A new life for an old reagent: Fluoroalkyl amino reagents as efficient tools for the synthesis of diversely fluorinated pyrazoles

Article abstract of DOI:10.1002/ejoc.201300561

Herein we describe the first practical method for the regioselective preparation of 3,5-bis(fluoroalkyl)pyrazoles. Starting from commercially available fluoroacetoacetates and by using (tetrafluoroethyl)dimethylamine as a convenient CF₂H transfer reagent, this straightforward one-pot sequence affords highly substituted pyrazoles in good yields and excellent regioselectivity. Furthermore, these carboxylate intermediates were converted into the corresponding pyrazolic acids, which are valuable building blocks for the design of novel bioactive ingredients. Copyright

Full text of DOI:10.1002/ejoc.201300561

Job/Unit: O30561
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Pages: 6
SHORT COMMUNICATION
Organofluorine Compounds
S. Pazenok, F. Giornal, G. Landelle,
N. Lui, J.-P. Vors,
F. R. Leroux* .................................... 1–6
A New Life for an Old Reagent: Fluoro-
alkyl Amino Reagents as Efficient Tools for
the Synthesis of Diversely Fluorinated
Pyrazoles
FAR out! Unsymmetrical 3,5-bis(fluoro-
alkyl)pyrazoles are regioselectively synthe-
sized by a straightforward one-pot se-
quence. Treatment of fluorinated β-keto es-
ters with (tetrafluoroethyl)dimethylamine
(TFEDMA) as a practical CF2H transfer
reagent and subsequent cyclocondensation
with hydrazine derivatives affords 3-(di-
fluoromethyl)-5-(fluoroalkyl)pyrazoles as
single isomers. Rf
group.
= fluorinated alkyl
Keywords: Fungicides / Agrochemistry /
Regioselectivity / Nitrogen heterocycles /
Fluorine
0000, 0–0
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S. Pazenok, F. Giornal, G. Landelle, N. Lui, J.-P. Vors, F. R. Leroux
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300561
A New Life for an Old Reagent: Fluoroalkyl Amino Reagents as Efficient
Tools for the Synthesis of Diversely Fluorinated Pyrazoles
Sergiy Pazenok,[a] Florence Giornal,[b] Grégory Landelle,[b] Norbert Lui,[a]
Jean-Pierre Vors,[c] and Frédéric R. Leroux*[b]
Dedicated to the 150th anniversary of Bayer
Keywords: Fungicides / Agrochemistry / Regioselectivity / Nitrogen heterocycles / Fluorine
Herein we describe the first practical method for the regiose-
lective preparation of 3,5-bis(fluoroalkyl)pyrazoles. Starting
from commercially available fluoroacetoacetates and by
using (tetrafluoroethyl)dimethylamine as a convenient CF2H
transfer reagent, this straightforward one-pot sequence af-
fords highly substituted pyrazoles in good yields and excel-
lent regioselectivity. Furthermore, these carboxylate interme-
diates were converted into the corresponding pyrazolic acids,
which are valuable building blocks for the design of novel
bioactive ingredients.
activated carbonyl groups.[5,6] Among them, (tetrafluoro-
ethyl)dimethylamine (TFEDMA, 1) is also considered as a
difluoroacetyl transfer reagent if it is activated in the pres-
ence of a Lewis acid and subsequently treated with carbon
nucleophiles.[7] Its facile and low-cost preparation from tet-
rafluoroethylene makes it a reagent of choice for industrial
applications. In 2006, Pazenok et al. discovered that
TFEDMA can be used in the preparation of (difluo-
romethyl)pyrazoles. After activation with boron trifluoride
and reaction with (dimethylamino)acrylate, the cyclocon-
densation of intermediate 4 with methylhydrazine furnished
desired mono(fluoroalkyl)pyrazole 5 with good regioselec-
tivity (Scheme 1).[8] This approach is very versatile, as other
FARs can be used to either introduce a 1,2,2,2-tetrafluoro-
ethyl substituent (by using the Ishikawa reagent, 2) or a
chlorofluoromethyl group (by using the Yarovenko reagent,
3) at the 3-position of the pyrazole.
Introduction
The introduction of fluorine atoms into lead structures
is a powerful strategy to optimize the properties of agricul-
tural and pharmaceutical products.[1] Hence, a significant
rise in the number of active ingredients containing at least
one fluorine atom has been observed over the last dec-
ades,[2] and a recent survey estimated that as many as 18%
of the pesticides on the market are fluorinated com-
pounds.[3] Among the vast array of fluorine-containing
functionalities, (fluoroalkyl)pyrazoles have attracted con-
siderable attention because of their potentially enhanced
biological properties.[4] In particular, huge interest was ac-
corded to (difluoromethyl)pyrazolecarboxamides, which be-
long to the class of succinate-dehydrogenase inhibitor
(SDHI) fungicides. At least four different compounds of
this class were recently introduced to the crop-protection
market (Figure 1).
Despite recent advances in the synthesis of fluorinated
pyrazoles,[9] the preparation of pyrazoles bearing two
fluorinated groups remains scarcely depicted in the litera-
ture,[10] even if 3,5-bis(fluoroalkyl)pyrazoles are an impor-
tant class of bioactive molecules.[11] The reported methods
often describe symmetrical fluorinated pyrazoles [Scheme 2,
Equation (1)], involve tedious multistep synthesis with re-
strictive stages [Scheme 2, Equation (2)], and only allow ac-
cess to 4-unsubstitued pyrazoles.[12] Consequently, the de-
velopment of efficient approaches to generate diversely
fluoroalkyl-substituted pyrazoles should open a new entry
to innovative agrochemical and pharmaceutical candidates.
Thus, we thought that fluorinated β-keto esters could react
as nucleophiles with TFEDMA to afford adduct 6 bearing
two fluoroalkyl substituents and provide access to 3,5-bis-
α-Fluoroalkyl amino reagents (FARs) are selective fluori-
nating agents commonly used for the synthesis of alkyl
fluorides and gem-difluorides by reaction with alcohols and
[a] Bayer CropScience AG,
Alfred-Nobel-Strasse 50, 40789 Monheim, Germany
[b] Laboratoire de Chimie Moléculaire, UMR CNRS 7509
Université de Strasbourg,
25 Rue Becquerel, 67087 Strasbourg Cedex 02, France
Fax: +33-3-68852742
E-mail: frederic.leroux@unistra.fr
Homepage: www.syncat.org
[c] Bayer S.A.S.,
14 Impasse Pierre Baizet, BP99163, 69263 Lyon Cedex 09,
France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300561.
2
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Synthesis of Diversely Fluorinated Pyrazoles
Figure 1. Second-generation broad-spectrum fungicides containing difluoromethylated pyrazoles. Rf = fluorinated alkyl group.
(fluoroalkyl)pyrazoles 7 after a cyclocondensation step with
hydrazine (Scheme 2).
Herein we document the first practical method for the
regioselective preparation of 3,5-bis(fluoroalkyl)pyrazoles
7. Starting from commercially available fluoroacetoacetates
and by using TFEDMA as a convenient CF2H transfer rea-
gent, this straightforward one-pot sequence affords highly
substituted pyrazoles in good yields and excellent regiose-
lectivity (Ͼ97:3, Scheme 2). Furthermore, these carboxylate
intermediates were converted into the corresponding pyr-
azolic acids, which are valuable building blocks for the de-
sign of novel bioactive ingredients.
Results and Discussion
According to the procedure developed by Wakselman et
al.,[7a] TFEDMA was activated with BF3·OEt2 (1 equiv.) in
CH2Cl2 at room temperature. Under these conditions, the
Scheme 1. Utilization of FARs for the synthesis of mono(fluoroalk-
yl)pyrazole carboxylates.
Scheme 2. Regioselective one-pot preparation of 3,5-bis(fluoroalkyl)pyrazoles.
Eur. J. Org. Chem. 0000, 0–0
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S. Pazenok, F. Giornal, G. Landelle, N. Lui, J.-P. Vors, F. R. Leroux
SHORT COMMUNICATION
Table 1. Optimization of the reaction conditions.
Entry
Additive
Temp. [°C]
Yield [%][a]
1
2
3
Cs2CO3 (3 equiv.)
KF (3 equiv.)
KF (3 equiv.)
r.t.
r.t.
0
n.r.
20
16
4
5
6
7
8
9
10
11
KF (3 equiv.)
–30
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
9
KF (3 equiv.), FeCl3 (1 equiv.)
KF (3 equiv.), TiCl4 (1 equiv.)
KF (3 equiv.), Yb(OTf)2 (0.2 equiv.)
KF (3 equiv.), Cu(OTf)2 (0.2 equiv.)
KF (3 equiv.), CuCl2 (0.2 equiv.)
KF (3 equiv.), CuCl2 (1 equiv.)
pyridine (3 equiv.)
n.r.[b]
n.r.[b]
13[b]
22[b]
16[b]
27[b]
63
[a] Isolated yield. n.r. = no reaction. [b] The Lewis acids was introduced prior to the addition of hydrazine at the indicated temperature.
electrophilic character of TFEDMA is enhanced, and imin- tion.[14] Different hydrazines (i.e., hydrazine hydrate and
ium salt A can undergo nucleophilic attack with various β- methyl-, phenyl-, and tert-butylhydrazine) were also used
keto esters. Ethyl trifluoroacetoacetate was then added in for the cyclocondensation, and the results are summarized
the presence of an inorganic base in CH3CN at –30 °C, and in Table 2.
after 12 h at room temperature, methylhydrazine was added
at the same temperature. No reaction was observed with the
Table 2. Scope of the reaction.
use of cesium carbonate, and a poor yield was obtained
with potassium fluoride (Table 1, Entries 1 and 2). Decreas-
ing the temperature during the addition of hydrazine did
not improve the outcome of the reaction (Table 1, En-
tries 2–4). At this point, we thought that the low yields
could be due to a lack of reactivity of adduct 6. It was
Entry
Rf
R
Compound
Yield [%][a]
thought that the addition of an azaphilic Lewis acid would
increase the electrophilicity of the carbon atom adjacent to
the NMe2 group. We therefore decided to examine various
additives with the hope of finding a Lewis acid that would
facilitate the 1,4-addition of hydrazine to the adduct
(Table 1, Entries 5–10).[13] When either iron(III) or titani-
um(IV) chloride (1 equiv.) was added to the reaction mix-
ture, no desired product was detected (Table 1, Entries 5
and 6), whereas catalytic amounts of ytterbium(III) and
copper(II) triflate did not improve the yield of the reaction
(Table 1, Entries 7 and 8). An unsatisfactory yield of 27%
was reached in the presence of stoichiometric copper(II)
chloride (Table 1, Entry 10), and this led us to reconsider
the choice of the base. Finally, the reaction was carried out
with pyridine as the organic base, and desired 3-(difluo-
romethyl)-5-(trifluoromethyl)pyrazole 7a was obtained in a
fair 63% yield (Table 1, Entry 11).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CF3
CF3
CF3
CH3
H
Ph
tBu
CH3
H
7a
7b[b]
7c
73
75
67
53
69
56
43
30
75
67
85
33
72
72
53
CF3
7d[c]
7e
CF2H
CF2H
CF2H
CF2H
C2F5
C2F5
C2F5
C2F5
CF2Cl
CF2Cl
CF2Cl
7f[b]
7g
Ph
tBu
CH3
H
7h[c]
7i
7j[b]
7k
Ph
tBu
CH3
H
7l[c]
7m
7n[b]
7o
Ph
[a] Isolated yield. [b] Hydrazine hydrate was used for the cyclocon-
densation step. [c] tBuNHNH2·HCl was used for the cycloconden-
sation step.
Having optimized the conditions for the one-pot se-
3,5-Bis(fluoroalkyl)pyrazoles 7a–o were obtained in
quence, we next decided to perform the reaction on several moderate to good yields depending on the fluoroalkyl
fluorinated β-keto esters to determine the scope of the group on the β-keto ester and the hydrazine employed.
methodology. The sequence was carried out with commer- Ethyl trifluoroacetoacetate provided the most consistent re-
cially available ethyl difluoro-, ethyl trifluoro-, and ethyl sults with yields between 53 and 75% (Table 2, Entries 1–
pentafluoroethylacetoacetates, whereas ethyl chlorodi- 4). Electronic effects appear to have a small influence on
fluoroacetoacetate was synthesized by Claisen condensa- the reaction, as the yields increased with the electron-with-
4
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Synthesis of Diversely Fluorinated Pyrazoles
drawing character of the Rf substituent on the β-keto ester
(Table 2, Entries 5–8 vs. Entries 9–12). The nucleophilicity
and the steric demand of the hydrazine have pronounced
effects on the outcome of the cyclocondensation. Methyl-
and phenylhydrazines led to higher yields than tert-butyl-
hydrazine and hydrazine hydrate. Fortunately, in all cases
3,5-bis(fluoroalkyl)pyrazoles 7 were formed as single re-
gioisomers, which were easily isolated by simple flash
chromatography.
We next investigated further transformations of these
versatile pyrazole building blocks. Saponification of the es-
ter group in these products would allow access to attractive
(difluoromethyl)pyrazolecarboxamides through peptide
coupling. To this end, carboxy esters 7 were treated with
aqueous sodium hydroxide in ethanol at room temperature.
Although N–H pyrazoles 7b, 7f, 7j, and 7n returned only
starting material under these conditions, the N-substituted
pyrazoles were readily hydrolyzed to corresponding carbox-
ylic acids 8 (Table 3). These acids were obtained in high
yields and in analytically pure form after aqueous workup.
Figure 2. Evidence for the regioselectivity of the reaction: 13C
NMR analysis of the signal for the NMe group of 7a (right), and
ORTEP diagram of compound 8a (left).[15]
Conclusions
We have developed a straightforward method for the syn-
thesis of unsymmetrical 3,5-bis(fluoroalkyl)pyrazoles. This
innovative one-pot sequence provides ethyl 3,5-bis(fluoro-
alkyl)pyrazole-4-carboxylates as single isomers from com-
mercially available β-keto esters and hydrazines by using
TFEDMA as a CF2H transfer reagent. This robust process
is suitable for multigram-scale synthesis and allows poten-
tial access to pyrazolecarboxamides after a simple saponifi-
cation step towards pyrazolic acids en route to promising
bioactive ingredients.
Table 3. Saponification of 3,5-bis(fluoroalkyl)pyrazoles 7.
Entry
Rf
R
Compound
Yield [%][a]
1
2
3
4
5
6
7
8
9
CF3
CF3
CF3
CH3
Ph
tBu
CH3
Ph
tBu
CH3
Ph
tBu
CH3
Ph
8a
8c
8d
8e
8g
8h
8i
8k
8l
8m
8o
98
94
94
97
98
97
97
98
99
80
99
Experimental Section
General Procedure for the Preparation of Pyrazoles 7a–o: BF3·OEt2
(50 mmol, 1 equiv.) was added to
CF2H
CF2H
CF2H
C2F5
C2F5
C2F5
CF2Cl
CF2Cl
a solution of TFEDMA
(50 mmol, 1 equiv.) in dry CH2Cl2 (50 mL) under argon in a Teflon
flask. The solution was stirred at room temperature for 15 min, and
CH2Cl2 was removed under reduced pressure. The mixture was
taken up in dry CH3CN (50 mL). In another Teflon flask, the fluo-
roacetoacetate (50 mmol, 1 equiv.) was added to a solution of pyr-
idine (150 mmol, 3 equiv.) in dry CH3CN (100 mL), and the mix-
ture was stirred at room temperature for 15 min. At –30 °C, the
contents of the first flask was added dropwise to the second flask,
and the reaction mixture was stirred at –30 °C for 2 h and allowed
to reach room temperature overnight. The desired hydrazine
(75 mmol, 1.5 equiv.) was added dropwise at room temperature,
and the reaction mixture was stirred for 24 h. The solution was
concentrated under reduced pressure and taken up in Et2O
(100 mL). The organic phase was washed with 1 m HCl (3ϫ 50 mL)
and brine (50 mL), dried with sodium sulfate, and concentrated at
atmospheric pressure. The crude material was purified by column
chromatography on silica gel to afford the expected 3,5-bis(fluo-
roalkyl)pyrazole.
10
11
[a] Isolated yield.
The cyclization step towards ethyl 3,5-bis(fluoroalkyl)-
pyrazole-4-carboxylates 7 was completely regioselective. In-
deed, with every hydrazine used (i.e., methyl-, phenyl-, and
tert-butylhydrazine) and every fluorinated β-keto ester, only
one regioisomer was observed by 1H/19F NMR spec-
troscopy. Furthermore, careful interpretation of the 13C
NMR spectra of compounds 7 showed a coupling constant
between the carbon atom of the N-alkyl group and the
fluorine atoms of the substituent at the 5-position of the
Supporting Information (see footnote on the first page of this arti-
4
cle): Experimental procedures, spectroscopic data, and copies of
pyrazole ring (e.g., in 7a: q, JC,F = 3.3 Hz; Figure 2). This
1
the H, 13C, and 19F NMR spectra.
clear evidence reveals that the unique isomer prepared in
these reactions was always the 3-(difluoromethyl)-5-(fluoro-
alkyl)pyrazole. In addition, we were able to perform a sin-
gle-crystal X-ray analysis of carboxylic acid 8a to confirm
unambiguously the regioselectivity of the reaction (Fig-
ure 2).[15]
Acknowledgments
We thank the Centre National de la Recherche Scientifique
(CNRS) and the Ministère de la Recherche of France and are very
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S. Pazenok, F. Giornal, G. Landelle, N. Lui, J.-P. Vors, F. R. Leroux
SHORT COMMUNICATION
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much grateful to Bayer S.A.S. for financial support to F. G. and
G. L.
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Received: April 18, 2013
Published Online: ᭿
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