New efficient synthetic routes to trifluoromethyl substituted pyrazoles and corresponding β-diketones

Article abstract of DOI:10.1016/j.tetlet.2016.02.092

An improved and more efficient synthesis procedure for trifluoromethyl substituted pyrazoles, namely 3,5-bis(trifluoromethyl)-1H-pyrazole (1a), 5-(pentafluoroethyl)-3-(trifluoromethyl)-1H-pyrazole (1b), 5-(heptafluoropropyl)-3-(trifluoromethyl)-1H-pyrazol

Full text of DOI:10.1016/j.tetlet.2016.02.092

Accepted Manuscript
New efficient synthetic routes to trifluoromethyl substituted pyrazoles and cor-
responding β-diketones
Mariano Grünebaum, Annika Buchheit, Christina Günther, Hans-D.
Wiemhöfer
PII:
S0040-4039(16)30201-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.092
TETL 47367
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
1 February 2016
22 February 2016
25 February 2016
Please cite this article as: Grünebaum, M., Buchheit, A., Günther, C., Wiemhöfer, Hans-D., New efficient synthetic
routes to trifluoromethyl substituted pyrazoles and corresponding β-diketones, Tetrahedron Letters (2016), doi:
http://dx.doi.org/10.1016/j.tetlet.2016.02.092
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1
New efficient synthetic routes to trifluoromethyl substituted pyrazoles
and corresponding β-diketones
a
a
a
a
Mariano Grünebaum , Annika Buchheit , Christina Günther , Hans-D. Wiemhöfer
a
Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstr. 28/30, D-48149 Münster,
Germany
Corresponding author:
Mariano Grünebaum
e-mail: mariano.gruenebaum@wwu.de
Tel: +49 251 83 36056
Fax: +49 251 83 36705

2
New efficient synthetic routes to trifluoromethyl substituted pyrazoles
and corresponding β-diketones
a
a
a
a
Mariano Grünebaum , Annika Buchheit , Christina Günther , Hans-D. Wiemhöfer
a
Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstr. 28/30, D-48149 Münster,
Germany
ABSTRACT
An improved and more efficient synthesis procedure for trifluoromethyl substituted
pyrazoles, namely 3,5-bis(trifluoromethyl)-1H-pyrazole (1a), 5-(pentafluoroethyl)-3-
(
(
trifluoromethyl)-1H-pyrazole (1b), 5-(heptafluoropropyl)-3-(trifluoromethyl)-1H-pyrazole
1c), 5-(nonafluorobutyl)-3-(trifluoromethyl)-1H-pyrazole (1d), 5-phenyl-3-(trifluoromethyl)-
1
H-pyrazole (1g), 5-(pentafluorophenyl)-3-(trifluoromethyl)-1H-pyrazole (1h), 5-methyl-3-
(
trifluoromethyl)-1H-pyrazole (1e) and 5-(tert-butyl)-3-(trifluoromethyl)-1H-pyrazole (1f) is
presented which starts from the corresponding ß-diketones (2a-h). In addition, the preparation
of some of the corresponding diketones (2b-d & 2h) is revisited with an emphasis on low-cost
1
and easy available starting materials. All products were characterized using multinuclear ( H,
1
3
19
C, F) NMR spectroscopy. Additionally, thermal properties of synthesized pyrazoles were
characterized using differential scanning calorimetry.

3
KEYWORDS
Trifluoromethyl substituted pyrazoles
Trifluoromethyl substituted β-diketones
CLAISEN-condensation
Chemical vapor deposition
Organic light emitting diodes

4
1
. Introduction
Perfluorinated and partially fluorinated pyrazoles are widely used for pharmaceutical and
agricultural applications. Due to their influence on acidity, modulation of lipophilicity,
changes in molecular conformity and metabolic stability, fluorinated pyrazoles show higher
1
-6
biological activity in comparison to non-fluorinated derivatives. A further interesting field
of application is the use of fluorinated pyrazoles as well adapted electron deficient ligands for
transition and rare earth metal complexes. Therefore pyrazole based complexes of metals such
as Rh, Ir, Pd, Pt Cu, Ag, Ca, Sr and Ba exhibit high volatility, useful for metal organic
7
-11
chemical vapor deposition (MOCVD).
Furthermore, perfluorinated pyrazole complexes
1
2, 13
have proven to be more efficient catalysts in comparison to their non-fluorinated analogs.
Perfluorinated pyrazoles as electron deficient ligands are also of interest in the field of organic
light emitting diodes (OLEDs), as they provide green and blue emitting complexes with
1
4-17
coinage and platinum-group metal, e.g. Cu, Ag, Pt and Os.
The important and versatile
applications of perfluorinated and partially fluorinated pyrazoles led to various synthetic
approaches: 3,5-bis(trifluoromethyl)pyrazole (1a) was first prepared by Milton et al. in 1966
by reaction of hexafluoroacetylacetone (2a) and hydrazine hydrate (3) in tetrahydrofuran
1
(
THF), but with low overall yield of only 9.2% (Scheme 1). The conversion of fluorinated β-
diketones (2) with hydrazine hydrate in ethanol was the most applied starting reaction to the
1
8-21
corresponding fluorinated pyrazoles (1) during the last decades until now.
Instead of β-
diketones (2), 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones (4) are an alternative starting point. The
synthetic routes were usually carried out under solvent free conditions, microwave irradiation
2
2-24
and high pressures (Scheme 1).
Other published approaches concern ring-closing
2
5
reactions between alkyne containing precursors such as fluorinated butynones (5) with
2
6
hydrazine, fluoroalkyl butynes (6) with hydrazine and ethenylbenzene (7) with 2-diazo-
2
7, 28
1
,1,1-trifluoroethane (8), see Scheme 1.
However, the alkynes and diazo-compounds as
listed here are expensive starting materials or can only be formed by multi-step synthesis with

5
2
9-33
moderate overall yields.
A further alternative toward fluorine substituted pyrazoles uses
catalytic trifluoromethylation reactions of non-fluorinated pyrazole (9) with gaseous
3
4
iodotrifluoromethane (10) or a Pd-catalyzed coupling of 3-iodo-5-trifluoromethylpyrazole-
3
3
4
-carboxylic acid (11) with phenylboronic acids (12) see Scheme 1. However, catalytic
trifluoromethylation often delivers mixtures of differently substituted pyrazoles in low to
moderate yields (2-49%). The latter are difficult to isolate and need two additional steps for
protecting and unprotecting the corresponding pyrazoles.
Scheme 1. Different preparation methods of trifluoromethyl substituted pyrazoles as described in the
1
-34
literature.
Here, our focus lies on the implementation of fluorinated pyrazoles (1a-h) as precursors for
lithium salts to be used in liquid electrolytes of lithium batteries with enhanced thermal and
chemical stability. We developed an improved preparation protocol, starting from β-diketones
(
2a-h), see Fig. 1, with an emphasis on reduced costs, prevention of difficult and time
consuming purification methods and therefore increased yields (up to 92%). Additionally, we
revisited the preparation of the corresponding β-diketones (2b-d & 2h) as appropriated low-

6
cost and easily available starting material for some of the fluorinated pyrazoles described in
the following. Furthermore, thermodynamic properties (e.g. melting and boiling points,
enthalpies and entropies) of the desired fluorinated pyrazoles (1a-h) were investigated.
Figure 1. Trifluoromethyl substituted β-diketones (2a-h) and pyrazoles (1a-h).
2
. Results and discussions
2
.1. Preparation of trifluoromethyl substituted β-diketones
Scheme 2 gives a short overview on our concept to revise and improve the preparation of
3
5
pure perfluoroalkyl substituted β-diketones and purification via Cu-complexes. Only the β-
diketones 2a and 2e-g were not prepared, as they are cheap and well available in good purity.
3
5-38
In the other cases, 2b-d and 2h were prepared via improved CLAISEN-condensation
of
1
,1,1,-trifluoroacetone (13) and the corresponding perfluoroalkyl substituted esters (14b-d) or
condensation of 1-(pentafluorophenyl)acetone (15) with ethyl 2,2,2-trifluoroacetate (14h) in
n-pentane (see Scheme 2). The raw β-diketones (2b-d and 2h) were purified by formation of
water insoluble Cu-complexes (16b-d and 16h) to separate them from aldol-byproducts and
unconverted starting materials. The β-diketones (2b-d and 2h) can easily be released from the
complexes by a small amount of sulfuric acid, see Scheme 2. The reaction conditions and
yields of as-prepared β-diketones (2b-d and 2h) are listed in Table 1. A general preparation
protocol is available in the supplemental data and can easily be extended to other fluorinated
β-diketones, not described here.

7
Scheme 2. Preparation and purification via copper complex of the corresponding β-diketones 2b-d & 2h.
The aldol-byproducts were formed by an accompanying side reaction wherein enolized
methylketones 13 or 15 are reacting with not enolized methylketones 13 or 15, see Scheme 3.
Additionally, the aldol reactions in the presence of alcoholates as mentioned here, particularly
39, 40
in the case of 1,1,1-trifluoroacetone (13) are well known from the literature.
For more
4
1
details regarding the above mentioned mechanism, see.

8
Scheme 3. Anticipated aldol side reaction of fluorinated methyl ketones 13 & 15 under basic conditions.
2
.2. Preparation of trifluoromethyl substituted pyrazoles
Conversion of fluorinated β-diketones (2a-h), especially in the case of bis(perfluoroalkyl)
substituted β-diketones (2a-d) with hydrazine hydrate ends in the formation of perfluoroalkyl
substituted hydroxy-4,5-dihydropyrazoles (17a-d) without further dehydration (Scheme 4 and
compare to NMR-spectra for 17a-d in the supporting information). To synthesize the desired
1
9, 42
(
1a-h)
we investigated four different acid catalyzed dehydrating methods for 2a to
encounter the strong electron withdrawing effect of the perfluoroalkyl substituents

9
(
Scheme 4, entrance I-IV). Afterwards the most efficient method was transferred to the other
©
fluorinated pyrazoles (1b-h). Using only Amberlyst as acid catalyst (entrance I) led to a
©
partially dehydration, therefore Amberlyst was used in combination with MgSO
4
as
dehydrating agent (entrance II). In this case no product was formed. Perhaps fluorinated β-
diketone (2a) forms a stable magnesium-complex 18a as described in the literature for other
1
0
alkaline-earth metals (Scheme 4). Another approach (entrance III) was to use 3Å molar
sieve. Entrance III showed the drawback that hydrazine is better absorbed from the molecular
sieve than water so that mainly the starting fluorinated β-diketone (2a) was isolated. Finally,
the use of phosphorus pentoxide as acid catalyst and dehydrating agent (entrance IV) led to
the intended complete conversion of the mentioned β-diketone (Scheme 4). In this context,
ethanol which was most often described as the reaction solvents in the literature has proven to
be not convenient. On the one hand, ethanol prevents crystallization of the product due to the
high solubility of the pyrazoles. On the other hand, evaporation of the solvent lowers the yield
caused by the high volatility of the fluorinated pyrazoles which is partially distilled with the
solvent. Additionally, ethanol is not compatible with phosphorus pentoxide. From that point,
we decided to use chloroform as reaction solvent. All of the here investigated pyrazoles (1a-h)
show good solubilities at higher temperatures (40-50 °C) but are sparely soluble at low
temperatures (< 0 °C) which allows isolation of pure trifluoromethyl substituted pyrazoles by
a direct crystallization from the reaction mixture. As described above, the approach according
to entrance IV was subsequently transferred to the other fluorinated pyrazoles (1b-h). All
investigated fluorinated pyrazoles (c.f. reaction conditions, yields etc.) are listed in Table 1. A
detailed description of a general preparation procedure as well as corresponding NMR-spectra
are available in the supporting information.

1
0
Scheme 4. Formation of the perfluoroalkyl substituted hydroxy-4,5-dihydropyrazoles (17a-h) and
investigation of different dehydrating agents on β-diketone 2a (entrance I-IV).

1
1
Table 1. Yields and reaction conditions to β-diketones (2b-d & 2h) and pyrazoles (1a-h).
Starting
material
Conditions
Ratio
Product
Yield
%
1
1
3
&
1) NaOMe, n-pentane, 1 : 1.15 2b
0°C, 1h 2) H SO 98%,
90
4b
2
4
0
°C, 1h,
NaOAc,
, H O, rt 5) H
8%, 0°C, distillation
3 & 14c 1) NaOMe, n-pentane, 1 : 1.15 2c
3
)
H
2
O, rt, 4)
SO
CuSO
9
4
2
2
4
1
86
79
74
0
0
3
°C, 1h 2) H
°C, 1h,
2 4
SO 98%,
)
NaOAc,
, H O, rt 5) H
8%, 0°C, distillation
1) NaOMe, n-pentane, 1 : 1.15 2d
0°C, 1h 2) H SO 98%,
H
2
O, rt, 4)
CuSO
9
4
2
2
SO
4
1
1
3
&
&
4d
2
4
0
°C, 1h,
NaOAc,
, H O, rt 5) H
8%, 0°C, distillation
1) 1) NaOtBu, n-pentane, 1 : 1.15 2h
0°C, 1h 2) O, rt 3)
CuSO , H O, rt 5) H SO
8%, 0°C, distillation
3
)
H
2
O, rt, 4)
SO
CuSO
9
4
2
2
4
1
1
5
4h
H
2
4
2
2
4
9
2
2
2
2
2
2
2
2
a
b
c
d
e
f
1)
CHCl
reflux, 3h
1)
hydrazine
hydrate
-
-
-
-
-
-
-
-
1a
1b
1c
1d
1e
1f
92
87
85
81
90
78
71
82
3
, reflux 1h, 2) P O ,
4 10
hydrazine
hydrate
CHCl
3
, reflux 1h, 2) P O ,
4 10
reflux, 3h
1)
CHCl
reflux, 3h
1)
CHCl
reflux, 3h
1)
CHCl
reflux, 3h
1)
CHCl
hydrazine
hydrate
3
, reflux 1h, 2) P O ,
4 10
hydrazine
hydrate
3
, reflux 1h, 2) P O ,
4 10
hydrazine
hydrate
3
, reflux 1h, 2) P O ,
4 10
hydrazine
hydrate
3
, reflux 1h, 2) P O ,
4 10
reflux, 3h
g
h
1)
CHCl
reflux, 3h
1)
hydrazine
hydrate
1g
1h
3
, reflux 1h, 2) P O ,
4 10
hydrazine
hydrate
CHCl
3
, reflux 1h, 2) P O ,
4 10
reflux, 3h
2
.3. Thermodynamic properties
All prepared fluoroalkyl substituted pyrazoles (1a-h) are volatile and white crystalline solids
at room temperature with more or less distinctive odors. Like most perfluoroalkyl substituted
heterocycles, they are poorly soluble in water, but soluble in organic solvents like methanol,

1
2
ethanol, acetonitrile, diethyl ether, tetrahydrofuran, dichloromethane, chloroform and
n-pentane. Thermodynamic properties were measured via differential scanning calorimetry
(
DSC). The corresponding melting/boiling enthalpies and entropies were calculated from peak
areas using ΔG = ΔH - TΔS at the phase transition temperatures and are listed in Table 2. By
comparing the melting and boiling points of the pyrazoles 1a-1d (except 1c) a clear trend can
be seen. The melting points get lower with increasing side chain length whereas the boiling
points decrease.
Table 2. Thermodynamic data from investigated pyrazoles (1a-h).
Compound

m

vap
m
 H
m
 S

vap
H
vap
 S
-
1
-1
-1
-1
(
°C)
(°C)
160
163
161
192
217
224
294
234
(J·g )
56.9
30.3
49.6
34.9
62.8
96.2
86.2
87.9
(J·(K·g) )
(J·g )
222.2
181.1
374.1
92.3
(J·(K·g) )
1
1
1
1
1
1
1
1
a
b
c
d
e
f
87
0.16
0.51
71
0.09
0.42
31
0.16
0.86
37
0.11
0.20
95
0.17
134.8
284.9
45.6
0.27
187
128
144
0.21
0.57
g
h
0.21
0.08
0.21
46.7
0.09
3
. Summary and conclusions
Five synthetic routes were investigated and optimized to obtain 3,5-
bis(trifluoromethyl)pyrazole (1a) under simple reflux conditions and via direct crystallization
from the mother liquors in high yield and purity. The most successful method was then
adopted to receive trifluoromethyl substituted pyrazoles 1b-h in high yield and purity.
Furthermore, the synthesis of trifluoromethyl substituted β-diketones (2b-d & 2h) was
reinvestigated, modified and considerably improved with an additional purification step based
on formation of copper-complexes. As a result, the preparation procedures as presented here

1
3
allow a much more convenient and facile access to trifluoromethyl substituted pyrazoles 1a-h
and trifluoromethyl substituted β-diketones (2b-d & 2h) starting from low-cost materials.
Additionally, anticipated reaction mechanism and possible side reactions, as well as
thermodynamic properties of pyrazoles 1a-h were discussed.
Acknowledgements
The authors acknowledge the support of the Bundesministerium für Bildung und Forschung
(
BMBF) within the research initiative “Insider” (No. 03EK3031A).
Supplementary data
1
13
19
Detailed descriptions of H, C and F NMR spectra and differential scanning calorimetry
(
DSC) spectra associated with this article can be found as supplementary data in the online
version, at:
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Highlights
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Access to fluorinated pyrazoles and β-diketones from low-cost starting materials.
Improved reaction to pure materials without further purification.
Easily scalable and transferrable to higher substituted pyrazoles and β-diketones.
Application in transition metal chemistry, MOCVD and organic light emitting diodes.
Interesting precursors for conducting salts in lithium ion batteries.

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Graphical Abstract
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New efficient synthetic routes to trifluoromethyl
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substituted pyrazoles and corresponding β-diketones
Mariano Grünebaum, Annika Buchheit, Christina Günther, Hans-D. Wiemhöfer