-pentafluoroethyl-1H-pyra-
zole-4-carboxylic Acid (5i). Colorless solid; 97%; mp 138−139
°C; 1H NMR (CDCl3, 300 MHz, 25 °C): δ = 11.16 (br s, 1H,
5
COOH), 7.09 (t, JH−F = 53.6 Hz, 1H, CHF2), 4.15 (t, JH−F
=
2.4 Hz, 3H, N−CH3) ; 13C NMR (CDCl3, 75 MHz, 25 °C): δ
2
= 165.2 (CO), 147.2 (t, JC−F = 25.2 Hz, CIVarom), 132.5 (t,
2JC−F = 29.8 Hz, CIVarom), 118.5 (qt, 1JC−F = 287.0 Hz, 2JC−F
=
1
37.5 Hz, CF2CF3), 114.6 (CIVarom), 109.9 (tq, JC−F = 258.0
2
Hz, JC−F = 41.7 Hz, CF2CF3), 108.8 (t, JC−F = 238.6 Hz,
CHF2), 41.4 (t, JC−F = 4.8 Hz, N−CH3) ; 19F NMR (CDCl3,
4
282 MHz, 25 °C): δ = −83.2 (CF2CF3), −108.9 (CF2CF3),
−116.8 (d, JF−H = 53.6 Hz, CHF2) ; elemental analysis: calcd
(%) C 32.67, H 1.71, N 9.52; found C 32.82, H 1.86, N 9.30.
1-Phenyl-3-difluoromethyl-5-pentafluoroethyl-1H-pyra-
zole-4-carboxylic Acid (5k). Colorless solid; 98%; mp 187−
1-Methyl-3-difluoromethyl-5-trifluoromethyl-1H-pyrazole
1
1
(6a). Colorless liquid (bp = 45−46 °C, 27 mbar); 50%. H
188 °C; H NMR (CDCl3, 300 MHz, 25 °C): δ = 7.60−7.37
(m, 5H, N-Phenyl), 7.14 (t, JH−F = 53.6 Hz, 1H, CHF2) ; 13C
NMR (CD3OD, 75 MHz, 25 °C): δ = 164.0 (CO), 148.6 (t,
2JC−F = 25.6 Hz, CIVarom), 141.4 (N−CIV Phenyl), 133.4 (CH
NMR (CDCl3, 300 MHz, 25 °C): δ = 6.84 (s, 1H, Harom),
6.66 (t, 1H, JH−F = 55 Hz, CHF2), 4.02 (s, 3H, N−CH3) ppm.
2
13C NMR (CDCl3, 75 MHz, 25 °C): δ = 145.6 (t, JC−F = 30
2
2
Hz, CIVarom), 133.3 (q, JC−F = 39.6 Hz, CIVarom), 119.5 (q,
Phenyl), 133.1 (t, JC−F = 29.1 Hz, CIVarom), 131.7 (CH
Phenyl), 130.0 (CH Phenyl), 120.6 (qt, 1JC−F = 287.6 Hz, 2JC−F
= 37.9 Hz, CF2CF3), 120.1 (CIVarom), 112.3 (t, JC−F = 236.4
JC−F = 267.2 Hz, CF3), 110.3 (t, JC−F = 233.2 Hz, CHF2), 105.2
(q, 3JC−F = 2.0 Hz, CHarom), 38.3 (q, 4JC−F = 1.6 Hz, N−CH3)
ppm. 19F NMR (CDCl3, 282 MHz, 25 °C): δ = −61.5 (CF3),
−113.0 (CHF2) ppm. HRMS (ESI positive) for C6H6F5N2 [M
+ H]: calcd 201.045 found 201.045.
1
2
Hz, CHF2), 112.1 (tq, JC−F = 262.5 Hz, JC−F = 40.5 Hz,
CF2CF3) ; 19F NMR (CDCl3, 282 MHz, 25 °C): δ = −83.5
(CF2CF3), −107.1 (CF2CF3), −117.9 (CHF2) ; elemental
analysis: calcd (%) C 43.84, H 1.98, N 7.86; found C 44.02, H
2.10, N 7.62.
1-Methyl-3,5-bis(difluoromethyl)-1H-pyrazole (6e). Color-
less liquid (bp = 78−80 °C, 28 mbar); 78%. 1H NMR (CDCl3,
300 MHz, 25 °C): δ = 6.73 (t, 1H, CHF2, JH−F = 53.4 Hz), 6.69
(s, 1H, Harom), 6.66 (t, 1H, CHF2, JH−F = 54.9 Hz), 4.01 (s,
3H, N−CH3) ppm. 13C NMR (CDCl3, 75 MHz, 25 °C): δ =
1-tert-Butyl-3-difluoromethyl-5-pentafluoroethyl-1H-pyra-
zole-4-carboxylic Acid (5l). Yellow solid; 99%; mp 97−98 °C;
1H NMR (CDCl3, 300 MHz, 25 °C): δ = 11.4 (br s, 1H,
COOH), 7.01 (t, JH−F = 53.9 Hz, 1H, CHF2), 1.78 (s, 9H, tBu)
145.6 (t, CIVarom, 2JC−F = 30.0 Hz), 136.5 (t, CIVarom, 2JC−F
=
13C NMR (CDCl3, 75 MHz, 25 °C): δ = 166.5 (CO), 143.9
2 2
26.6 Hz), 110.6 (t, CHF2, JC−F = 234.1 Hz), 108.2 (t, CHF2,
;
J
C−F = 236.5 Hz), 104.7 (m, CHarom), 38.1 (s, N−CH3) ppm.
(t, JC−F = 26.3 Hz, CIVarom), 131.5 (q, JC−F = 31.0 Hz,
19F NMR (CDCl3, 282 MHz, 25 °C): δ = −112.5 (CHF2, JF−H
= 54.9 Hz), −113.7 (d, JF−H = 53.3 Hz, CHF2) ppm. HRMS
(ESI positive) for C6H7F4N2 [M + H]: calcd 183.054 found
183.055.
1
2
CIVarom), 120.0 (qt, JC−F = 288.1 Hz, JC−F = 38.1 Hz,
CF2CF3), 117.4 (CIVarom), 110.6 (tq, 1JC−F = 258.7 Hz, 2JC−F
=
41.2 Hz, CF2CF3), 109.5 (t, JC−F = 237.9 Hz, CHF2), 68.3 (N−
CIV tBu), 30.6 (t, 5JC−F = 3.7 Hz, CH3 tBu) ; 19F NMR (CDCl3,
282 MHz, 25 °C): δ = −80.3 (CF2CF3), −100.4 (CF2CF3),
−116.3 (d, JF−H = 53.9 Hz, CHF2) ; HRMS (ESI negative) for
C11H10F7N2O2 [M-H]: calcd 335.064; found 335.065.
1-Methyl-3-difluoromethyl-5-pentafluoroethyl-1H-pyra-
zole (6i). Colorless liquid (bp = 53−54 °C, 28 mbar); 63%. 1H
NMR (CDCl3, 300 MHz, 25 °C): δ = 6.84 (s, 1H, Harom),
6.67 (t, 1H, JH−F = 54.8 Hz, CHF2), 4.05 (s, 3H, N−CH3) ppm.
13C NMR (CDCl3, 75 MHz, 25 °C): δ = 146.0 (t, 2JC−F = 30.1
1-Methyl-3-difluoromethyl-5-chlorodifluoromethyl-1H-
pyrazole-4-carboxylic Acid (5m). Colorless solid; 80%; mp
1
2
111−112 °C; H NMR (CDCl3, 300 MHz, 25 °C): δ = 12.15
Hz, CIVarom), 131.2 (t, JC−F = 28.9 Hz, CIVarom), 118.5 (qt,
2
1JC−F = 285.7 Hz, JC−F = 37.3 Hz, CF2CF3), 110.2 (t, JC−F
=
(br s, 1H, COOH), 7.07 (t, JH−F = 53.6 Hz, 1H, CHF2), 4.15 (t,
5JH−F = 2.1 Hz, 3H, N−CH3) ; 13C NMR (CDCl3, 75 MHz, 25
234.8 Hz, CHF2), 109.8 (tq, 1JC−F = 252.7 Hz, 2JC−F = 40.6 Hz,
2
°C): δ = 165.8 (CO), 146.4 (t, JC−F = 25.3 Hz, CIVarom),
CF2CF3), 106.9 (br s, CHarom), 39.2 (br s, N−CH3) ppm. 19
F
138.9 (t, 2JC−F = 33.6 Hz, CIVarom), 119.6 (t, JC−F = 289.4 Hz,
NMR (CDCl3, 282 MHz, 25 °C): δ = −84.4 (CF2CF3), −111.1
F
dx.doi.org/10.1021/op500102h | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
(CF2CF3), −113.0 (d, JF−H = 54.8 Hz, CHF2) ppm. HRMS
(ESI positive) for C7H6F7N2 [M + H]: calcd 251.042; found
251.042.
(d, JF−H = 55.0 Hz, CHF2) ppm. HRMS (ESI positive) for
C9H13F4N2 [M + H]: calcd 225.102; found 225.101.
Protocol for the Deprotection of tert-Bu-N-pyrazoles
and Access to N-H-Pyrazoles. A mixture of 1-tert-butyl-1H-
pyrazole 6d (0.41 mmol, 1 equiv), anisole (0.13 g, 0.14 mL, 1.2
mmol, 3 equiv) and trifluoroacetic acid (2 mL) was stirred and
heated to 90 °C for 16 h. The reaction mixture was cooled to
20 °C and neutralised by the addition of a solution of sodium
hydroxide (8.4 g, 0.21 mol) in water (30 mL) until pH = 8. The
aqueous layer was extracted with diethyl ether (3 × 30 mL).
The combined organic layers were washed with brine (30 mL)
and dried over sodium sulfate, and the solvent was evaporated
under atmospheric pressure. The crude material was purified by
column chromatography on silica gel.
1-Phenyl-3-difluoromethyl-5-trifluoromethyl-1H-pyrazole
(6c). Colorless oil; 84%. 1H NMR (CDCl3, 300 MHz, 25 °C): δ
= 7.55−7.48 (m, 5H, phenylH), 7.07 (br s, 1H, Hpyrazole),
6.78 (t, 1H, JH−F = 54.6 Hz, CHF2) ppm. 13C NMR (CDCl3, 75
2
MHz, 25 °C): δ = 146.9 (t, JC−F = 30.5 Hz, CIVpyrazole),
2
138.4 (s, N−CIVphenyl), 134.2 (q, JC−F = 40.0 Hz,
CIVpyrazole), 130.0 (s, CHphenyl), 129.3 (s, CHphenyl),
125.7 (s, CHphenyl), 119.2 (q, JC−F = 269.4 Hz, CF3), 110.4 (t,
JC−F = 235.1 Hz, CHF2), 106.4 (br s, CHpyrazole) ppm. 19F
NMR (CDCl3, 282 MHz, 25 °C): δ = −58.4 (CF3), −112.9 (d,
JF−H = 54.6 Hz, CHF2) ppm. HRMS (ESI positive) for
C11H8F5N2 [M + H]: calcd 263.061; found 263.060.
3-Difluoromethyl-5-trifluoromethyl-1H-pyrazole (7a). Col-
orless solid, mp 72−73 °C; 76%. 1H NMR (CDCl3, 300 MHz,
25 °C): δ = 13.38 (br s, 1H, N−H), 6.84 (s, 1H, Harom), 6.79
(t, 1H, JH−F = 54.7 Hz, CHF2) ppm. 13C NMR (CDCl3, 75
MHz, 25 °C): δ = 141.1 (br s, CIVarom, C-1 and C-3), 120.1
(q, JC−F = 268.8 Hz, CF3), 108.3 (t, JC−F = 238.2 Hz, CHF2),
1-Phenyl-3,5-bis(difluoromethyl)-1H-pyrazole (6g). Color-
1
less oil; 87%. H NMR (CDCl3, 300 MHz, 25 °C): δ = 7.54−
7.46 (m, 5H, N-Phenyl), 6.97 (s, 1H, CHarom), 6.76 (t, 1H,
JH−F = 54.8 Hz, CHF2), 6.61 (t, 1H, JH−F = 53.4 Hz, CHF2)
ppm. 13C NMR (CDCl3, 75 MHz, 25 °C): δ = 147.4 (t, 2JC−F
=
=
3
103.6 (d, JC−F = 1.6 Hz, CHarom) ppm. 19F NMR (CDCl3,
2
30.2 Hz, CIVarom), 138.2 (N−CIV Phenyl), 137.8 (t, JC−F
282 MHz, 25 °C): δ = −62.3 (CF3), −114.2 (CHF2) ppm.
HRMS (ESI positive) for C5H4F5N2 [M + H]: calcd 187.029;
found 187.029.
30.3 Hz, CIVarom), 129.62 (CH Phenyl), 129.60 (CH Phenyl),
125.1 (CH Phenyl), 110.7 (t, JC−F = 234.8 Hz, CHF2), 107.9 (t,
JC−F = 236.6 Hz, CHF2), 104.8 (s, CHarom)ppm. 19F NMR
(CDCl3, 282 MHz, 25 °C): δ = −110.6 (CHF2), −112.2
(CHF2) ppm. HRMS (ESI positive) for C11H9F4N2 [M + H]:
calcd 245.070; found 245.070.
3-Difluoromethyl-5-pentafluoroethyl-1H-pyrazole (6l).
1
Colorless solid (bp = 63−65 °C, 55 mbar); 46%. H NMR
(CDCl3, 300 MHz, 25 °C): δ = 11.87 (br s, 1H, NH), 6.87 (br
s, 1H, Harom), 6.80 (t, 1H, JH−F = 54.7 Hz, CHF2) ppm. 13C
NMR (CDCl3, 75 MHz, 25 °C): δ = 141.5 (br s, CIVarom),
139.5 (br s, CIVarom), 118.4 (qt, 1JC−F = 285.4 Hz, 2JC−F = 37.3
1-Phenyl-3-difluoromethyl-5-pentafluoroethyl-1H-pyra-
1
zole (6k). Colorless oil; 88%. H NMR (CDCl3, 300 MHz, 25
°C): δ = 7.54−7.43 (m, 5H, phenylH), 7.03 (br s, 1H,
Hpyrazole), 6.76 (t, 1H, JH−F = 54.6 Hz, CHF2) ppm. 13C
NMR (CDCl3, 75 MHz, 25 °C): δ = 147.4 (t, 2JC−F = 30.4 Hz,
1
2
Hz, CF2CF3), 109.9 (tq, JC−F = 252.2 Hz, JC−F = 40.1 Hz,
CF2CF3), 108.4 (t, JC−F = 238.2 Hz, CHF2), 104.9 (br s,
CHpyrazole) ppm. 19F NMR (CDCl3, 282 MHz, 25 °C): δ =
−85.1 (CF2CF3), −113.5 (CF2CF3), −113.8 (d, JF−H = 54.7
Hz, CHF2) ppm. HRMS (ESI positive) for C6H4F7N2 [M +
H]: calcd 237.026 found 237.026.
2
CIVpyrazole), 139.1 (s, N−CIVphenyl), 132.4 (t, JC−F = 28.1
Hz, CIVpyrazole), 130.2 (s, CHphenyl), 129.1 (s, CHphenyl),
1
126.7 (s, CHphenyl), 118.5 (qt, JC−F = 286.3 Hz, 2JC−F = 36.8
Hz, CF2CF3), 110.4 (t, JC−F = 235.3 Hz, CHF2), 109.5 (tq,
2
1JC−F = 252.0 Hz, JC−F = 40.4 Hz, CF2CF3), 107.5 (br s,
CHpyrazole) ppm. 19F NMR (CDCl3, 282 MHz, 25 °C): δ =
−83.9 (CF2CF3), −107.1 (CF2CF3), −113.0 (d, JF−H = 54.6
Hz, CHF2) ppm. HRMS (ESI positive) for C12H8F7N2 [M +
H]: calcd 313.058; found 313.058.
ASSOCIATED CONTENT
* Supporting Information
Spectra of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
1-tert-Butyl-3-difluoromethyl-5-trifluoromethyl-1H-pyra-
zole (6d). Colorless liquid (bp = 68−69 °C, 32 mbar); 83%. 1H
NMR (CDCl3, 300 MHz, 25 °C): δ = 6.94 (br s, 1H, Harom),
6.68 (t, 1H, JH−F = 54.8 Hz, CHF2), 1.69 (s, 9H, CH3) ppm.
13C NMR (CDCl3, 75 MHz, 25 °C): δ = 143.5 (t, 2JC−F = 30.4
AUTHOR INFORMATION
Corresponding Author
*E-mail: frederic.leroux@unistra.fr.
Notes
■
2
Hz, CIVarom), 132.7 (q, JC−F = 40.1 Hz, CIVarom), 119.9 (q,
The authors declare no competing financial interest.
J
C−F = 268.9 Hz, CF3), 110.8 (t, JC−F = 233.9 Hz, CHF2), 108.0
(q, 3JC−F = 3.8 Hz, CHarom), 64.2 (s, CIVtBu), 29.8 (q, 5JC−F
=
ACKNOWLEDGMENTS
2.1 Hz, tBu CH3) ppm. 19F NMR (CDCl3, 282 MHz, 25 °C): δ
= = −55.6 (CF3), −112.3 (d, JF−H = 54.9 Hz, CHF2) ppm.
HRMS (ESI positive) for C9H12F5N2 [M + H]: calcd 243.092
found 243.094.
■
We thank the CNRS France and are very much grateful to
Bayer S.A.S. for giving grants to F.G. and G.L. The French
Fluorine Network (GIS Fluor) is also acknowledged.
1-tert-Butyl-3,5-bis(difluoromethyl)-1H-pyrazole (6h). Col-
orless liquid (bp = 90−91 °C, 24 mbar); 64%. H NMR
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