Acid-Mediated Three Component Assembly of 4-Fluoropyrazoles from α-Fluoronitroalkenes, Hydrazines, and Aldehydes

Article abstract of DOI:10.1002/ejoc.202000841

A new approach for the synthesis of highly pharmaceutically relevant 4-fluoropyrazoles via oxidative annulation of α-fluoronitroalkenes with in situ prepared hydrazones was developed. The reaction is efficiently promoted by trifluoroacetic acid while atmo

Full text of DOI:10.1002/ejoc.202000841

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Acid-mediated three component assembly of 4-fluoropyrazoles
from α-fluoronitroalkenes, hydrazines and aldehydes
Authors: Vladimir Motornov, Andrey Tabolin, Yulia Nelyubina,
Valentine Nenajdenko, and Sema Ioffe
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000841
Link to VoR: https://doi.org/10.1002/ejoc.202000841
01/2020

10.1002/ejoc.202000841
European Journal of Organic Chemistry
FULL PAPER
Acid-mediated three component assembly of 4-fluoropyrazoles
from α-fluoronitroalkenes, hydrazines and aldehydes
Vladimir A. Motornov,[a,b] Andrey A. Tabolin,*[a] Yulia V. Nelyubina,[c] Valentine G. Nenajdenko[d] and
Sema L. Ioffe[a]
[a]
[b]
Vladimir A. Motornov, Dr. Andrey A. Tabolin, Prof. Dr. Sema L. Ioffe
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences
Leninsky prosp. 47, 119991 Moscow, Russia.
E-mail: tabolin87@mail.ru; atabolin@ioc.ac.ru
https://zioc.ru/institute/laboratories/laboratory-of-organic-and-metal-organic-nitrogen-oxygen-systems-9; http://nitrogroup.tilda.ws/
Vladimir A. Motornov
Higher Chemical College
D. I. Mendeleev University of Chemical Technology of Russia
Miusskaya sq. 9, 125047, Moscow, Russia
[c]
[d]
Dr. Yulia V. Nelyubina
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences
Vavilov str. 28, 119991, Moscow, Russia
Prof. Dr. Valentine G. Nenajdenko
Department of Chemistry
M. V. Lomonosov Moscow State University
Leninskie Gory 1, 119991, Moscow, Russia
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract:
A
new approach for the synthesis of highly
been only one example of cycloaddition leading to
4-fluoropyrazole described in the literature, namely the reaction
of diazomethane with 1-fluoro-2-trimethylsilylacetylene.[14]
Evidently, the key problem of such approaches is the availability
of 1-fluoroalkynes, that are described as unstable and explosive
compounds.[15] Recently we have demonstrated efficient
synthesis and application of α-fluorinated nitroalkenes as
synthetic equivalents of fluoroalkynes in [3+2]-cycloadditions
towards monofluorinated pyrroles, NH- and 2,5-disubstituted
triazoles, indolizines and pyrazolo[1,5-a]pyridines,[16,17] while Roy
et al. described the synthesis of 1,5-disubstituted triazoles.[18,19]
Preparation of 4-fluoropyrazoles from nitroalkenes is highly
pharmaceutically relevant 4-fluoropyrazoles via oxidative annulation
of α-fluoronitroalkenes with in situ prepared hydrazones was
developed. The reaction is efficiently promoted by trifluoroacetic acid
while atmospheric oxygen was used as an oxidant. Broad substrate
scope was demonstrated. Both electron-rich and electron-deficient
nitroalkenes as well as different hydrazones derived from aromatic
aldehydes can be used. Mechanistic details were outlined.
Introduction
attractive as
a straightforward route to these type of
Fluorinated heterocycles are important compounds frequently
used in medicinal chemistry and drug design.[1] Fluorinated
pyrazoles are of special interest with Celecoxib (Celebrex®)
being among the most representative examples (Figure 1).[2]
This drug belongs to the coxib family of COX-2 inhibitors used
pharmaceutically important heterocycles. Herein we report a
new efficient synthesis of 4-fluoropyrazoles using oxidative
annulation of fluoronitroalkenes with in situ prepared hydrazones
(Scheme 1).
for treatment of inflammation.[3,4] Various bioactivities, such as
[5]
antiviral,
antithrombotic,[6] antiparasitic,[7] antitumor[8] of
fluorinated pyrazoles, including 4-fluoro-substituted ones have
been explored, which makes the development of new synthetic
methods an important task. In contrast to chlorinated and
brominated pyrazoles, which can be easily prepared via direct
electrophilic halogenation of the pyrazole ring,[9] the synthesis of
fluoropyrazoles is more difficult and less studied (Scheme 1). In
most of the recent reports, 4-fluoropyrazoles were prepared by
condensation of monofluorinated β-ketocarbonyl compounds or
fluorinated β-ketonitriles with hydrazines, [10] using intramolecular
[11]
annulation of alkynyl-hydrazones,
double C–H activation of
N-alkyl hydrazones, [12] or direct fluorination of pyrazoles. [10c,13]
Limited scope and availability of starting fluorinated compounds
are the main drawbacks of these methods.
[3+2]-Cycloaddition reactions are quite attractive approaches for
heterocyclic chemistry to provide the most straightforward route
to five-membered heterocycles. An important advantage of such
synthesis is high functional group tolerance. However, there has
1
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10.1002/ejoc.202000841
European Journal of Organic Chemistry
FULL PAPER
showed no formation of target fluorinated pyrazole 3a when
DCE or MeCN were used as solvents (entries 1-2). However,
using methanol as a solvent the product was observed in poor
yield and low conversion of starting nitroalkene (entry 3).
Utilization of base (K2CO3) led to traces of the product (entry 4).
To our delight, switching the solvent from methanol to more
acidic trifluoroethanol led to significant improvement of both
conversion and yield of target product 3a (entry 5). Therefore,
positive impact of acidic, rather than basic conditions was taken
into account. Indeed, addition of catalytic amount of
trifluoroacetic acid resulted in the acceleration of the reaction
and improvement of the yield (entry 6). Increase of the acid
amount afforded higher conversion, though the reaction was still
incomplete to give moderate yields of pyrazole at room
temperature (entries 6-9). Variation of acids showed that TsOH
and sulfamic acid are less efficient than TFA (entries 9-11).
Finally, complete conversion and good yield of pyrazole was
observed, when reflux in 2,2,2-trifluoroethanol (TFE) was
employed (entry 12). Increasing of TFA amount to 2 equiv.
afforded target 4-fluoropyrazole in 81% yield (entry 13). It should
be noted that the reaction in other protic solvents, like methanol
and hexafluoroisopropanol, did not afford complete conversion
of starting materials (entries 14-15).
Figure 1. Representative bioactive fluorinated pyrazoles.
Table 1. Optimization of reaction conditions[a]
Entry
Additive (equiv.)
Solvent
Conversion
Yield
1a, % [b]
3a, % [b]
1
-
DCE
MeCN
MeOH
MeOH
TFE
<10
<10
25
n.d.
n.d.
17
2
-
3
-
4
K2CO3 (1.5)
-
<10
45
trace
39
5
6
TFA (0.2)
TFA (0.1)
TFA (0.5)
TFA (1)
TsOH‧H2O (1)
HSO3NH2 (1)
TFA (1)
TFA (2)
TFA (2)
TFA (2)
TFE
40
46
7
TFE
33
52
Scheme 1. Selected approaches to 4-fluoropyrazoles.
8
TFE
49
52
9
TFE
76
51
Results and Discussion
10
11
12[c]
13[c]
14[c]
15[c]
TFE
30
42
We started our study with the model reaction of fluoronitroalkene
1a and hydrazone 2a in situ prepared from the corresponding
aldehyde and hydrazine by stirring at room temperature for 1
hour. Such one-pot three component protocol would open the
possibility to perform synthetically attractive procedure starting
from readily available benzaldehydes and hydrazines. Moreover,
it should provide independent variation of all three inputs for the
construction of target 4-fluoropyrazoles 3 to make this approach
very modular. First experiments towards pyrazole synthesis
TFE
48
41
TFE
100
100
70
72
TFE
81
MeOH
HFIP
11
72
51
2
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10.1002/ejoc.202000841
European Journal of Organic Chemistry
FULL PAPER
found general for sterically and electronically different
benzaldehydes. Thus, high yields were achieved for electron
rich p-methoxy-substituted aldehydes (3p, 3q), electron-neutral
p-chloro-substituted (3o), electron poor p-cyano- (3r) as well as
for sterically hindered o-bromo-substituted hydrazones (3t).
Some heterocyclic aldehydes (e.g., 2-thiophenecarboxaldehyde)
can be also involved in the reaction (product 3u). Unfortunately,
[a] Reaction conditions: p-TolCHO (0.24 mmol), PhNHNH2 (0.24 mmol) in
solvent (2 ml) were stirred at r.t. for 1 h. After that 1a (0.2 mmol) and additive
were
added,
and
the
mixture
was
stirred
overnight
at
r.t., unless noted otherwise. [b] Yields were determined by 19F NMR with
PhCF3 as internal standard and calculated based on recovery of starting 1a;
[c] The mixture was refluxed for 6 h; n. d. = not detected (1a was recovered)
Having the optimized conditions (Table 1, entry 13) in hand, the
substrate scope of N-arylated fluoropyrazoles was investigated.
First, differently substituted fluoronitroalkenes 1 were tested
(Table 2). A brief investigation of the functional group influence
showed the reaction to proceed efficiently with electron-neutral
(3a-3b) or electron-deficient (3c) nitroalkenes giving target
fluorinated pyrazoles 3 in good to excellent yields. The reaction
with electron-rich p-methoxy-substituted nitroalkene (product 3d)
was significantly slower demanding 9 h for completion. Variation
of arylhydrazines showed good yields for neutral and donor
substituents (3e-i) while p-nitrophenyl hydrazine gave inferior
results.
hydrazones
derived
from
aliphatic
aldehydes
(e.g.
isobutyraldehyde, hydrocinnamic aldehyde) failed to give target
pyrazoles, producing mixture of multiple decomposition
products. The reaction is not limited to the application of
methylhydrazine as other different N-substituted pyrazoles were
found to be available by this method. Thus, N-benzylpyrazole 3v
was prepared in good yield. Importantly, NH-pyrazole 3w was
obtained from unsubstituted hydrazone as well, though the
reaction required much longer time because of low solubility of
hydrazone in alcohol solvents.
Ar
F
F
Ar'
NO2
1
Ar'
Ar'CHO
+
RNHNH2
MeOH
r.t.,1 h
N
N
TFA (2 equiv.),
MeOH, 65°C,
4-14 h
Ar
RHN
Me
N
R
3
Table 2. Synthesis of N-aryl-4-fluoropyrazoles 4 from various nitroalkenes 1,
aldehydes and arylhydrazines.
2
Me
Me
F
F
F
N
N
N
N
N
N
Cl
Br
Cl
F3C
Me
Me
Me
3n
3m
, 77%
3l
, 71%
, 76%
6 h
6 h
6 h
MeO
OMe
OMe
OMe
3
X1
X2
X3
time, h
Yield 3, %
F
F
F
3a
3b
3c
3d
3e
3f
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-OMe
4-СN
H
4-Cl
6
72
81
78
62
57
56
62
52
56
67
39
N
N
N
N
N
N
Cl
Cl
Cl
Me
Me
Me
H
4-F
5
3o
3p
3q
, 52%
6 h
, 80%
, 65%
6 h
H
4-CO2Me
4-OMe
4-Cl
3
6 h
MeO
CN
Cl
H
9
Br
4-Me
4-Ph
4-F[a]
4-OMe[a]
2-OEt[a]
H
5
F
F
F
4-Cl
11
4
N
N
N
N
N
N
Cl
Cl
Me
Me
Me
3g
3h
3i
4-Cl
3t, 60%
5 h
3s
3r
, 75%
, 63%
4 h
4-Cl
6
6 h
Cl
Me
S
N
4-Cl
7
F
F
F
3j
4-Cl
4
N
N
N
N
N
H
3k
H
4-Cl
15
Cl
Me
Cl
Cl
3u
, 25%
7 h
[a] Ar2NHNH2 was prepared in situ from the corresponding salt and NEt3
[a]
3w
, 57%
15 h
3v, 79%[a]
Next, the scope of alkyl hydrazines for the preparation of
N-substituted fluoropyrazoles was investigated (Scheme 2).
Importantly, in the case of N-methylhydrazones the reaction
efficiently proceeds in methanol as a solvent, most probably,
because of significantly higher nucleophilicity of hydrazone.[20]
Generally, the reaction proceeded smoothly for differently
substituted nitroalkenes, aldehydes and hydrazines resulting in a
broad variety of pyrazoles 3l-3w in high yields. The reaction was
5 h
Scheme 2. Synthesis of fluoropyrazoles 3e-3n from different
fluoronitroalkenes 1 and hydrazones 2. Yields refer to isolated products 3. [a]
TFE was used as a solvent.
3
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10.1002/ejoc.202000841
European Journal of Organic Chemistry
FULL PAPER
Obtained pyrazoles were characterized by 1H, 13C and 19F NMR
spectra as well as by HRMS data. In addition, single crystal X-
ray analysis was performed for pyrazole 3o (Figure 2).[21] It
should be also noted that in all cases only 4-fluoroderivatives
were isolated, while for similar annulation with chloro- and
bromo-nitroalkenes the formation of mixtures of 4-halo and 4-
nitro-pyrazoles was occasionally observed.[22]
acceptors.[16b,c] We believe, that the favorability of acid-mediated
approach for fluoronitroalkenes and lack of their reactivity with
hydrazones under basic conditions (Table 1) makes the
concerted mechanism more likely (Scheme 4). However, it’s
worth noting that no uncyclized intermediates were detected at
any stage of the reaction. Proposed mechanism involves
protonation of hydrazone followed by concerted [3+2]-
cycloaddition of intermediately forming 1,3-dipole
B with
fluoronitroalkene, leading to the formation of pyrazolidine 4 as a
key intermediate. Subsequent oxidation of intermediate 4 by
atmospheric oxygen results in pyrazoline C. Finally, pyrazoline 4
undergoes fast HNO2 elimination, leading to the formation of
4-fluoropyrazole 3. Here chemoselectivity of the reaction may be
attributed to the high energy of C–F comparatively to the C–NO2
bond.[16a-d, 17a] We believe that cycloaddition is the rate limiting
step of the whole sequence since in most cases neither
pyrazolidines 4 nor pyrazolines C were observed. However,
oxidation step became more important for electron-poor
aldehydes (see Scheme 3) as the presence of electon-
withdrawing group at the position 3 should increase the
oxidation potential of pyrazolidine 4.
Figure 2. General view of the compound 3o in representation of atoms via
thermal ellipsoids at 50% probability level.
Different situation was observed in the case of hydrazone
derived from electron-deficient 4-nitrobenzaldehyde. The
reaction of its N-methyl hydrazone with fluoronitroalkene
resulted in unexpected formation of mixture of pyrazole 3x and
unknown product that was tentatively assigned as pyrazolidine
4x. The latter was found to be relatively stable under the
reaction conditions (Scheme 3). Fortunately, stirring of the
suspension of 4x in MeOH at rt under air for 3 days resulted in
complete conversion to target pyrazole 3x in moderate total
yield. Alternatively, negligible amounts of 4x were observed due
to acceleration of the oxidation step when annulation was
performed under oxygen atmosphere. We believe that the
presence of bulky aryl groups[23] and electron-withdrawing
substituents[24] as well as low solubility of 4x makes its oxidative
aromatization more difficult.
Scheme 4. Proposed mechanism of oxidative annulation.
To demonstrate the value of the developed approach to
4-fluoropyrazoles, the target-oriented synthesis was attempted.
Thus, recently pyrazole derivative 5 was shown as an effective
FABP3 (fatty acid binding protein 3) ligand and hence to be a
promising agent for the treatment of Parkinson’s disease.[26]
Considering the importance of fluorine heterocycles for
medicinal chemistry we decided to prepare its fluorinated
analogue 6 (Scheme 5).
Starting from commercially available salicylaldehyde, the
aldehyde 7 was prepared. Then assembly of pyrazole nucleus
was accomplished via sequential treatment of aldehyde 7 with
phenylhydrazine and nitroalkene 1g as a key step. The ester-
substituted pyrazole 8 was isolated as a crude product and used
without further purification. Hydrolysis of the ester group by
KOH/MeOH afforded target acid 9 in 41% total yield starting
from 1g. This sequence allowed to prepare target fluorinated
FABP3 ligand 6 starting from commercially available reagents
and nitroalkene 1g in four steps in 35% overall yield.
Scheme 3. Synthesis of 3-nitrophenylpyrazole 3x.
From the mechanistic point of view, concerted and stepwise
mechanisms of [3+2]-cycloaddition are possible for this
reaction.[20,22,24] While stepwise mechanisms involving Michael
addition/cyclization are known to be more favored for
annulations of nitroalkenes in basic conditions involving strong
nucleophilic reaction partners,[25] mechanism of acid-mediated
annulations is a subject of discussions. [20,22] Comparatively to
α-unsubstituted nitroalkenes and even α-alkylated nitroalkenes
halonitroalkenes are considered to be weaker Michael
4
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10.1002/ejoc.202000841
European Journal of Organic Chemistry
FULL PAPER
CO2Me
was used as its salt, 1.2 equi.v of NEt3 was added before the addition of
aldehyde), and the mixture was stirred at r.t. for 1 h until the hydrazone
formation was complete (TLC monitoring). To the resulting solution TFA
(2 equiv.) was added, followed by addition of fluoronitroalkene 1 (1 equiv).
The mixture was maintained at 78°C (oil bath) for 3-15 h (TLC
monitoring). After the reaction was complete, it was evaporated with
silica gel and the products were purified by column chromatography
(PE/CH2Cl2 or PE/EtOAc) to afford target fluoropyrazoles 3.
O
O
Cl
K2CO3, KI
DMF, 90°C, 3 h
O
CO2Me
OH
7, 86%
1. PhNHNH2
TFE, rt, 2 h
KOH, MeOH,
60°C, 4 h
then
HCl/H2O
F
O
N
Cl
5-(4-Chlorophenyl)-4-fluoro-3-(4-methylphenyl)-1-phenyl-1H-
NO2
N
pyrazole (3a). Pyrazole 3a was obtained from α-fluoronitroalkene 1a
(30.2 mg, 0.15 mmol), p-tolualdehyde and phenylhydrazine following the
general procedure 1 (reaction time - 6 h). Column chromatography
afforded 3a (39 mg, 72%) as a yellow solid. Rf = 0.48 (PE/DCM, 3:1)
2.
Ph
OMe
F
Cl
1g
O
TFE, TFA (2 equiv.)
8
70°C, 22 h
1
without purification
(UV); mp 122-124°C (CHCl3). H NMR (300 MHz, CDCl3): δ 2.41 (s, 3H,
Me), 7.23 (d, J = 8.5 Hz, 2H, CHAr), 7.28 (d, J = 8.1 Hz, 2H, CHAr), 7.34-
7.41 (m, 7H, CHAr), 7.89 (d, J = 8.1 Hz, 2H, CHAr). 13C NMR (75 MHz,
CDCl3): δ 21.4 (Me), 124.9 (CHAr), 125.8 (d, 3JCF = 3.9 Hz, CAr), 126.1 (d,
4JCF = 3.6 Hz, CHAr), 127.7 (CAr, overlapped), 127.73 (CHAr), 128.1 (d,
2JCF = 23.2 Hz, C5), 129.0 (CHAr), 129.1 (CHAr), 129.4 (CHAr), 130.2 (d,
H
O
F
O
N
N
Ph
N
N
2
4JCF = 1.9 Hz, CHAr), 134.7 (C-Cl), 138.2 (CAr), 138.5 (d, JCF = 6.3 Hz,
OH
Ph
1
C3), 139.8 (CAr), 145.7 (d, JCF = 254.5 Hz, C4). 19F NMR (282 MHz,
OH
Cl
Cl
5
O
O
CDCl3): δ -172.1 (s). IR (KBr): ν˜=1593 (m), 1494 (s), 1483 (s), 1395 (m),
1364 (s), 1316 (m), 1185 (s), 1089 (s), 1015 (m), 963 (s), 833 (vs), 820
(vs), 776 (vs), 724 (s), 696 (vs), 653 (s) cm−1. HRMS (ESI): m/z calcd. for
[C22H16ClFN2+H+]: 363.1059, found: 363.1059.
potent FABP3 ligand (ref.[26]
)
6
41% (from 7)
Scheme 5. Synthesis of fluorinated analogue of FABP ligand 5.
4-Fluoro-5-(4-fluorophenyl)-3-(4-methylphenyl)-1-phenyl-1H-
pyrazole (3b). Pyrazole 3b was obtained from α-fluoronitroalkene 3b (37
mg, 0.2 mmol), p-tolualdehyde and phenylhydrazine following the general
procedure 1 (reaction time 5 h). Column chromatography afforded 3b
(55.8 mg, 81%) as a yellow solid. Rf = 0.39 (PE/DCM, 1:1) (UV); mp 128-
130°C (CHCl3). 1H NMR (300 MHz, CDCl3): δ 2.41 (s, 3H, Me), 7.07 (t, J
= 8.7 Hz, 2H, CHAr), 7.23-7.42 (m, 9H, CHAr), 7.89 (d, J = 8.0 Hz, 2H,
CHAr). 13C NMR (75 MHz, CDCl3): δ 21.4 (Me), 115.8 (d, 2JCF = 13.7 Hz,
CHAr), 123.5-123.6 (m, CAr), 124.9 (CHAr), 126.2 (d, 4JCF = 3.6 Hz, CHAr),
127.8 (d, 3JCF = 4.1 Hz, CAr), 127.8 (CHAr), 128.2 (d, 2JCF = 23.4 Hz, C5),
129.1 (CHAr), 129.4 (CHAr), 130.9 (dd, JCF = 8.3, 1.6 Hz, CHAr), 138.1
(CAr), 138.4 (d, 3JCF = 6.2 Hz, C3), 139.8 (CAr), 145.6 (d, 1JCF = 253.6 Hz,
Conclusion
In conclusion, the efficient method for the preparation of
4-fluoropyrazoles based on acid-mediated annulation of
α-fluoronitroalkenes with in situ prepared N-substituted
hydrazones was developed. Broad substrate scope regarding
fluoronitroalkenes, hydrazines and aromatic aldehydes was
demonstrated. Synthesis of fluorinated analogue of potent
FABP3 ligand was performed. This work is
a
further
1
C4), 162.7 (d, JCF = 249.5 Hz, CAr-F). 19F NMR (282 MHz, CDCl3): δ -
investigation of unique reactivity of fluorinated nitroalkenes as
synthetic equivalents of elusive fluoroalkynes for the synthesis of
pharmaceutically relevant heterocycles.
112.0 (s, 1F, CAr-F), -172.8 (s, 1F, C4-F). HRMS (ESI): m/z calcd. for
[C22H16F2N2+H+]: 347.1354, found: 347.1358.
4-Fluoro-5-(4-(methoxycarbonyl)phenyl)-3-(4-methylphenyl)-1-
phenyl-1H-pyrazole (3c). Pyrazole 3c was obtained from
α-fluoronitroalkene 1c (45 mg, 0.2 mmol), p-tolualdehyde and
phenylhydrazine following the general procedure 1 (reaction time 3 h).
Column chromatography afforded 3c (60.3 mg, 78%) as a slightly yellow
solid. Rf = 0.14 (PE/DCM, 1:1) (UV); mp 118-121°C (CHCl3). 1H NMR
(300 MHz, CDCl3): δ 2.43 (s, 3H, Me), 3.95 (s, 3H, CO2Me), 7.30 (d, J =
8.0 Hz, 2H, CHAr), 7.34-7.43 (m, 7H, CHAr), 7.92 (d, J = 8.0 Hz, 2H, CHAr),
8.06 (d, J = 8.3 Hz, 2H, CHAr). 13C NMR (75 MHz, CDCl3): δ 21.3 (Me),
52.2 (CO2Me), 124.9 (CHAr), 126.2 (d, 4JCF = 3.6 Hz, CHAr), 127.6 (d, 3JCF
= 4.2 Hz, CAr), 127.8 (CHAr), 128.1 (d, 2JCF = 22.8 Hz, C5), 128.8 (d, 4JCF
Experimental Section
All reactions were performed in oven-dried (150 °C) glassware. Most of
the chemicals were acquired from commercial sources and used as
received. Starting fluoronitroalkenes XC6H4CH=C(F)NO2 (1a (X = p-Cl),
1b (X = p-F), 1c (X = p-CO2Me), 1d (X = p-OMe), 1e (X = p-Br), 1f (X =
p-CF3), 1g (X = o-Cl)) were prepared by radical nitration of corresponding
fluorobromostyrenes by Fe(NO3)3.[16e] Hydrazines were either purchased
or prepared according to literature methods.[27] TLC were performed on
silica coated on aluminium with UV254 indicator. Visualization was
accomplished with UV. Column chromatography was performed on silica
(0.04–0.063 mm, 60 Å). NMR spectra were recorded at Bruker Fourier
300 and Bruker AV-300 instruments at the 300 MHz (1H NMR), 75 MHz
(13C NMR), and 282 MHz (19F NMR) frequencies. Multiplicities are
denoted as s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet),
br (broad). Assignment of carbon atoms of pyrazole ring core was made
basing on 2D NMR (1H-13C HMBC) for selected compounds (3h, 3m, 3p,
3r) and literature data. IR spectra were recorded at SImex FT-801
spectrometer in KBr tablets. High resolution mass spectra were acquired
at Bruker micrOTOF spectrometer using electrospray ionization (ESI).
= 2.0 Hz, CHAr), 129.1 (CHAr), 129.4 (CHAr), 129.7 (CHAr), 131.7 (d, 3JCF
=
3.8 Hz, CAr), 138.2 (CAr), 138.6 (d, 2JCF = 6.2 Hz, C3), 139.8 (CAr), 145.9
(d, JCF = 255.8 Hz, C4), 166.4 (CO2Me).19F NMR (282 MHz, CDCl3):
1
δ -171.3 (s, 1F). IR (KBr): ν˜= 1719 (vs), 1596 (m), 1498 (s), 1482 (s),
1358 (s), 1273 (vs), 1183 (s), 1111 (s), 962 (s), 827 (s), 758 (vs), 710 (s),
692 (s) cm−1. HRMS (ESI): m/z calcd. for [C24H19FN2O2+H+]: 387.1503,
found: 387.1510.
4-Fluoro-5-(4-methoxyphenyl)-3-(4-methylphenyl)-1-phenyl-1H-
pyrazole (3d). Pyrazole 3d was obtained from α-fluoronitroalkene 1d
(39.4 mg, 0.2 mmol), p-tolualdehyde and phenylhydrazine following the
general procedure 1 (reaction time 9 h). Column chromatography
afforded 3d (44.2 mg, 62%) as a yellow solid. Rf = 0.53 (PE/EtOAc, 3:1)
(UV); mp 95-97°C (CHCl3). 1H NMR (300 MHz, CDCl3): δ 2.41 (s, 3H,
General procedure 1 for the synthesis of N-aryl-4-fluoropyrazoles
3a-k. To the solution of arylhydrazine (1.2 equiv.) in TFE (10 ml / 1 mmol
of 1) and arylcarbaldehyde (1.2 equiv.) was added (when arylhydrazine
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000841
European Journal of Organic Chemistry
FULL PAPER
Me), 3.83 (s, 3H, OMe), 6.90 (d, J = 8.7 Hz, 2H, CHAr), 7.23 (d, J = 8.7
Hz, 2H, CHAr), 7.26-7.39 (m, 7H, CHAr), 7.90 (d, J = 8.0 Hz, 2H, CHAr).
13C NMR (75 MHz, CDCl3): δ 21.4 (Me), 55.2 (OMe), 114.1 (CHAr), 119.7
1H NMR (300 MHz, CDCl3, COSY): δ 2.40 (s, 3H, Me), 3.83 (s, 3H, OMe),
6.89 (d, J = 8.7 Hz, 2H, CHAr), 7.21 (m, 6H, CHAr), 7.34 (d, J = 8.7 Hz, 2H,
CHAr), 7.86 (d, J = 8.1 Hz, 2H, CHAr). 13C NMR (75 MHz, CDCl3, HSQC,
3
(d, 3JCF = 3.9 Hz, CAr), 124.8 (CHAr), 126.2 (d, 4JCF = 3.6 Hz, CHAr), 127.4
HMBC): δ 21.4 (Me), 55.3 (OMe), 114.3 (CHAr), 125.9 (d, JCF = 4.0 Hz,
3
(CHAr), 128.0 (d, JCF
=
3.9 Hz, CAr), 128.9 (CHAr), 129.1 (C5,
CAr), 126.1 (d, 4JCF = 3.6 Hz, CHAr), 126.5 (CHAr), 127.8 (d, 3JCF = 4.2 Hz,
4
2
overlapped), 129.3 (CHAr), 130.4 (d, JCF = 1.5 Hz, CHAr), 137.9 (CAr),
CAr), 128.1 (d, JCF = 22.9 Hz, C5), 129.0 (CHAr), 129.4 (CHAr), 130.2 (d,
138.3 (d, JCF = 6.2 Hz, C3), 140.1 (CAr), 145.4 (d, 1JCF = 252.4 Hz, C4).
4JCF = 2.0 Hz, CHAr), 133.0 (CAr), 134.5 (C-Cl), 138.0 (CAr), 138.1 (С3,
2
19F NMR (282 MHz, CDCl3): δ -173.2 (s). IR (KBr): ν˜= 1619 (m), 1596
(m), 1499 (s), 1514 (s), 1482 (s), 1364 (s), 1291 (m), 1249 (vs), 1173 (vs),
1105 (m), 1036 (m), 1024 (m), 961 (s), 839 (s), 822 (vs), 760 (vs), 693 (s)
cm−1. HRMS (ESI): m/z calcd. for [C23H19FN2O+ H+]: 359.1554, found:
359.1549.
overlapped signal), 145.4 (d, JCF = 254.5 Hz, C4), 159.1 (C-OMe). 19F
1
NMR (282 MHz, CDCl3): δ -172.5 (s). HRMS (ESI): m/z calcd. for
[C23H18ClFN2O+ H+]: 393.1164, found: 393.1159.
5-(4-Chlorophenyl)-1-(2-ethoxyphenyl)-4-Fluoro-3-(4-methylphenyl)-
1H-pyrazole (3i). Pyrazole 3i was obtained from α-fluoronitroalkene 1a
(40.3 mg, 0.2 mmol), p-tolualdehyde and 2-ethoxyphenylhydrazinium
chloride following the general procedure 1 (reaction time 7 h). Column
chromatography afforded 3i (45.5 mg, 56%) as a yellow solid.Rf = 0.55
(PE/EtOAc, 3:1) (UV); mp 130-133°C (CHCl3). 1H NMR (300 MHz,
CDCl3): δ 1.01 (t, J = 7.0 Hz, 3H, OCH2CH3), 2.43 (s, 3H, Me), 3.71 (q, J
= 7.0 Hz, 2H, OCH2CH3), 6.83 (d, J = 8.2 Hz, 1H, CHAr), 7.07 (t, J = 7.2
Hz, 1H, CHAr), 7.18-7.29 (m, 6H, CHAr), 7.35 (td, J = 8.0, 1.6 Hz, 1H,
CHAr), 7.56 (dd, J = 8.0, 1.6 Hz, 1H, CHAr), 7.88 (d, J = 8.0 Hz, 2H, CHAr).
13C NMR (75 MHz, CDCl3): δ 14.2 (OCH2CH3), 21.3 (Me), 63.8
5-(4-Chlorophenyl)-4-Fluoro-1,3-bis(4-methylphenyl)-1H-pyrazole
(3e). Pyrazole 3e was obtained from α-fluoronitroalkene 1a (40.3 mg, 0.2
mmol), p-tolualdehyde and p-tolylhydrazinium chloride following the
general procedure 1 (reaction time 5 h). Column chromatography
afforded 3e (43 mg, 57%) as a white solid. Rf = 0.67 (PE/EtOAc, 3:1)
1
(UV); mp 148-149°C (CHCl3). H NMR (300 MHz, CDCl3): δ 2.38 (s, 3H,
Me), 2.41 (s, 3H, Me 7.15-7.30 (m, 8H, CHAr), 7.35 (d, J = 8.6 Hz, 2H,
CHAr), 7.89 (d, J = 8.0 Hz, 2H, CHAr). 13C NMR (75 MHz, CDCl3): δ 21.0
(Me), 21.3 (Me), 124.8 (CHAr), 125.9 (d, 3JCF = 4.0 Hz, CAr), 126.1 (d, 4JCF
3
2
4
= 3.7 Hz, CHAr), 127.8 (d, JCF = 4.0 Hz, CAr), 127.9 (d, JCF = 23.4 Hz,
(OCH2CH3), 113.0 (CHAr), 121.0 (CHAr), 126.1 (d, JCF = 3.6 Hz, CHAr),
4
3
3
C5), 128.9 (CHAr), 129.3 (CHAr), 129.7 (CHAr), 130.2 (d, JCF = 1.9 Hz,
126.5 (CHAr), 126.9 (d, JCF = 4.3 Hz, CAr), 128.0 (d, JCF = 4.3 Hz, CAr),
CHAr), 134.5 (C-Cl), 137.3 (CAr), 137.7 (CAr), 138.1 (СAr), 138.2 (d, 2JCF
=
128.5 (CHAr), 128.8 (d, JCF = 3.6 Hz, CHAr), 128.9 (CAr), 129.3 (CHAr),
4
6.0 Hz, C3), 145.5 (d, 1JCF = 254.3 Hz, C4). 19F NMR (282 MHz, CDCl3):
δ -172.3 (s). HRMS (ESI): m/z calcd. for [C23H18ClFN2+H+]: 377.1215,
found: 377.1212.
129.8 (d, JCF = 22.0 Hz, C5), 130.2 (CHAr), 134.0 (C-Cl), 138.0 (CAr),
2
2
1
138.2 (d, JCF = 6.1 Hz, С3), 144.7 (d, JCF = 253.1 Hz, C4), 153.1 (C-
OEt). 19F NMR (282 MHz, CDCl3): δ -173.5 (s). HRMS (ESI): m/z calcd.
for [C24H20ClFN2O+ H+]: 407.1321, found: 407.1309.
1-Biphenyl-4-yl-5-(4-chlorophenyl)-4-fluoro-3-(4-methylphenyl)-1H-
pyrazole (3f). Pyrazole 3f was obtained from α-fluoronitroalkene 1a (40.3
mg, 0.2 mmol), p-tolualdehyde and biphenyl-4-ylhydrazine following the
general procedure 1 (reaction time 11 h). Column chromatography
afforded 3a (49 mg, 56%) as a slightly yellow solid. Rf = 0.66 (PE/EtOAc,
3:1) (UV); mp 167-169°C (CHCl3). 1H NMR (300 MHz, CDCl3): δ 2.43 (s,
3H, Me), 7.26-7.31 (m, 4H, CHAr), 7.36-7.49 (m, 8H, CHAr), 7.57-7.64 (m,
4H, CHAr), 7.92 (d, J = 8.0 Hz, 2H, CHAr). 13C NMR (75 MHz, CDCl3,13C
5-(4-Chlorophenyl)-4-fluoro-3-(4-methoxyphenyl)-1-phenyl-1H-
pyrazole (3j). Pyrazole 3j was obtained from α-fluoronitroalkene 1a (30.3
mg, 0.15 mmol), p-methoxybenzaldehyde and phenylhydrazine following
the general procedure 1 (reaction time 4 h). Column chromatography
afforded 3a (38 mg, 67%) as a yellow solid. Rf = 0.48 (PE/EtOAc, 3:1)
1
(UV); mp 131-132°C (CHCl3). H NMR (300 MHz, CDCl3): δ 3.86 (s, 3H,
OMe), 7.00 (d, J = 8.9 Hz, 2H, CHAr), 7.23 (d, J = 8.5 Hz, 2H, CHAr),
7.32-7.38 (m, 6H, CHAr), 7.92 (d, J = 8.5 Hz, 2H, CHAr). 13C NMR (75
3
GATED): δ 21.3 (Me), 125.0 (CHAr), 125.9 (d, JCF = 4.0 Hz, CAr), 126.2
4
3
3
(d, JCF = 3.7 Hz, CHAr), 127.0 (CHAr), 127.7 (CHAr), 127.8 (d, JCF = 4.3
Hz, CAr), 128.1 (d, 2JCF = 23.3 Hz, C5), 128.9 (CHAr), 129.0 (CHAr), 129.3
MHz, CDCl3): δ 55.3 (OMe), 114.1 (CHAr), 123.2 (d, JCF = 4.1 Hz, CAr),
124.9 (CHAr), 125.9 (d, 3JCF = 3.9 Hz, CAr), 127.5 (CHAr ), 127.8 (d, 4JCF
=
4
2
2
(CHAr), 130.3 (d, JCF = 2.0 Hz, CHAr), 134.8 (C-Cl), 138.7 (d, JCF = 6.2
4.2 Hz, CHAr), 128.0 (d, JCF = 23.3 Hz, C5), 129.0 (CHAr), 129.1 (CHAr),
130.2 (d, 4JCF = 1.9 Hz, CHAr), 134.7 (C-Cl), 138.4 (d, 2JCF = 6.1 Hz, C3),
Hz, C3), 138.9 (CAr), 139.9 (CAr), 140.6 (CAr), 143.0 (CAr), 145.8 (d, 1JCF
=
254.7 Hz, C4). 19F NMR (282 MHz, CDCl3): δ -171.9 (s). HRMS (ESI):
m/z calcd. for [C28H20ClFN2+ H+]: 439.1372, found: 439.1363.
139.8 (CAr), 145.5 (d, JCF = 254.1 Hz, C4), 159.7 (C-OMe). 19F NMR
1
(282 MHz, CDCl3):
δ -172.6 (s). HRMS (ESI): m/z calcd. for
[C22H16ClFN2O+ H+]: 379.1008, found: 379.1000.
4-Fluoro-5-(4-chlorophenyl)-3-(4-methylphenyl)-1-(4-fluorophenyl)-
1H-pyrazole (3g). Pyrazole 3g was obtained from α-fluoronitroalkene 1a
(30.2 mg, 0.15 mmol), p-tolualdehyde and 4-fluorophenylhydrazinium
chloride following the general procedure 1 (reaction time 6 h). Column
chromatography afforded 3a (47 mg, 62%) as a slightly yellow solid. Rf =
0.69 (PE/EtOAc, 3:1) (UV); mp 136-138°C (CHCl3). 1H NMR (300 MHz,
CDCl3): δ 2.41 (s, 3H, Me), 7.07 (t, J = 8.6 Hz, 2H, CHAr), 7.21 (d, J = 8.1
Hz, 2H, CHAr), 7.25-7.40 (m, 6H, CHAr), 7.86 (d, J = 8.1 Hz, 2H, CHAr).
4-(5-(4-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazol-3-yl)benzonitrile
(3k). Pyrazole 3k was obtained from α-fluoronitroalkene 1a (20.1 mg, 0.1
mmol), 4-formylbenzonitrile and phenylhydrazine following the general
procedure 1 (reaction time 15 h). Column chromatography afforded 3a
(14.5 mg, 39%) as a white amorphous solid. Rf = 0.49 (PE/EtOAc, 3:1)
(UV). 1H NMR (300 MHz, CDCl3): δ 7.24 (d, J = 8.4 Hz, 2H, CHAr), 7.32-
7.48 (m, 7H, CHAr), 7.76 (d, J = 8.3 Hz, 2H, CHAr), 8.13 (d, J = 8.3 Hz, 2H,
CHAr). 13C NMR (75 MHz, CDCl3): δ 111.6 (CN), 118.9 (C-CN), 124.9
(CHAr), 125.2 (d, 3JCF = 3.8 Hz, CAr), 126.5 (d, 4JCF = 4.3 Hz, CHAr), 128.3
2
13C NMR (75 MHz, CDCl3): δ 21.4 (Me), 116.0 (d, JCF = 23.0 Hz, CHAr),
125.6 (d, 3JCF = 4.0 Hz, CAr), 126.1 (d, 4JCF = 3.7 Hz, CHAr), 126.7 (d, 3JCF
3
2
2
= 8.6 Hz, CHAr), 127.5 (d, JCF = 4.0 Hz, CAr), 128.2 (d, JCF = 23.3 Hz,
C5), 129.1 (CHAr), 129.4 (CHAr), 130.2 (d, 4JCF = 1.9 Hz, CHAr), 134.9 (C-
Cl), 135.9 (d, 4JCF = 2.6 Hz, CAr), 138.3 (CAr), 138.7 (d, 2JCF = 6.2 Hz, С3),
(CHAr), 128.9 (d, JCF = 23.6 Hz, C5), 129.1 (CHAr), 129.3 (CHAr), 130.2
4
3
(d, JCF = 2.1 Hz, CHAr), 132.5 (CHAr ), 135.0 (d, JCF = 4.1 Hz, CAr),
2
1
135.2 (C-Cl), 136.4 (d, JCF = 6.0 Hz, C3), 139.5 (CAr), 146.0 (d, JCF
=
1
145.6 (d, JCF = 254.6 Hz, C4). 19F NMR (282 MHz, CDCl3): δ -113.3 (s,
256.1 Hz, C4). 19F NMR (282 MHz, CDCl3): δ -170.4 (s). HRMS (ESI):
m/z calcd. for [C22H13ClFN3+ H+]: 374.0855, found: 374.0846.
1F, CAr-F), -172.1 (s, 1F, C4-F). HRMS (ESI): m/z calcd. for
[C22H15ClF2N2+ H+]: 381.0965, found: 381.0963.
General procedure 2 for the synthesis of N-methyl-4-fluoropyrazoles
3l-3w. To the solution of N-methylhydrazine (1.2 equiv.) in MeOH (10 ml /
1 mmol of 1) corresponding aromatic aldehyde (1.2 equiv.) was added,
and the mixture was stirred at r.t. for 30 min-2 h until the hydrazone
formation was complete (TLC monitoring). To the resulting solution TFA
(2 equiv.) was added, followed by addition of fluoronitroalkene 1 (1 equiv).
The mixture was maintained at 65°C (oil bath) for 4-15 h (TLC
5-(4-Chlorophenyl)-4-Fluoro-1-(4-methoxyphenyl)-3-(4-
methylphenyl)-1H-pyrazole (3h). Pyrazole 3h was obtained from
α-fluoronitroalkene 1a (40.3 mg, 0.2 mmol), p-tolualdehyde and 4-
methoxyphenylhydrazinium oxalate following the general procedure 1
(reaction time 4 h). Column chromatography afforded 3a (40.5 mg, 52%)
as a yellow solid. Rf = 0.55 (PE/EtOAc, 3:1) (UV); mp 119-124°C (CHCl3).
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000841
European Journal of Organic Chemistry
FULL PAPER
monitoring). After the reaction was complete, it was evaporated with
silica gel and the products were purified by column chromatography
(PE/EtOAc) to afford target 4-fluoropyrazoles 3.
(vs), 725 (s), 602 (m) cm−1
.
HRMS (ESI): m/z calcd. for
[C16H11Cl2FN2+H+]: 321.0356, found: 321.0356.
5-(4-Chlorophenyl)-4-fluoro-3-(4-methoxyphenyl)-1-methyl-1H-
pyrazole (3p). Pyrazole 3p was obtained from α-fluoronitroalkene 1a
(40.3 mg, 0.2 mmol), p-methoxybenzaldehyde and methylhydrazine
5-(4-Chlorophenyl)-4-Fluoro-1-methyl-3-(4-methylphenyl)-1H-
pyrazole (3l). Pyrazole 3l was obtained from α-fluoronitroalkene 1a (40.3
mg, 0.2 mmol), p-tolualdehyde and methylhydrazine following the general
procedure 2 (reaction time 6 h). Column chromatography (PE/EtOAc,
12:1) afforded 3l (43 mg, 71%) as a slightly yellow solid. Rf = 0.29
(PE/EtOAc, 3:1) (UV); mp 100-102°C (CHCl3). 1H NMR (300 MHz,
CDCl3): δ 2.42 (s, 3H, Me), 3.88 (s, 3H, N-Me), 7.28 (d, J = 8.0 Hz, 2H,
CHAr), 7.43 (d, J = 8.5 Hz, 2H, CHAr), 7.52 (d, J = 8.5 Hz, 2H, CHAr), 7.82
(d, J = 8.0 Hz, 2H, CHAr). 13C NMR (75 MHz, CDCl3): δ 21.3 (Me), 38.2
following the general procedure
2 (reaction time 6 h). Column
chromatography (PE/EtOAc, 4:1) afforded 3p (41 mg, 65%) as a slightly
1
yellow solid. Rf = 0.15 (PE/EtOAc, 5:1) (UV); mp 101-104°C (CHCl3). H
NMR (300 MHz, CDCl3): δ 3.84 (s, 6H), 6.97 (d, J = 8.7 Hz, 2H, CHAr),
7.41 (d, J = 8.5 Hz, 2H, CHAr), 7.49 (d, J = 8.5 Hz, 2H, CHAr), 7.82 (d, J =
8.7 Hz, 2H, CHAr). 13C NMR (75 MHz, CDCl3, HMBC): δ 38.2 (N-Me),
3
3
55.3 (OMe), 114.1 (CHAr), 123.6 (d, JCF = 4.1 Hz, CAr), 125.8 (d, JCF
=
4
2
(N-Me), 125.8 (d, JCF = 3.6 Hz, CHAr), 125.9 (CAr), 128.0 (d, JCF = 4.2
Hz, CAr), 128.8 (d, 2JCF = 23.3 Hz, C5), 129.2 (CHAr), 129.3 (CHAr), 130.1
(d, 4JCF = 1.2 Hz, CHAr), 135.0 (C-Cl), 136.4 (d, 4JCF = 5.4 Hz, C3), 137.7
3.8 Hz, CAr), 127.2 (d, 5JCF = 3.6 Hz, CHAr), 128.8 (d, 2JCF = 23.4 Hz, C5),
5
2
129.2 (CHAr), 130.2 (d, JCF = 1.2 Hz, CHAr), 135.0 (C-Cl), 136.2 (d, JCF
= 6.2 Hz, C3), 143.9 (d, 1JCF = 251.0 Hz, C4), 159.4 (CAr-OMe). 19F NMR
(282 MHz, CDCl3): δ -175.0 (s). IR (KBr): ν˜= 1612 (m), 1546 (m), 1485
(s), 1442 (m), 1396 (m), 1360 (m), 1312 (m), 1245 (s), 1178 (s), 1111 (m),
1091 (s), 1047 (s), 1030 (s), 1009 (m), 842 (vs), 821 (m), 733 (m), 609
(s), 597 (s) cm−1. HRMS (ESI): m/z calcd. for [C17H14ClFN2O+H+]:
317.0851, found: 317.0854.
1
(CAr), 144.2 (d, JCF = 251.5 Hz, C4). 19F NMR (282 MHz, CDCl3):
δ -174.1 (s). IR (KBr): ν˜= 1582 (m), 1545 (m), 1484 (s), 1443 (s), 1396
(m), 1357 (s), 1314 (s), 1299 (m), 1268 (m), 1201 (m), 1090 (s), 1046 (m),
1003 (m), 829 (vs), 725 (s), 605 (s), 594 (m) cm−1. HRMS (ESI): m/z
calcd. for [C17H14ClFN2+H+]: 301.0902, found: 301.0900.
5-(4-Bromophenyl)-4-fluoro-1-methyl-3-(4-methylphenyl)-1H-
5-(4-Chlorophenyl)-4-fluoro-1-methyl-3-(3,4,5-trimethoxyphenyl)-1H-
pyrazole (3m). Pyrazole 3m was obtained from α-fluoronitroalkene 1e
(74 mg, 0.3 mmol), p-tolualdehyde and methylhydrazine following the
general procedure 2 (reaction time 6 h). Column chromatography
(PE/EtOAc, 15:1) afforded 3m (78 mg, 76%) as a slightly yellow solid. Rf
= 0.38 (PE/EtOAc, 3:1) (UV); mp 114-116°C (CHCl3). 1H NMR (300 MHz,
CDCl3): δ 2.41 (s, 3H, Me), 3.87 (s, 3H, N-Me), 7.27 (d, J = 8.0 Hz, 2H,
CHAr), 7.37 (d, J = 8.3 Hz, 2H, CHAr), 7.67 (d, J = 8.3 Hz, 2H, CHAr), 7.80
(d, J = 8.0 Hz, 2H, CHAr). 13C NMR (75 MHz, CDCl3, HMBC): δ 21.3 (Me),
pyrazole (3q). Pyrazole 3q was obtained from α-fluoronitroalkene 1a
(60.5
mg,
0.3
mmol),
3,4,5-trimethoxy-benzaldehyde
and
methylhydrazine following the general procedure 2 (reaction time 6 h).
Column chromatography (PE/EtOAc, 3:1 to 1:1) afforded 3q (59 mg,
52%). Rf = 0.09 (PE/EtOAc, 3:1) (UV); mp 108-111°C (CHCl3). 1H NMR
(300 MHz, CDCl3): δ 3.87 (s, 3H), 3.89 (s, 3H), 3.93 (s, 6H), 7.14 (s, 2H,
CHAr), 7.42 (d, J = 8.5 Hz, 2H, CHAr), 7.51 (d, J = 8.5 Hz, 2H, CHAr). 13
C
NMR (75 MHz, CDCl3): δ 38.3 (N-Me), 56.0 (OMe), 60.9 (OMe), 103.2 (d,
4JCF = 4.2 Hz, CHAr), 125.6 (d, 3JCF = 4.1 Hz, CAr), 126.4 (d, 3JCF = 4.2 Hz,
CAr), 129.3 (CHAr), 130.2 (d, 4JCF = 1.0 Hz, CHAr), 135.2 (C-Cl), 136.1 (d,
38.2 (N-Me), 123.2 (C-Br), 125.8 (d, 4JCF = 3.6 Hz, CHAr), 126.3 (d, 3JCF
=
3
2
3.8 Hz, CAr), 128.0 (d, JCF = 4.0 Hz, CAr), 128.9 (d, JCF = 23.4 Hz, C5),
129.3 (CHAr), 130.4 (d, JCF = 1.2 Hz, CHAr), 132.2 (CHAr), 136.4 (d, 2JCF
2JCF = 5.9 Hz, C3), 144.1 (d, JCF = 251.7 Hz, C4), 153.5 (2×CAr-OMe).
4
1
= 5.8 Hz, C3), 137.7 (CAr), 144.2 (d, 1JCF = 251.8 Hz, C4). 19F NMR (282
The signal of C5 could not be unambiguously identified due to
overlapping and broadening. 19F NMR (282 MHz, CDCl3): δ -174.9 (s).
HRMS (ESI): m/z calcd. for [C19H18ClFN2O3+H+]: 377.1063, found:
377.1056.
MHz, CDCl3):
δ
-173.9 (s). HRMS (ESI): m/z calcd. for
[C17H1479BrFN2+H+]: 345.0397, found: 345.0396.
4-Fluoro-1-methyl-3-(4-methylphenyl)-5-(4-trifluoromethyl-phenyl)-
1H-pyrazole (3n). Pyrazole 3n was obtained from α-fluoronitroalkene 1f
(70.5 mg, 0.3 mmol), p-tolualdehyde and methylhydrazine following the
general procedure 2 (reaction time 6 h). Column chromatography
afforded 3n (77 mg, 77%) as a white solid. Rf = 0.43 (PE/EtOAc, 3:1)
(UV). 1H NMR (300 MHz, CDCl3): δ 2.40 (s, 3H, Me), 3.90 (s, 3H, N-Me),
7.26 (d, J = 8.0 Hz, 2H, CHAr), 7.62 (d, J = 8.0 Hz, 2H, CHAr), 7.79 (m,
4H). 13C NMR (75 MHz, CDCl3): δ 21.3 (Me), 38.5 (N-Me), 123.8 (q, 1JCF
= 272.4 Hz, CF3), 125.87 (CHAr), 125.91 (CHAr), 125.90-125.98 (m, 2×C,
4-(5-(4-Chlorophenyl)-4-fluoro-1-methyl-1H-pyrazol-3-yl)benzonitrile
(3r). Pyrazole 3r was obtained from α-fluoronitroalkene 1a (40.3 mg, 0.2
mmol), 4-formylbenzonitrile and methylhydrazine following the general
procedure 2 (reaction time 6 h). Column chromatography afforded 3r (39
mg, 63%) as a white solid. Rf = 0.26 (PE/EtOAc, 3:1) (UV); mp 186-
190°C (PE/EtOAc). 1H NMR (300 MHz, CDCl3): δ 3.88 (s, 3H, N-Me),
7.41 (d, J = 8.5 Hz, 2H, CHAr), 7.52 (d, J = 8.5 Hz, 2H, CHAr), 7.71 (d, J =
8.4 Hz, 2H, CHAr), 8.00 (d, J = 8.4 Hz, 2H, CHAr). 13C NMR (75 MHz,
3
2
4
overlapped), 127.9 (d, JCF = 4.2 Hz, CAr), 128.9 (d, JCF = 23.1 Hz, C5),
129.2 (d, 4JCF = 1.7 Hz, CHAr), 130.8 (q, 2JCF = 28.9 Hz, C-CF3), 136.6 (d,
CDCl3, HMBC): δ 38.6 (N-Me), 111.1 (CN), 118.9 (C-CN), 125.2 (d, JCF
5
2
= 3.8 Hz, CAr), 126.1 (d, JCF = 4.3 Hz, CHAr), 128.7 (d, JCF = 25.6 Hz,
C5), 129.4 (CHAr), 130.2 (d, 5JCF = 1.1 Hz, CHAr), 132.5 (CHAr), 134.4 (d,
1
2JCF = 5.9 Hz, C3), 137.9 (CAr-Ме), 144.5 (d, JCF = 253.0 Hz, C4). 19F
2
NMR (282 MHz, CDCl3): δ -62.8 (s, 3F, CF3), -173.4 (s, 1F, C4-F). HRMS
(ESI): m/z calcd. for [C18H14F4N2]: 335.1166, found: 335.1177.
4JCF = 5.4 Hz, CAr), 135.4 (d, JCF = 4.0 Hz, C3), 136.5 (C-Cl), 144.7 (d,
1JCF = 253.7 Hz, C4). 19F NMR (282 MHz, CDCl3): δ -171.8 (s). HRMS
(ESI): m/z calcd. for [C17H11ClFN3+H+]: 312.0698, found: 312.0700.
3,5-Bis(4-chlorophenyl)-4-fluoro-1-methyl-1H-pyrazole (3o). Pyrazole
3o was obtained from α-fluoronitroalkene 1a (40.3 mg, 0.2 mmol), p-
chlorobenzaldehyde and methylhydrazine following the general
procedure 2 (reaction time 6 h). Column chromatography (PE/EtOAc,
9:1) afforded 3o (51.6 mg, 80%) as a white solid. Rf = 0.26 (PE/EtOAc,
3:1) (UV); mp 123-126°C (CHCl3). 1H NMR (300 MHz, CDCl3): δ 3.85 (s,
3H, N-Me), 7.40 (m, 4H), 7.50 (d, J = 8.5 Hz, 2H, CHAr), 7.82 (d, J = 8.5
5-(4-Chlorophenyl)-4-fluoro-3-(3-methoxyphenyl)-1-methyl-1H-
pyrazole (3s). Pyrazole 3s was obtained from α-fluoronitroalkene 1a
(60.3 mg, 0.3 mmol), m-methoxybenzaldehyde and methylhydrazine
following the general procedure
2 (reaction time 6 h). Column
chromatography (PE/EtOAc, 4:1) afforded 3s(72 mg, 75%) as a yellow
amorphous solid. Rf = 0.26 (PE/EtOAc, 3:1) (UV). 1H NMR (300 MHz,
CDCl3): δ 3.87 (s, 6H), 6.90 (dd, J = 8.1, 1.7 Hz, 1H, CHAr), 7.35 (t, J =
7.9 Hz, 1H, CHAr), 7.41 (d, J = 8.5 Hz, 2H, CHAr), 7.45-7.53 (m, 4H, CHAr).
Hz, 2H, CHAr). 13C NMR (75 MHz, CDCl3): δ 38.4 (N-Me), 125.5 (d, 3JCF
=
5
3.8 Hz, CAr), 127.1 (d, JCF = 4.0 Hz, CHAr), 128.9 (C5, overlapped),
128.9 (CHAr), 129.3 (CHAr), 129.4 (d, 3JCF = 4.3 Hz, CAr), 130.2 (d, 5JCF
=
13C NMR (75 MHz, CDCl3): δ 38.3 (N-Me), 55.3 (OMe), 110.9 (d, JCF
=
2
1.2 Hz, CHAr), 133.6 (C-Cl), 136.2 (d, JCF = 5.7 Hz, C3), 136.2 (C-Cl),
3.4 Hz, CHAr), 114.1 (CHAr), 118.5 (d, 4JCF = 4.1 Hz, CHAr), 125.7 (d, 3JCF
144.2 (d, JCF = 252.2 Hz, C4).19F NMR (282 MHz, CDCl3): δ -173.3 (s).
= 3.2 Hz, CAr), 129.0 (d, JCF = 23.0 Hz, C5), 129.2 (CHAr), 129.7 (CHAr),
1
2
IR (KBr): ν˜= 1582 (m), 1537 (m), 1479 (s), 1442 (m), 1395 (s), 1357 (m),
1306 (m), 1267 (m), 1205 (m), 1089 (s), 1044 (m), 1012 (m), 843 (s), 823
130.2 (d, 4JCF = 0.6 Hz, CHAr), 132.1 (d, 3JCF = 3.5 Hz, CAr), 135.1 (C-Cl),
1
136.1 (br s, С3), 144.4 (d, JCF = 252.7 Hz, C4), 159.9 (CAr-OMe). 19F
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000841
European Journal of Organic Chemistry
FULL PAPER
NMR (282 MHz, CDCl3): δ -173.5 (s). HRMS (ESI): m/z calcd. for
methylhydrazine following the general procedure 2 (reaction time 16 h).
Column chromatography (PE/EtOAc, 4:1), afforded 43 mg of mixture.
This mixture of 4x/3x was maintained at r.t. in MeOH (3 mL) under air for
3 days with stirring, resulting in complete conversion to pyrazole 3r (36
mg, 54% from 1a) that precipitated as bright yellow crystals.
2. Fluoronitroalkene 1a (30.1 mg, 0.15 mmol) was subjected to general
procedure 2 with the following change: after the addition of nitroalkene
reaction mixture was stirred at 60 °C under 1 atm of oxygen (balloon) for
8 h and then worked up as described. Column chromatography afforded
unreacted 1a (17.5 mg, 58 %) and 4x (14.5 mg, 29 %, 69% based on
recovered 1a). 4x (characteristic signals): 1H NMR (300 MHz, CDCl3): δ
2.70 (s, 3H, N-Me), 3.04 (d, J = 9.2 Hz, 1H, H2), 4.13 (d, J = 11.7 Hz, 1H,
H3), 4.99 (d, J = 16.7 Hz, 1H, H5), 7.32 (d, J = 8.5 Hz, 2H, CHAr), 7.36-
7.50 (m, 6H, CHAr), 8.23 (d, J = 8.5 Hz, 2H, CHAr). 19F NMR (282 MHz,
CDCl3): δ -121.7 (t, JCF = 13.9 Hz). 3x: Rf = 0.24 (PE/EtOAc, 3:1) (UV);
mp 200-201°C (CHCl3) (decomp.). 1H NMR (300 MHz, CDCl3): δ 3.93 (s,
3H, N-Me), 7.44 (d, J = 8.5 Hz, 2H, CHAr), 7.55 (d, J = 8.5 Hz, 2H, CHAr),
8.08 (d, J = 8.9 Hz, 2H, CHAr), 8.31 (d, J = 8.9 Hz, 2H, CHAr). 13C NMR
[C17H14ClFN2O+H+]: 317.0851, found: 317.0854.
3-(2-Bromophenyl)-5-(4-chlorophenyl)-4-fluoro-1-methyl-1H-pyrazole
(3t). Pyrazole 3t was obtained from α-fluoronitroalkene 1a (40.3 mg, 0.2
mmol), o-bromobenzaldehyde and methylhydrazine following the general
procedure 2 (reaction time 5 h). Column chromatography (PE/EtOAc,
9:1) afforded 3t (44 mg, 60%) as a slightly yellow oil, which solidifies
upon storage in a refrigerator. Rf = 0.25 (PE/EtOAc, 5:1) (UV). 1H NMR
(300 MHz, CDCl3): δ 3.91 (s, 3H, N-Me), 7.27 (td, J = 7.6, 1.8 Hz, 1H,
CHAr), 7.39 (d, J = 7.6, 0.9 Hz, 1H, CHAr), 7.45 (d, J = 8.6 Hz, 2H, CHAr),
7.47-7.54 (m, 3H, CHAr), 7.69 (d, J = 8.0 Hz, 1H, CHAr). 13C NMR (75
3
MHz, CDCl3): δ 38.3 (N-Me), 123.2 (C-Br), 125.2 (d, JCF = 3.9 Hz, CAr),
2
127.3 (CHAr), 128.7 (d, JCF = 22.8 Hz, C5), 129.3 (CHAr), 130.2 (CHAr),
130.3 (d, 4JCF = 1.4 Hz, CHAr), 131.3 (d, 3JCF = 3.5 Hz, CAr), 131.8 (CHAr),
2
1
133.1 (CHAr), 136.3 (C-Cl), 136.9 (d, JCF = 9.8 Hz, C3), 143.6 (d, JCF
=
251.2 Hz, C4). 19F NMR (282 MHz, CDCl3): δ -169.3 (s). HRMS (ESI):
m/z calcd. for [C16H1179Br35ClFN2+H+]: 364.9851, found: 364.9851.
3
(75 MHz, CDCl3): δ 38.7 (N-Me), 124.1 (CHAr), 125.1 (d, JCF = 3.9 Hz,
4
2
CAr), 126.2 (d, JCF = 4.4 Hz, CHAr), 129.4 (CHAr), 129.6 (d, JCF = 23.6
5-(4-Chlorophenyl)-4-fluoro-1-methyl-3-(thiophen-2-yl)-1H-pyrazole
(3u). Pyrazole 3u was obtained from α-fluoronitroalkene 1a (60.5 mg, 0.3
mmol), thiophene-2-carbaldehyde and methylhydrazine following the
4
3
Hz, C5), 130.2 (d, JCF = 1.7 Hz, CHAr), 134.1 (d, JCF = 5.6 Hz, CAr),
135.6 (C-Cl), 137.3 (d, 2JCF = 4.1 Hz, C3), 144.9 (d, 1JCF = 253.9 Hz, C4),
147.1 (C-NO2). 19F NMR (282 MHz, CDCl3): δ -171.5 (s). HRMS (ESI):
m/z calcd. for [C16H11ClFN3O2+H+]: 332.0597, found: 332.0595.
general procedure
2 (reaction time 7 h). Column chromatography
afforded 3u (22 mg, 25%) as a slightly yellow oil, which solidifies upon
storage in a refrigerator. Rf = 0.39 (PE/EtOAc, 3:1) (UV). 1H NMR (300
MHz, CDCl3): δ 3.84 (s, 3H, N-Me), 7.11 (dd, J = 5.0, 3.7 Hz, 1H, CH),
7.31 (dd, J = 5.0, 0.9 Hz, 1H, CH), 7.38-7.54 (m, 5H, CHAr and CH). 13C
NMR (75 MHz, CDCl3): δ 38.3 (N-Me), 124.7 (d, JCF = 0.9 Hz, CHAr),
124.8 (d, 4JCF = 4.2 Hz, CHAr), 125.5 (d, 3JCF = 3.9 Hz, CAr), 127.6 (CHAr),
128.9 (d, 2JCF = 22.4 Hz, C5), 129.3 (CHAr), 130.2 (d, 4JCF = 1.6 Hz, CHAr),
Methyl 4-(2-formylphenoxy)butanoate (7). To the solution of
salicylaldehyde (244 mg, 2 mmol, 1 equiv.) in DMF (5 ml) methyl 4-
chlorobutyrate (273 mg, 2 mmol, 1 equiv.) was added, followed by
addition of K2CO3 (415 mg, 3 mmol, 1.5 equiv.) and KI (333 mg, 2 mmol,
1 equiv.). The mixture was heated at 90°C until the starting aldehyde was
consumed (4 h, TLC monitoring). After the reaction was complete, the
product was extracted by EtOAc/H2O (50+50 ml). Organic layer was
washed by concentrated NaCl solution (30 ml), dried by anhydrous
Na2SO4 and evaporated. Product 7 (382 mg, 86%) was obtained as
slightly yellow oil and used without further purification.
3
2
132.7 (d, JCF = 4.8 Hz, CAr), 132.8 (d, JCF = 7.9 Hz, C3), 135.3 (C-Cl),
143.2 (d, 1JCF = 252.1 Hz, C4). 19F NMR (282 MHz, CDCl3): δ -173.7 (s).
HRMS (ESI): m/z calcd. for [C14H10ClFN2S+H+]: 293.0310, found:
293.0306.
1-Benzyl-5-(4-chlorophenyl)-4-fluoro-3-(4-methylphenyl)-1H-pyrazole
(3v). Pyrazole 3v was obtained from α-fluoronitroalkene 1a (40.3 mg, 0.2
mmol), p-tolualdehyde and benzylhydrazine following the general
procedure 1 (reaction time 5 h). Recrystallization of the crude product
from TFE afforded 3v (62 mg, 79%) as a white crystalline solid. Rf = 0.57
(PE/EtOAc, 3:1) (UV); mp 132-135°C (CHCl3). 1H NMR (300 MHz,
CDCl3): δ 2.41 (s, 3H, Me), 5.31 (s, 2H, CH2), 7.05-7.11 (m, 2H, CHAr),
7.24-7.33 (m, 6H, CHAr), 7.42 (d, J = 8.5 Hz, 2H, CHAr), 7.85 (d, J = 8.0
Hz, 2H, CHAr). 13C NMR (75 MHz, CDCl3): δ 21.3 (Me), 54.2 (CH2), 125.7
(d, 3JCF = 3.8 Hz, CAr), 126.0 (d, 4JCF = 3.7 Hz, CHAr), 126.7 (CHAr), 127.7
(CHAr), 128.1 (d, 3JCF = 4.1 Hz, CAr), 128.1 (d, 2JCF = 22.9 Hz, C5), 128.7
4-(2-(5-(2-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazol-3-
yl)phenoxy)butanoic acid (6). The solution of 6 (80 mg, 0.36 mmol) and
phenylhydrazine (39 mg, 0.36 mmol) in TFE (3 ml) was stirred at room
temperature for 2 hours. Then nitroalkene 1g (60.5 mg, 0.3 mmol) and
TFA (68 mg, 0.6 mmol, 2 equiv.) were added and the resulting mixture
was heated at 70°C under open air for 22 hours. After the reaction was
complete (TLC monitoring) it was evaporated under reduced pressure to
give crude product 8 containing also intermediate hydrazone. Then the
preheated solution of KOH (840 mg, 15 mmol, 50 equiv.) in MeOH/H2O
(3+3 ml) was added and the mixture was heated at 60°C for 3 hours, and
then poured into 0.1M aqueous solution of HCl. The product was
extracted by EtOAc (3x30 ml). Combined organic layer was dried by
anhydrous Na2SO4 and evaporated. Crude product was purified by
column chromatography (2:1 to 1:1 PE/EtOAc + ca. 1 mg/ml TFA) to give
6 (54.5 mg, 41% based on 1g) as a slightly yellow oil, which solidifies
upon storage in a refrigerator. Rf = 0.11 (PE/EtOAc, 1:1) (UV). 1H NMR
(300 MHz, CDCl3): δ 2.16 (m, 2H, -CH2-), 2.62 (d, J = 7.3 Hz, 2H, -CH2-
CO2H), 4.14 (d, J = 5.7 Hz, 2H, OCH2-), 7.02 (d, J = 8.3 Hz, 1H, CHAr),
7.09 (t, J = 7.5 Hz, 1H, CHAr), 7.22-7.43 (m, 9H, CHAr), 7.48 (d, J = 7.8
Hz, 1H, CHAr), 7.72 (dd, J = 7.5, 1.1 Hz, 1H, CHAr), 8.48 (br s, 1H, CO2H).
13C NMR (75 MHz, CDCl3): δ 24.5 (CH2), 30.5 (CH2), 66.9 (OCH2), 112.2
(CHAr), 119.7 (d, 3JCF = 3.2 Hz, CAr), 120.9 (CHAr), 123.8 (CHAr), 126.3 (d,
4
(CHAr), 129.1 (CHAr), 129.3 (CHAr), 130.4 (d, JCF = 0.8 Hz, CHAr), 135.1
2
(C-Cl), 136.9 (CAr), 137.1 (d, JCF = 6.0 Hz, С3), 137.8 (CAr), 145.4 (d,
1JCF = 252.4 Hz, C4). 19F NMR (282 MHz, CDCl3): δ -173.5 (s). HRMS
(ESI): m/z calcd. for [C23H18ClFN2+ H+]: 377.1215, found: 377.1212.
3,5-Bis(4-chlorophenyl)-4-fluoro-1H-pyrazole (3w). Pyrazole 3w was
obtained from α-fluoronitroalkene 1a (20.1 mg, 0.2 mmol), p-tolualdehyde
and hydrazine hydrate following the general procedure 2 using TFE
instead of MeOH as
a solvent (reaction time 15 h). Column
chromatography (PE/EtOAc 4:1 to 2:1) afforded 3w (17.5 mg, 57%) as
amorphous white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.58 (s, 4H,
CHAr), 7.80 (s, 4H, CHAr), 13.62 (br s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): δ 127.4 (CHAr), 129.3 (CHAr), 131.5 (br m, C3, C5), 133.3 (br
s, CAr), 144.2 (d, 1JCF = 251.5 Hz, C4). 19F NMR (282 MHz, DMSO-d6): δ
-174.3 (s). HRMS (ESI): m/z calcd. for [C15H9Cl2FN2+H+]: 306.0127,
found: 306.0126.
3
2JCF = 26.3 Hz, C5), 126.9 (CHAr), 127.0 (d, JCF = 3.4 Hz, CAr), 127.3
(CHAr), 128.9 (CHAr), 130.0 (CHAr), 130.2 (CHAr), 130.8 (overlapped,
2
2×CHAr), 132.5 (CHAr), 134.7 (C-Cl), 136.9 (d, JCF = 6.6 Hz, C3), 139.8
1
(CAr), 146.3 (d, JCF = 254.0 Hz, C4), 156.5 (CAr-OR), 178.7 (CO2H). 19F
NMR (282 MHz, CDCl3): δ -164.4 (s). HRMS (ESI): m/z calcd. for
[C25H20ClFN2O3+H+]: 451.1219, found: 451.1216.
5-(4-Chlorophenyl)-4-fluoro-1-methyl-3-(4-nitrophenyl)-1H-pyrazole
(3x)
nitrophenyl)pyrazolidine (4x). 1. Pyrazolidine 4x was obtained as
inseparable mixture with pyrazole 3x (4:3x ratio 4:1) from α-
fluoronitroalkene 1a (40.3 mg, 0.2 mmol), p-nitrobenzaldehyde and
and
5-(4-chlorophenyl)-4-fluoro-1-methyl-4-nitro-3-(4-
=
Acknowledgements
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000841
European Journal of Organic Chemistry
FULL PAPER
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This work was supported by the Council on grants of the
President of the Russian Federation (grant MD-1312.2020.3)
The authors thank Dr. N. G. Kolotyrkina and Dr. A. O. Chizhov
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10.1002/ejoc.202000841
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.202000841
European Journal of Organic Chemistry
FULL PAPER
Key topic: Fluorinated heterocycles
Entry for the Table of Contents
F
Ar'
N
N
Ar
R
Ar'
Ar'
F
TFA
open air
O
+
Ar
N
Ar
N
R
F
RNHNH2
NO2
three component
one pot
good yields
easy access to fluorinated heterocycles
nitroalkenes as equivalents of fluoroalkynes
Three-component one pot assembly of 4-fluoropyrazoles is described. The method involves formal oxidative [3+2]-annulation
between elusive fluoroalkynes and azomethine imines.
11
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