Practical synthetic method for functionalized 1-methyl-3/5-(trifluoromethyl)-1H-pyrazoles

Article abstract of DOI:10.1021/acs.oprd.0c00300

A new, high-yielding, and practical method for synthesis of 1-methyl-3-(trifluoromethyl)-1H-pyrazole and 1-methyl- 5-(trifluoromethyl)-1H-pyrazole, key intermediates for important building blocks relevant to medicinal and agrochemistry, is developed. A one-step procedure for synthesis of the regioisomeric mixture of target pyrazoles was proposed starting from 4-ethoxy- 1,1,1-trifluoro-3-buten-2-one. The procedure for separation of this mixture was elaborated on the basis of the boiling point vs pressure diagram analysis. The efficient synthetic strategies for regioisomeric building blocks bearing CF3 groups at the 3rd and 5th positions were demonstrated. A set of 1-methyl-3-(trifluoromethyl)-1H-pyrazoles containing such a functional group as aldehyde, acid, boron pinacolate, lithium sulfinate, and sulfonyl chloride was synthesized based on lithiation of 1-methyl-3-(trifluoromethyl)- 1H-pyrazole in a flow reactor. Bromination of both 1-methyl-3-(trifluoromethyl)-1H-pyrazole and 1-methyl-5-(trifluoromethyl)-1Hpyrazole by NBS in mild conditions was performed. The introduction of the functional group at the 4th position of 1-methyl-5- (trifluoromethyl)-1H-pyrazole was illustrated by the optimized synthesis of the corresponding aldehyde and acid based on the Br-Li exchange in an appropriate bromide. Alternatively, the introduction of the functional group (acid and boron pinacolate) at the 5th position of 1-methyl-5-(trifluoromethyl)-1H-pyrazole was performed based on the direct ortho-metalation (DoM) reaction of 4- bromo-1-methyl-5-(trifluoromethyl)pyrazole followed by catalytic reductive debromination.

Full text of DOI:10.1021/acs.oprd.0c00300

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Full Paper
A Practical Synthetic Method for Functionalized
-Methyl-3/5-(trifluoromethyl)-1H-pyrazoles
1
Maxim Tairov, Vitalina Levchenko, Ivan Stadniy, Yurii V. Dmytriv, Serhii
Dehtiarov, Mykola Kibalnyi, Anton Melnyk, Stanislav Veselovych, Yurii
Borodulin, Sergey Kolotilov, Sergey V. Ryabukhin, and Dmitriy M. Volochnyuk
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00300 • Publication Date (Web): 02 Sep 2020
Downloaded from pubs.acs.org on September 2, 2020
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A Practical Synthetic Method for Functionalized 1-
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Methyl-3/5-(trifluoromethyl)-1H-pyrazoles
a
a
a
a,b
Maxim A. Tairov, Vitalina Levchenko, Ivan A. Stadniy, Yurii V. Dmytriv, Serhii O.
a
a
a
a
Dehtiarov, Mykola O. Kibalnyi, Anton V. Melnyk, Stanislav Y. Veselovych, Yurii V.
Borodulin, Sergey V. Kolotilov, Sergey V. Ryabukhin,* Dmitriy M.Volochnyuk*a,d,e.
a
c
a,d
a
Enamine Ltd, 78 Chervonotkatska str., Kyiv, Ukraine
b
National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute”, 37
Peremohy Ave., Kyiv, 03056, Ukraine
c
L. V. Pisarzhevskii Institute of Physical Chemistry of the National Academy of Sciences
of Ukraine, Prospekt Nauki 31, Kyiv, 03028, Ukraine
d
Taras Shevchenko National University of Kyiv, 60 Volodymyrska str., Kyiv, Ukraine.
e
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5
Murmanska str., Kyiv, Ukraine.
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TABLE OF CONTENTS
O
O
CF3
NH NHMe
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F3C
-
-
kilo scales
cost-effective
- user-friendly
N
CF3
N
N
N
1
,5 kg
1,8 kg
F3C
F3C
FG
FG
FG
N
N
N
N
FG
CF3
CF3
N
N
N
N
FG = Br, CHO, CO H, BPin, SOCl, SO Cl, NH
2
2
2
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ABSTRACT. A new, high yielding and practical synthesis of 1-methyl-3-(trifluoromethyl)-
1
H-pyrazole and 1-methyl-5-(trifluoromethyl)-1H-pyrazole, key intermediates for
important Medicinal and Agro Chemistry relevant building blocks, is developed. One step
procedure for the regioisomeric mixture of target pyrazoles was proposed starting from 4-
ethoxy-1,1,1-trifluoro-3-buten-2-one. The procedure for separation of this mixture was
elaborated on the basis of the boiling point vs. pressure diagrams analysis. The efficient
synthetic strategies to regioisomeric building blocks bearing CF -group at the 3-rd and
3
the 5-th positions were demonstrated. A set of 1-methyl-3-(trifluoromethyl)-1H-pyrazoles
containing such functional group as aldehyde, acid, boron pinacolate, lithium sulfinate
and sulfonyl chloride was synthesized based on lithiation of 1-methyl-3-(trifluoromethyl)-
1H-pyrazole in flow reactor. The bromination of both 1-methyl-3-(trifluoromethyl)-1H-
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pyrazole and 1-methyl-5-(trifluoromethyl)-1H-pyrazole by NBS in mild conditions was
performed. The introduction of the functional group into the 4-th position of 1-methyl-5-
1
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(trifluoromethyl)-1H-pyrazole was illustrated by the optimized synthesis of the
corresponding aldehyde and acid based on Br-Li exchange in the appropriate bromide.
Alternatively, the introduction of the functional group (acid and boron pinacolate) into the
5-th position of 1-methyl-5-(trifluoromethyl)-1H-pyrazole was performed based on DoM
reaction of 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole followed by catalytic reductive
debromination.
KEYWORDS. trifluoromethyl pyrazoles, regioisomer separation, flow lithiation, bromine-
lithium exchange, direct ortho-methalation, hydrogenative dehalogenation; building
blocks.
INTRODUCTION
Pyrazole derivatives are the scaffolds of primary importance for medicinal,1,2
agricultural,3 supramolecular4 chemistry as well as for materials sciences.5,6
3/5-Trifluoromethylpyrazoles, well-known examples of pyrazole derivatives, are key
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privileged fragments, which are present in many agrochemicals and pharmaceuticals.7,8
Among agrochemicals, herbicide Fluazolate (JV-485) I, used on winter wheat developed
by Monsanto and Bayer AG, and fungicide Penthiopyrad II, developed by Mitsui
Chemicals and DuPont, can be mentioned. Promising drug candidates ERDRP-00519 III,
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non-nucleoside inhibitor of the measles virus RNA-dependent RNA-polymerase, and
compound IV, interleukin-1 receptor-associated kinase inhibitor10 can be highlighted
(Figure 1). All these data clearly show that 3/5-trifluoromethylpyrazole fragments are
playing an important role in different Agro and Medicinal Chemistry programs. Therefore,
to continue our in-house program directed to the design and synthesis of fluorine-
containing building blocks,11 we desired to expand our stock by diverse functionalized
3/5-trifluoromethyl pyrazoles. Among innumerable possible variations of compounds with
such core, the parent N-methyl-3/5-trifluoromethyl pyrazoles bearing the functional
groups at the 4-th or the 3-d/5-th positions were chosen. These simplest derivatives are
useful candidates in compound libraries design due to compliance with the “rule-of-two”
12
(
Ro2). On the other side, for the generation of any preliminary SAR the introduction of
regioisomeric simplest N-methyl substituent is desired.
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S
Cl
O
O
F
F3C
NH
Br
O
N
N
N
CF3
N
I
II
Fluazolate
Penthiopyrad
O
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N
O
2
H N
F3C
F3C
HN
H
N
N
H
N
N
O
N
N
N
N
N
S
N
O
III
O
IV
IC50 (IRAK4) = 0.3 nM
ERDRP-00519
Figure 1. Examples of biologically active 1-methyl-3/5-(trifluoromethyl)-1H-pyrazoles.
Despite the apparent simplicity, the selective synthesis of functionalized N-methyl
pyrazoles is still a challenge. The traditional method for the synthesis of diverse
functionalized 3/5-CF -substituted pyrazoles 1 and 2 is based on the cyclocondensation
3
of 1,3-diketones 3 (or their synthetic equivalents) with hydrazines 4 (way A). However,
this approach is limited by the availability of prefunctionalized starting materials and poor
regioselectivity. Usually it gives a mixture of hardly separable regioisomers 1 and 2.13
Nevertheless, the use of acetylenic or β-functionally substituted unsaturated fluorine-
containing ketones as synthetic equivalents of 1,3-diketones is more efficient. The desired
14
pyrazoles were formed with better regioselectivity in such cases. All these approaches
did not lead, nonetheless, to the high regioselectivity level and/or robust separation
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especially in the case of alkyl hydrazines. Moreover, MeNHNH is the most inconvenient
2
partner in such cyclocondensations due to the similar activity of the two nucleophilic
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centers. Alternatively the regioselective approach to 3-CF pyrazoles 1 was developed
3
on the basis of the electrophilic trifluoromethylation/cyclization of α,β-alkynic hydrazones
15
5
with Togni reagent (way B). This approach was not tested on hydrazones, derived
from methylhydrazine. In addition, the cost of Togni reagent is still high for use on a large
scale. Recently the [3+2] cycloaddition based on the reaction of alkynes 6 and in situ
generated CF CHN (7) affording the pyrazoles 8 was elaborated in our company (way
3
2
16
17
C). This approach was later adapted to flow chemistry as well as for the late-stage
functionalization.18 However, further alkylation of the N-unsubstituted pyrazoles 10
proceeds unselectively and again leads to a hardly separable mixture of regioisomers 1
and 2.19 It should be noted that the regioselective [3+2] cycloaddition involving CF3-
20
containing sydnone 9, which results in 5-CF pyrazoles, was reported (way D). The
3
method was applied for the synthesis of N-methyl pyrazole derivatives but the scale-up
remains to be complex. To the best of our knowledge, only one example of a kilo-scale
21
synthesis of pyrazoles, using sydnones, was described. Finally, the approach based on
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[
4+1] cyclocondensation via Vilsmeier-Haack formylation of hydrazones derived from
trifluoroacetone 10 was tested in our group (way E). Unfortunately, in the case of
1
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methylhydrazine derivatives, the reaction was accompanied by side processes. The
22
synthesis of the starting hydrazone also had scale-up problems. The modification of the
[
4+1] cyclocondensation based on phthalimide-substituted acetone led to the
development of the approach to (4-(trifluoromethyl)-1-methyl-1H-pyrazol-3-
yl)methanamine. However, this approach was proven to be non-flexible and hazardous,
23
because toxic SF was required (Scheme 1).
4
F3C
N
NH
F3C
10
R
N+
N-
R2
H
7
R2
F3C
R1
+
POCl3-DMF
F3C
R2
N
[
4+1]
R
NH2
R1= H
R2 = CHO
O
O
E
N
3
4
R1
[3+2]
N
or it's synthetic
equvivalent
H
R1
8
F3C
R2
R1
R2
6
RX - HX
+
N
N
R1
CF3
A
N
R
N
R
C
1
2
R
O-
CF3+"
Togni reagent
"
HN
N
O+
[3+2]
R1
R2
+
N
N
CF3
H
R2 = H
B
D
5
6
R
9
R1
Scheme 1. Approaches to 3/5-(trifluoromethyl)-pyrazoles.
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Br–Li
exchange
F3C
F3C
F3C
Br
F3C
FG
1
. RLi
Br2, cat
1. R'Li
2. E+
12a 3. FGI
N
FG
11
N
N
N
N
. E+
2
N
N
N
1a
12
3
. FGI
3
-CF -5-FG
3-CF -4-FG
3
3
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Br–Li
exchange
Br
FG
Br2, cat
1. R'Li
N
N
N
CF3
CF3
13a
2. E+
CF3
13
N
N
N
2a
3. FGI
1
2
3
. RLi
5-CF -4-FG
3
. E+
DoM
. FGI
FG = CO H, CHO, NH
2
2,
-
+
SO Cl, SO2 Li , BPin
2
FG
FG
N
Br
[H]
N
CF3
CF3
N
N
14
15
5
-CF -3-FG
3
Scheme 2. The general strategy for the synthesis of functionalized 1-methyl-3/5-
(trifluoromethyl)-pyrazoles chosen for the scale-up.
In order to solve all the above-mentioned problems with regioselectivity and to elaborate
the scale-up procedures, we drew our attention to seminal Schlosser paper dealing with
selective lithiation of N-substituted 3/5-(trifluoromethyl)-pyrazoles.24 In this work, we
describe our results of optimization and scale-up the synthesis of 1-methyl-3/5-
(
trifluoromethyl)-pyrazoles 1a and 2a bearing functional groups in all possible positions.
The functional groups cover the range of the commonly used ones for the array synthesis
25
via amide/sulfamide coupling and reductive amination (NH , CO H, SO Cl, CHO) as
2
2
2
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well as BPin derivatives and sulfinates26 as partners for Pd-catalyzed cross-coupling
reactions. The general strategy chosen in this work is depicted on Scheme 2. For the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
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2
2
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4
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8
9
0
synthesis of the 3-CF -5-FG derivatives 11, the next sequence was studied: the lithiation
3
at the 5-th position / electrophilic substitution / functional group interconversion of 1-
methyl-3-(trifluoromethyl)-1H-pyrazole 1a. For the introduction of the functional group in
the 4-th position of pyrazole 1a (the synthesis of 3-CF -4-FG derivatives 12) the
3
electrophilic bromination/Br-Li exchange followed by functionalization was used. In the
case of 5-CF derivatives, the installation of function in both positions started with
3
electrophilic bromination of 2a. Then, in the case of 5-CF -4-FG derivatives 13, the Br-Li
3
exchange followed by further functionalization was optimized. From the other side, for the
synthesis of 5-CF -3-FG building blocks 14, the bromine atom was used as a directing
3
group for the DoM functionalization. This atom was then removed by hydrogenation. We
recently used a similar approach for the pyridine derivatives synthesis.27
RESULTS AND DISCUSSION
The first milestone for the fulfillment of the above-mentioned strategy was to develop
the kilo scale access to key starting pyrazoles 1a and 2a. Unfortunately, previous works,
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including the seminal Schlosser's paper, in which a possible selective synthesis of both
isomers of 1-methyl-5/3-(trifluoromethyl)-1H-pyrazoles from 4-ethoxy-1,1,1-trifluoro-3-
0
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8
9
0
28
buten-2-one 16 and MeNHNH in different condition was postulated, was not
2
reproduced in multi-gram scale. In all cases, the mixtures of both regioisomers were
formed with different ratios. Therefore, we decided to elaborate a robust protocol for their
separation. Due to the low molecular weight (150 Da) we expected that the isomers could
29
be separated by distillation. The boiling point vs. pressure diagram was measured for
both regioisomers. It was found, that at 1 atm the difference of the boiling points for the
isomers was ca 50 °C (90 and 140 °C), which was very promising for the successful
separation (Figure 2). The measurement of the temperature-composition diagram at 1
atm for the mixture of compounds proved this assumption because, at a molar fraction of
1-methyl-3-(trifluoromethyl)-pyrazole (1a) from 0 to ca 0.75 in the liquid phase, the molar
fraction of 1-methyl-5-(trifluoromethyl)-pyrazole (1b) in the gas phase exceeded 0.95
(Figure 3).
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8
9
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Figure 2. The boiling point–pressure diagram for compounds 1a and 2a.
Figure 3. The temperature - composition diagram for the mixture of compounds 1a and
2a at 1 atm pressure.
Based on the data obtained the practical kilo scale synthesis of both individual
regioisomers, including separation by distillation, was elaborated and optimized. The 4-
ethoxy-1,1,1-trifluoro-3-buten-2-one reacts with MeNHNH hydrochloride in the refluxed
2
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MeOH-H O mixture (at 1:0.75 volume ratio) affording the mixture of regioisomeric
2
pyrazoles 1a and 2a in 0.7:1 ratio according to the 19F NMR spectra. The solubility of
these two isomeric compounds in water is limited. Therefore, the addition of the excess
of water to the reaction mixture leads to biphasic system formation, which could be easily
separated. On this step, such impurities as unreacted methylhydrazine hydrochloride and
HCl formed are also eliminated. The first fractional distillation of the crude mixture at 55–
0
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9
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155 °С and atmospheric pressure gave several fractions, wherein the distillation residue
contained only crude 1a. The fraction boiling at 55–75 °С includes methanol, ethanol and
a small amount of 2a. The next fraction (75–125 °С) was the main one and contained the
regioisomeric mixture of pyrazoles enriched by 2a (0.2:1 isomers ratio). And the last
fraction (125–155 °С) was the regioisomeric mixture of pyrazoles 1a and 2a in 1:1 ratio.
The mass ratio between the main and other fractions was ca. 8:1. The further double re-
st
nd
distillation (the 1 at atmospheric pressure, the 2 using diaphragm pump) of the main
fraction enriched by an isomer 2a led to the desired compound in 38% yield. It appeared
to be reasonable to collect the last fraction from several synthetic runs and it also could
be separated. The re-distillation of combined residues after the first distillation led to 1a
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in 32% yield. This process worked well on 5.3 kg scale of the starting 4-ethoxy-1,1,1-
trifluoro-3-buten-2-one 16 (Scheme 3).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
3
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5
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0
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8
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4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1. Heating to reflux
in 30L reactor
2
. Addition of
19F NMR
19F NMR
MeNHNH2*HCl
during 1.5 h
s, 60.98 ppm
s, 62.44 ppm
F3C
O
2.86 kg
in 7.5L H O
2
+
N
O
CF3
N
N
CF3
3
. Reflux 3h
4. Transfer to extractor
N
16
5
.3 kg
5. Adding of 20L H O
6. Mixing 20 min
1a
2a
2
in 10L MeOH
0.7 : 1
7. Separation of layers
after overnight standing
distillation at 1 atm
from 5L reactor
8. Drying over Na2SO4
residue
after 155 °C)
fraction 75-125 °C
(
crude 1a
crude 1a : 2a = 0.2 : 1
1. Distillation at 1 atm
1
. Drying over P2O5
(fraction 95-102 °C)
2. Drying over P2O5
3. Distillation in diaphragm
a vacuum pump (fraction 34-53 °C)
2. Distillation in diaphragm
a vacuum pump (fraction 42-43 °C)
F3C
N
N
CF3
N
N
1a
2a
1.5 kg 32%
1.8 kg 38%
Scheme 3. Kilogram-Scale Process for the synthesis of 1-methyl-3-(trifluoromethyl)-1H-
pyrazole and 1-methyl-5-(trifluoromethyl)-1H-pyrazole.
Taking the kilo scale access to key pyrazoles 1a and 2a, we started the elaboration of
the convenient approaches to all building blocks depicted on Scheme 4. Firstly, we tested
the lithiation of 1-methyl-3-(trifluoromethyl)-1H-pyrazole leading to 3-CF -5-FG
3
derivatives type 12. In order to develop the scale-up protocol, we studied the lithiation of
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2
2
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3
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4
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5
5
5
5
5
5
5
5
5
6
2
7
compound 1a in a flow variant using our in-house developed flow systems. In-house
flow-apparatus trim is shown in Figure 4.
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8
9
0
b) Flow spirals. 1) 90 ml pre-
cooling spiral; 2) 110 ml pre-
cooling spiral; 3) 620 ml
spiral; 4) 320 ml spiral.
a) The general appearance of the flow system. 1) PFA flow spirals, mixers, temperature
sensors for all stages inside a dry ice-cooled insulated IPA bath; 2) Temperature sensor
connectors; 3) Liquid inlet/outlet connectors; 4) Stirred product collection bottle, under argon;
c) Example of the mixer (1 of
5) Reagent and wash solvent bottles, under argon; 6) Process controller (emergency pressure
3
). 1) tee piece, stainless
system shutoff and temperature sensors readouts); 7) Argon pressure regulator for
reagent/product bottles; 8) Peristaltic pump bank, pressure sensors and reagent/wash selector
valves.
steel; 2) static mixer,
stainless steel; 3) Pt100
temperature sensor port; 4)
outlet to spiral.
Figure 4. In-house flow-apparatus for lithiation.
The preliminary experiments with 0.33 M THF solution of pyrazole 1a and 2.5 M solution
of n-BuLi in THF allowed us to find optimal flow conditions for the generation of lithium
derivative 11x (for the general flow set up see Scheme 4, the reactor volumes were 200
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mL and 100 mL, respectively). More concentrated solutions of the compound 1a in THF
could not be used in our procedure due to the formation of precipitate during the flow
process. It was found that the optimal temperature was –50 °C while the generation
residence time was 12 min for the 600 mL reactor volume. The further treatment of the
lithiated pyrazole 11x was carried out in two different ways. In the case of synthesis of
aldehyde 11b and boronic ester derivative 11d the solution of electrophilic reagent (1.5
eq of DMF or 1.2 eq. of i-PrOBPin, respectively) in THF was added via the third channel
and further reaction started in the second 300 mL reactor with 5 min residence time at –
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
50 °C. In the case of DMF, this 5 min time appeared to be sufficient for the reaction
completion. The reaction mixture could be treated for further isolation/purification
immediately giving the desired product 11b in 74% yield. In the case of boronic ester
derivative 11d the reaction time 5 min at –50 °C was not sufficient for its completion.
Therefore, in this case the collected reaction mixture was additionally maintained in a
batch reactor at room temperature overnight before product isolation. The yield of the
purified boronic ester derivative 11d was 57%. In the case of acid 11c and lithium
pyrazolylsulfinate 11e, the electrophilic reagents were gaseous. Therefore, for these
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5
5
6
syntheses, another approach was used. To avoid the principal re-designing of flow
system pure THF was added to the third channel and ca ~0.25 M solution of lithiated
pyrazole 11x in THF formed in the batch variant. For 11c ~0.25 M solution of 11x was
collected into the reactor containing 2-fold excess of dry ice. After the reaction completion
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
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7
8
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
at room temperature and evaporation of the excess of CO the desired acid 11c was
2
isolated in 78% yield. For the efficient synthesis of lithium pyrazolylsulfinate 11e, the
above-mentioned solution of organolithium 11x was collected in the batch reactor cooled
to –50 °C. The 5-fold excess of gaseous SO was bubbled through this solution. Then the
2
reaction mixture was kept at room temperature and the sulfinate 11e precipitated in 78%
yield. All these processes could be easily scaled up to kilo-scale. Even in the above-
mentioned system the productivity of the processes was 116-152 g/h (Scheme 4, Table
1). Finally, the important building block – corresponding sulfonyl chloride 11f – was
obtained by batch chlorination of pyrazolylsulfinate 11e by NCS in DCM at 0 °C in 56%
yield affording more than 30 g of the compound in one synthetic run (Scheme 4).
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F3C
Addition of
reagents (see Table 1)
N
N
10 mL / min
1
a
F3C
Reaction solution
0.33 M in THF
4.2 mL/min
60 mL / min
4
N
Li
N
11x
6
00 mL
1 = 12 min
300 mL
2 = 5 min
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
n-BuLi
2.5 M in hexane
.8 mL/min
- 50 °C
5
F3C
F3C
F3C
N
F3C
Batch
Procedures
for compounds 11
O
O
S
N
N
N
CHO
CO2H
B
N
N
N
N
O
O Li
see Table 1
1
1b, 74%
16 g/h
11c, 78%
11d, 57%
139 g/h
11e, 78%
152 g/h
1
134 g/h
was used in the next step without
additional purification
F3C
F3C
NCS
DCM, 0 °C
O
N
N
S
56 %
SO2Cl
N
N
O Li
11e
11f
Scheme 4. The synthesis of 5-functionalyzed 1-methyl-3-(trifluoromethyl)-1H-pyrazoles
(
3-CF -5-FG) 11 (flow system A).
3
During this part of the project, we met the problem of stable operation of the flow system
presented on Scheme 4. Due to the significant misbalance of the flow rates of THF
solution of pyrazole 1a (44 mL/min) and 2.5 M solution of n-BuLi (6 mL/min) the system
worked stably only for 15-30 min. After this time some problems with temperature control
occurred as well as some precipitate formed. Therefore, for a long-time stable operation,
we decided to reduce the productivity of the system. In this case, we added 110 mL
reactor to the system for the dilution of the 2.5 M solution of n-BuLi in hexane by THF at
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
–
50 °C and 90 mL reactor for the pre-cooling of 0.33 M THF solution of pyrazole 1a. The
residence time for the 620 mL and 320 mL reactors was similar to the previous cases.
This system was tested and its behavior was stable during more than 8h operation time.
However, this modification of the system reduced productivity by 38% (Scheme 5).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
n-BuLi
A
2.5 M in
hexane
3.8 mL/min
B
THF
2
3.3 mL/min
F3C
Reaction solution
60 mL / min
110 mL
F3C
N
Li
N
N
N
11x
C
D
620 mL
1 = 11 min
320 mL
2 = 5 min

15
0
2
.33 M in THF
7,1 mL/min
90 mL
Addition
of reagents
Batch
-
50 °C
Procedures
for compounds 11
see Table 1
(
see Table 1)
5.8 mL/min
F3C
F3C
F3C
N
F3C
O
O
S
N
N
N
CHO
CO2H
B
N
N
N
N
O
O Li
11b, 74%
1 g/h
11c, 78%
82 g/h
11d, 57%
85 g/h
11e, 78%
93 g/h
7
Scheme 5. Synthesis of the 5-functionalyzed 1-methyl-3-(trifluoromethyl)-1H-pyrazoles
(3-CF -5-FG) 11 (flow system B).
3
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Table 1. Conditions for the flow synthesis of the compounds 11b-e.
Productivit
Additional
Yield,
%
#
1
Cpd FG
Batch procedures
y,
A/B)
g/h
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reagent
(
1
. Saturated NH Cl
4
2. Evaporation
2.2 M DMF 3. MTBE-H O treatment
2
11b CHO
74
116 / 71
in THF
4 Organic phase evaporation
. Chromatography SiO /hexane-
5
2
MTBE (10:1, Rf = 0.9).
1. The reaction solution was collected
in a batch with dry ice (~2 eq).
2. The mixture was maintained
overnight at rt.
2
11c CO H
pure THF
78
134 / 82
2
3
After CO evaporation the residue
2
was treated by DCM-H O.
2
4. The water phase was acidified by
H PO to pH = 2 and the precipitate
3
4
formed was collected by filtration
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
. The reaction solution was collected
and maintained overnight at rt.
2. Evaporation
1.8
M
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
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8
9
0
3
11d BPin
iPrOBPin
in THF
3. MTBE-H O treatment
57
139 / 85
2
4
The organic phase was evaporated
5. Chromatography SiO /hexane-
2
MTBE (85:15, Rf = 0.85)
1. The reaction solution was collected
in a batch cooled to -50 °C.
2. The flow of gaseous SO was
2
passed (5-fold excess) through a
solution formed.
4
11e SO Li
pure THF
78
152 / 93
2
3. The solution was maintained
overnight at rt.
4. The precipitate formed was
collected by filtration and washed by
MTBE
For the insertion of the functionality into the 4-th position in both regioisomeric
trifluoromethylpyrazoles 1a and 2a the electrophilic bromination was optimized and
scaled up. The bromination of 1.3 M solution of both pyrazoles in DMF by 1.3 eq of NBS
at 60 °C during 10h was the optimal condition. Product isolation was provided by vacuum
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distillation of the reaction mixture. This developed procedure appears to be more
convenient for the scale-up compared to the Schlosser's one, where Br /Fe system at
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
00 °C was utilized.24 When the 200 g of staring pyrazoles 1a and 2a were taken the
preparative yields of corresponding brominated derivatives 12a and 13a were 92% and
83%, respectively (Scheme 6).
F3C
Br 1.3 eg NBS F3C
1.3 eg NBS
DMF, 60 °C
Br
DMF, 60 °C
N
N
N
N
CF3
CF3
13a
N
N
N
N
92%
83%
12a
1a
2a
Scheme 6. Bromination of trifluoromethylpyrazoles.
Among two brominated isomers, 4-bromo-5-CF one was chosen for the further Br-Li
3
exchange. In the case of 4-functionalized-3-CF building blocks, the core starting material
3
is the corresponding acid, which is now readily commercially available (according to
SciFinder > 10 suppliers propose it in a kilo scale). The route to the acid was based on
cyclizations of 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoates with methylhydrazine
derivatives and it was developed during Penthiopyrad project.30 Previously 4-bromo-1-
methyl-5-(trifluoromethyl)pyrazole 13a was selectively lithiated by t-BuLi in Et O at -
2
24
7
5 °C. The lack of such an approach was the use of both t-BuLi and Et O which was
2
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
not a convenient reagent/solvent combination for safe performance, especially in a large
scale. We found that selective Br-Li exchange could be achieved by n-BuLi treatment in
THF at -78 °C in a batch reactor. The adaptation of the protocol to the flow reactor failed
due to precipitation of the LiBr from the reaction mixture. Generation of the corresponding
lithium derivative 13x was scaled up to 50g of starting bromide 13a in 2L three-necked
reactor. The subsequent reaction of this organolithium derivative 13x with DMF or CO2
afforded the aldehyde 13b or corresponding acid 13c in 77% and 82% yields, respectively
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Scheme 7). These examples indicated the perspective of the approach to 5-CF -4-FG
3
derivatives in scale.
Starting from 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole 13a we also tested the
multigram scale approach to 5-CF -3-FG derivatives 14 based on DoM lithiation-
3
functionalization-debromination (see Scheme 2). In seminal Schlosser paper, the DoM
lithiation was performed by the reverse addition of the substrate to LDA solution in
THF/hexane. We checked if the “normal” addition of LDA solution to the pyrazole 13a
could be performed. It was found, that the reaction proceeded cleanly but at the
temperatures below -85 °C. The process requiring such low temperatures could not be
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successfully adapted to flow mode. Using the flow reactor in the conditions typical for
similar purposes (-70 °C to -30 °C, residence time on lithiation step from 5 to 20 min, and
trapping residence from 2 to 10 min) led to the significant formation of the isomeric side
product due to the “halogen dance” reaction.31 As in the previous case with Br-Li
exchange, the DoM generation of lithium derivative 15x was scaled up to 50g of the
starting bromide 13a in 2L three-necked reactor but at -85 °C. The trapping of the
organolithium derivative 15x by dry ice afforded the corresponding acid 15c in 66%
preparative yield. Alternatively, compound 15x was subjected to the reaction with
iPrOBPin leading to the corresponding boronic acid pinacolate 15d formation in 43%
preparative yield. The structure of the boron derivative was unambiguously determined
by the single-crystal X-ray diffraction study which proved the absence of the “halogen
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
2
2
2
3
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3
3
3
3
3
4
4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
dance” reaction (Scheme 3, Figure 5). For the synthesis of parent 5-CF -3-FG derivatives,
3
we tested the debromination by catalytic hydrogenation over Pd/C catalyst. In the case of
bromoacid 15c, the hydrogenation proceeded cleanly at 50 atm in MeOH at the presence
of triethylamine producing the desired product 14c in 94% preparative yield on 30 g scale.
The similar hydrogenation of brominated boronic acid 15d was accomplished by
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1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
deborylation, but the target pinacolate 14d could be preparatively isolated in 28% yield
on 30 g scale of the starting material (Scheme 7).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
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8
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0
1
2
3
4
5
6
7
8
9
0
DMF
78 °C to rt,
THF, 30 min
CHO
CF3
3b
dry ice
rt, overnigh
-
CO2H
CF3
Li
N
N
N
N
CF3
13x
.5 M n-BuLi in hexane
77%
N
82%
N
1
13c
O
2
O
B
- 78 °C, THF, 45 min
HO2C
Br
N
CF3
N
N
CF3
14c
N
14d
N
CF3
N
H2, 50 atm
13a
10% Pd/C
H2, 50 atm
10% Pd/C
TEA,
28%
O
O
LDA (from 1 M n-BuLi
in THF-hexane, HN(iPr)2)
TEA,
MeOH
B
94%
O
-
85 °C, THF, 45 min
MeOH
O
B
-
85 °C, THF, 45 min
dry ice
Li
Br
HO C
Br
O
Br
2
to rt, than overnight
rt, overnigh
66%
N
N
N
CF3
15x
CF3
CF3
15d
N
N
N
43%
15c
Scheme 7. Lithiation of 4-bromo-5-CF -pyrazole.
3
Figure 5. X-ray structure of compound 15d.32
In this project, the functional group interconversion was illustrated by Curtius-type
rearrangement of two regioisomeric acids 11c and 14c. This transformation is important
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because the insertion of the amino function via lithiated intermediates is problematic due
to the lack of appropriate nitrogen-centered electrophiles. The multigram scale
transformation was performed by DPPA induced Curtius-type rearrangement in t-BuOH
at the presence of TEA at 100 °C. As a result, the corresponding Boc-protected amines
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
11g and 14g were formed and isolated in 67% and 54% yield, respectively. The Boc-
deprotection was achieved by treatment in DCM with 10M HCl solution in dioxane. The
final amines 11h and 14h were isolated as hydrochlorides in 83% and 77% yields,
respectively (Scheme 8).
1.2 eq. DPPA
3
eq. TEA
t-BuOH
10 M HCl
F3C
rt to 100 °C, 2h
then 57 °C 8h
F3C
in dioxane F3C
DCM, rt, 6h
O
tBu
N
N
O
N
CO2H
67%
N
83%
NH3 Cl
11h
N
N
O
N
H
1
1c
11g
1.2 eq. DPPA
3
eq. TEA
t-BuOH
rt to 100 °C, 2h
then 57 °C 8h
10 M HCl
in dioxane
DCM, rt, 6h
HO2C
Cl
N
NH
H3N
tBu
O
N
CF3
54%
N
77%
N
N
CF3
CF3
14h
N
14c
14g
Scheme 8. Curtius-type rearrangement of pyrazolylcarboxylic acids.
CONCLUSION
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In summary, an efficient and practical kilo-scale procedure for 1-methyl-3-
(
trifluoromethyl)-1H-pyrazole
and
1-methyl-5-(trifluoromethyl)-1H-pyrazole
was
0
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developed on the basis of cyclization of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one with
methylhydrazine hydrochloride with subsequent regioisomers separation by distillation.
This protocol opens the door to the active use of these compounds as starting materials
for the design and synthesis of important MedChem and AgroChem relevant building
blocks. For the introduction of the functional group into the 5-th position of 1-methyl-3-
(trifluoromethyl)-1H-pyrazole, the flow lithiation by n-BuLi was developed followed with
trapping by the electrophilic reagent. The efficiency of the methodology was proven by
the synthesis of corresponding examples of aldehyde, acid, boron pinacolate and lithium
sulfinate in 57-78% yield and productivity 116-152 g/h. The batch mild conditions for the
bromination of both 1-methyl-3-(trifluoromethyl)-1H-pyrazole and 1-methyl-5-
(
trifluoromethyl)-1H-pyrazole by NBS were developed and the synthesis was scaled up
to 200 g in one synthetic run. The Br-Li exchange in 4-bromo-1-methyl-5-
(
trifluoromethyl)pyrazole was optimized, and a hazardous combination of t-BuLi in Et O
2
was replaced by much more safe n-BuLi in THF. Based on the method, the corresponding
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aldehyde and acid were synthesized in 50 g scale. Also, in the same scale, the direct
ortho-metalation of the 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole by LDA was
developed for the synthesis of the corresponding acid and boron pinacolate. For the
synthesis of “parent” 1-methyl-5-(trifluoromethyl)-1H-pyrazoles bearing function in the 3-
rd position, the catalytic hydrogenative debromination of the DoM products was
accomplished. Finally, the handy procedure for the Curtius-type rearrangement leading
to amines was proposed.
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1
1
1
1
1
1
1
1
1
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2
2
2
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2
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0
EXPERIMENTAL SECTION
General. The solvents were purified according to the standard procedures. All starting
materials were obtained from Enamine Ltd. Melting points were measured on automated
melting point system. H, 13C, and 19F NMR spectra were recorded on a Bruker 170
Avance 500 spectrometer (at 500 MHz for Protons and 126 MHz for Carbon-13) and
Varian Unity Plus 400 spectrometer (at 400 MHz for protons, 101 MHz for Carbon-13,
1
1
13
19
and 376 MHz for Fluorine-19). Tetramethylsilane ( H, C) or C F ( F) were used as
6
6
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