Synthesis of fluorovinyl pyrazolyl (thio)ethers by the reaction of gem-difluoroalkenes with pyrazolin-5-ones (thiones)

Article abstract of DOI:10.1016/j.jfluchem.2015.12.007

A mild and efficient method for the preparation of fluorovinyl pyrazolyl ethers and thioethers by the reaction of gem-difluoroalkenes having aryl substituents with pyrazolin-5-ones and pyrazolin-5-thiones, respectively, in the presence of t-BuOK is described.

Full text of DOI:10.1016/j.jfluchem.2015.12.007

Accepted Manuscript
Title: Synthesis of fluorovinyl pyrazolyl (thio)ethers by the
reaction of gem-difluoroalkenes with pyrazolin-5-ones
(thiones)
Author: Tao Huang Xianghu Zhao Xinfei Ji Wei Wu Song Cao
PII:
S0022-1139(15)30019-1
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2015.12.007
FLUOR 8704
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
1-10-2015
21-12-2015
23-12-2015
Please cite this article as: Tao Huang, Xianghu Zhao, Xinfei Ji, Wei Wu, Song
Cao, Synthesis of fluorovinyl pyrazolyl (thio)ethers by the reaction of gem-
difluoroalkenes with pyrazolin-5-ones (thiones), Journal of Fluorine Chemistry
http://dx.doi.org/10.1016/j.jfluchem.2015.12.007
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Synthesis of fluorovinyl pyrazolyl (thio)ethers by the reaction of gem-difluoroalkenes with
pyrazolin-5-ones (thiones)
Tao Huang, Xianghu Zhao, Xinfei Ji, Wei Wu, Song Cao*
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of
Science and Technology (ECUST), Shanghai 200237, China
*
Corresponding author. Tel: +86-21-64253452
E-mail address: scao@ecust.edu.cn
1

Graphical abstract
A mild and efficient method for the preparation of fluorovinyl pyrazolyl ethers and thioethers by the
reaction of gem-difluoroalkenes with pyrazolin-5-ones and pyrazolin-5- thiones, respectively, in the
presence of t-BuOK is described.
2

Highlights
•
•
An efficient method for the synthesis of fluorovinyl pyrazolyl (thio)ethers is reported.
The reaction of gem-difluoroalkenes with pyrazolin-5-ones (thiones) proceeds efficiently under
mild conditions.
•
The addition of potassium tert-butoxide is essential for efficient conversion.
Abstract: A mild and efficient method for the preparation of fluorovinyl pyrazolyl ethers and
thioethers by the reaction of gem-difluoroalkenes having aryl substituents with pyrazolin-5-ones and
pyrazolin-5-thiones, respectively, in the presence of t-BuOK is described.
Keywords: gem-difluoroalkenes; pyrazolone; potassium tert-butoxide; fluorovinyl pyrazolyl ethers
1
. Introduction
Pyrazolone derivatives have found many applications in the fields of dyes, agrochemicals and
pharmaceuticals [1]. For example, O-pyrazole glucopyranoside (Fig 1, compound I) can be used as
antidiabetic agent [2] and arene-ruthenium (II) acylpyrazolonato complexe (Fig 1, compound II) is
particularly active in inducing cell death in all cell lines [3]. Pyrazolones are also used as useful
building blocks and intermediates in organic synthesis [4]. Therefore, much effort has been devoted
to the exploration of new reaction types of pyrazolones [5]. The current interest is always focused on
the Michael addition reaction at activated methylene group of the pyrazolone ring [6] or Michael
addition-cyclization reaction occurring at C4 and C5-OH positions [7]. However, example of the
3

preferential reactivity of the oxygen anion (enol oxygen) over carbon anion has been scarcely reported.
More recently, Liu and Zhang reported a novel method for the synthesis of O-pyrazole
polyfluoroarylated ethers by the S Ar reaction of pyrazolones with polyfluoroarenes. This
N
transformations involved the use of enol oxygen of pyrazolone as a nucleophile [8].
gem-Difluoroalkenes display unusual reactivity toward nucleophiles due to their highly electron-
deficient nature of carbon–carbon double bond and the excellent leaving-group ability of the fluoride
ion [9]. Therefore, they usually serve as versatile electrophile partner in the fluorovinylation of a
variety of nucleophiles [10]. In continuation of our work on the functionalization of the C–F bond of
gem-difluoroalkenes [11], in this paper, we report an efficient -fluorovinylation of pyrazolin-5-ones
and pyrazolin-5-thiones with gem-difluoroalkenes via nucleophilic vinylic substitution reaction
(
S V) with the assistance of t-BuOK.
N
2
. Results and discussion
We used (2,2-difluoroethene-1,1-diyl)dibenzene 1a and 3-methyl-1-phenyl-1H-pyrazol-5(4H)-
one 2a as model reactants for the optimization of the aryloxylation reaction conditions, and the results
are shown in Table 1. Initially, the effects of different solvents were evaluated. Generally polar aprotic
solvents are effective for the reaction and DMSO proved to be a more suitable solvent for this
transformation (entries 1–6). The choice of the base was critical in achieving high efficiency. No
reaction took place without the addition of base (entry 7). Among the various bases examined, t-
BuOK provided the best result (entry 6) and replacement of t-BuOK with other bases led to decreased
yields (entries 8–12). Two equivalent of t-BuOK were essential for achieving high conversion and
increasing or decreasing the amount of t-BuOK would diminish the yield of 3aa (entries 6 and 13–
1
4). The influence of the temperature on the reaction was also examined (entries 6 and 15–17). With
4

increasing the reaction temperature from 25 °C to 60 °C, the conversion of 1a significantly increased
giving highest yield (94 %). Further increase in reaction temperature (at 75 °C) could not improve
the conversion. Finally, two equivalents of 2a was required to obtain satisfactory yield (entry 6) and
reducing the amount of 2a to 1.5 equivalent resulted in lower yield of 3aa (entry 18).
With the optimal reaction conditions in hand (Table 1, entry 6), the scope of the aryloxylation
reaction was extended to various symmetrical gem-difluoroalkenes and pyrazolones. The results are
summarized in Table 2. As demonstrated in Table 2, most substrates could afford -fluorovinyl
pyrazolyl ethers in moderate to excellent yields. Generally, gem-difluoroalkenes bearing electron-
withdrawing or neutral groups gave the desired products in higher yields than substrates bearing
electron-donating group (for example 3ba vs. 3ga). Replacing the methyl group with the phenyl group
in pyrazolone also afforded the desired products in high yields (3aa vs. 3ab). However, the
replacement of methyl group with trifluoromethyl group would result in a loss of reactivity of
pyrazolones and the yields dropped sharply (3ac, 3bc and 3fc). Moreover, unsymmetrical gem-
difluoroalkene (1i) could also be served as substrate to give an inseparable mixture of E- and Z-olefin
isomers in excellent yield. The ratio of two isomers was 65/35. However, we were unable to
1
distinguish between two isomers due to the similarity of their H NMR spectra. Interestingly, when
the reactions of 9-(difluoromethylene)-9H-fluorene 1h with 2a or 2b were performed under the
optimized reaction conditions, no desired product was observed and a large amount of byproduct 9-
fluorenone was generated due to the thermal and hydrolytical instability of 1h. Thus, to avoid the
decomposition of 1h, we envisioned that the reaction should be performed in nonoxidizing and less
polar solvent at low temperature within a short reaction time. To our delight, the desired products
(
3ha, 3hb) were obtained in good yields when the reaction was performed in CH CN at room
3
temperature for 2 h by using 1.0 equivalent of 2a or 2b. Furthermore, when the amount of 2a or 2b
5

was increased to 2.0 equivalents, double aryloxylation products (3ha’, 3hb’) were obtained in
moderate yields after 4 hours of stirring at room temperature.
The scope of the aryloxylation reaction was examined with several unsymmetrical gem-
difluoroalkenes 1j–o (one is hydrogen and the other is aryl group). These unsymmetrical
difluoroalkenes reacted smoothly with pyrazolone 2a producing the expected products in good yields
but with low E/Z-selectivity (Table 3). To our delight, the Z- and E-isomers of 3ja and 3ka could be
separated by column chromatography. However, attempts to obtain the pure E- or Z- isomers of 3la–
oa were unsuccessful.
Inspired by the successful aryloxylation of gem-difluoroalkenes with pyrazolin-5-ones, we next
investigated the reaction of gem-difluoroalkenes with some pyrazolin-5-thiones under the above-
optimized conditions (Table 4). As expected, pyrazolin-5- thiones behaved similarly as pyrazolin-5-
ones in the arylthiolation reaction with different gem-difluoroalkenes and afforded the desired
products in good yields.
Conclusions
In summary, we have developed an efficient and versatile method for the -fluorovinylation of
pyrazolin-5-ones and pyrazolin-5- thiones with gem-difluoroalkenes having aryl substituents with the
assistance of t-BuOK. The reaction is applicable to a variety of gem-difluoroalkenes and pyrazolin-
5
-(thi)ones and provide -fluorovinyl pyrazolyl (thio)ethers in good to excellent yields under mild
conditions.
4
. Experimental
All reagents were of analytical grade, and obtained from commercial suppliers and used without
further purification. THF and other solvents were dried by standard method prior to use. Melting
6

points were measured in an open capillary using Büchi melting point B-540 apparatus and are
1
13
1
uncorrected. H NMR and C NMR spectra were recorded on a 400 spectrometer (400 MHz for H
1
3
19
and 100 MHz for C NMR, respectively) using TMS as internal standard, The F NMR spectra were
obtained using a 400 spectrometer (376 MHz). CDCl was used as the NMR solvent in all cases. High
3
resolution mass spectra (HRMS) were recorded under electron impact conditions using a MicroMass
GCT CA 055 instrument and recorded on a MicroMass LCTTM spectrometer. Silica gel (300−400
mesh size) was used for column chromatography. TLC analysis of reaction mixtures was performed
using silica gel plates.
4
.1 Preparation of symmetrical gem-difluoroalkenes 1a–i and unymmetrical gem-difluoroalkenes 1j–
o
The symmetrical gem-difluoroalkenes (1a–i) were prepared according to the Hu’s reported
procedure [12]. The unsymmetrical gem-difluoroalkenes (1j–o) were prepared according to the
reported procedure [13].
4
.2 Preparation of pyrazolones 2a–c and pyrazol-5-thiones 2d–e
The pyrazolones 2a–c were prepared according to the reported procedure [14]. The pyrazol-5-
thiones 2d and 2e were prepared according to literature procedures [15].
4
.3 General procedure for the target compounds 3
To a stirred solution of pyrazolones 2a–c (1.0 mmol) or pyrazol-5-thiones 2d or 2e (1.0 mmol)
and t-BuOK (1.0 mmol, 112 mg) in DMSO (4 mL), gem-difluoroalkenes 1a–o (0.5 mmol) were added.
The mixture was then stirred at 60 °C for 24 h under an argon atmosphere. The progress of the reaction
was monitored by TLC. After the completion of reaction, the mixture was extracted with H O (20
2
mL) and ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine, then dried
7

over anhydrous Na
2
SO , filtered, and concentrated under vacuum. The crude residue was then
4
purified by column chromatography on silica gel using n-hexane/ethyl acetate mixture (40/1 to 10/1)
as the eluent to afford pure target compound 3.
4
.3.1. 5-((1-Fluoro-2,2-diphenylvinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (3aa)
1
Light yellow solid, mp: 85.8–86.4 °C; H NMR (400 MHz, CDCl
3
) δ 7.38–7.20 (m, 15H), 5.88
) δ 150.5 (d, 1JCF = 290.7 Hz), 149.0,
37.8, 135.4 (d, 3JCF = 3.7 Hz), 135.2 (d, 3JCF = 4.2 Hz), 129.71, 129.68, 129.65, 129.6, 128.9, 128.4
1
3
(
d, J = 2.4 Hz, 1H), 2.28 (s, 3H) ; C NMR (100 MHz, CDCl
3
1
(
d, 4JCF = 4.0 Hz), 127.8, 127.7, 126.9, 122.8, 106.0 (d, 2JCF = 21.6 Hz), 90.3 (d, 4JCF = 1.3 Hz), 14.6 ;
19F NMR (376 MHz, CDCl
found: 370.1483.
) δ –91.2 (s, 1F) ; HRMS (EI): calc. for C24
H19FN
O [M] : 370.1481,
+
3
2
4
.3.2. 5-((1-Fluoro-2,2-bis(4-fluorophenyl)vinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (3ba)
1
Light yellow solid, mp: 69.5–70.3 °C; H NMR (400 MHz, CDCl
.13 (m, 2H), 7.06–7.02 (m, 2H), 6.96–6.91 (m, 2H), 5.85 (d, J = 2.0 Hz, 1H), 2.29 (s, 3H) ; C NMR
) δ 162.2 (d, 1JCF = 246.4 Hz), 162.1 (d, 1JCF = 246.5 Hz), 150.5 (d, 1JCF = 296.8
Hz), 149.0, 148.6 (d, 3JCF = 2.9 Hz), 137.6, 131.3–131.2 (m), 131.0–130.8 (m), 129.6–129.5 (m),
3
) δ 7.39–7.22 (m, 7H), 7.16–
1
3
7
(100 MHz, CDCl
3
1
1
–
28.9, 128.4 (d, 3JCF = 5.5 Hz), 127.0, 122.8, 115.45 (d, 2JCF = 21.5 Hz), 115.43 (d, 2JCF = 21.5 Hz),
04.1 (d, 2JCF = 22.4 Hz), 90.4 (d, 4JCF = 1.6 Hz), 14.6 ; F NMR (376 MHz, CDCl
19
) δ –91.0 (s, 1F),
3
+
113.5 to –113.6 (m, 2F) ; HRMS (EI): calc. for C24
H
17
F
3
N
2
O [M] : 406.1293, found: 406.1296.
4
.3.3. 5-((1-Fluoro-2,2-bis(3-fluorophenyl)vinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (3ca)
1
Oil; H NMR (400 MHz, CDCl
3
) δ 7.40–7.20 (m, 7H), 7.05–6.90 (m, 6H), 5.87 (d, J = 2.8 Hz,
) δ 162.7 (d, 1JCF = 244.6 Hz), 162.6 (d, 1JCF = 245.1
1
3
1
H ), 2.30 (s, 3H) ; C NMR (100 MHz, CDCl
3
Hz), 150.9 (d, 1JCF = 292.7 Hz), 149.0, 148.1 (d, 3JCF = 2.4 Hz), 137.5, 136.8 (dd, 3JCF = 8.0 Hz, 3JCF
8

=
3.9 Hz), 136.6 (dd, 3JCF = 8.3 Hz, 3JCF = 4.6 Hz), 130.0–129.9 (m), 129.0, 127.1, 125.42–125.37
(
(
(
m), 125.3 (dd, 4JCF = 4.4 Hz, 4JCF = 3.0 Hz), 122.9, 116.7 (dd, 2JCF = 19.3 Hz, 4JCF = 3.3 Hz), 116.5
dd, 2JCF = 19.4 Hz, 4JCF = 3.0 Hz), 115.0 (d, 2JCF = 20.9 Hz), 114.9 (d, 2JCF = 20.9 Hz), 104.1–104.0
m), 103.9–103.8 (m), 90.6 (d, 4JCF = 1.7 Hz), 14.5 ; F NMR (376 MHz, CDCl
19
) δ –88.6 (s, 1F),
O [M]+:
3
–
4
4
112.4 to –112.5 (m, 1F), –112.6 to –112.7 (m, 1F) ; HRMS (EI): calc. for C24
06.1293, found: 406.1295.
H
17
F
3
N
2
.3.4. 5-((2,2-Bis(4-chlorophenyl)-1-fluorovinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (3da)
1
White solid, mp: 142.5–144.3 °C; H NMR (400 MHz, CDCl
3
) δ 7.38–7.27 (m, 7H), 7.21–7.18
1
3
(
m, 4H), 7.10–7.08 (m, 2H), 5.86 (d, J = 2.4 Hz, 1H), 2.29 (s, 3H) ; C NMR (100 MHz, CDCl
3
) δ
1
50.7 (d, 1JCF = 292.0 Hz), 149.0 148.3 (d, 3JCF = 2.6 Hz), 137.5, 133.9, 133.8, 133.3 (d, 3JCF = 3.9
Hz), 133.2 (d, 3JCF = 4.3 Hz), 130.95 (d, 4JCF = 3.1 Hz), 130.93, 130.8, 129.0, 128.7 (d, 4JCF = 2.6 Hz),
19
1
–
4
27.1, 122.8, 103.9 (d, 2JCF = 22.4 Hz), 90.6 (d, 4JCF = 1.5 Hz), 14.6 ; F NMR (376 MHz, CDCl
3
) δ
+
89.4 (s, 1F) ; HRMS (EI): calc. for C24
H17Cl
2
FN
2
O [M] : 438.0702, found: 438.0705.
.3.5. 5-((2,2-Bis(4-bromophenyl)-1-fluorovinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (3ea)
1
Yellow solid, mp: 153.5–155.3 °C ; H NMR (400 MHz, CDCl
3
) δ 7.47 (d, J = 8.4 Hz, 2H), 7.37–
7
3
1
1
1
5
4
.29 (m, 7H), 7.12 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 5.85 (d, J = 2.4 Hz, 1H), 2.29 (s,
H) ; C NMR (100 MHz, CDCl
) δ 150.6 (d,1JCF = 292.2 Hz), 149.0, 148.2 (d, 3JCF = 2.6 Hz), 137.6,
1
3
3
33.7 (d, 3JCF = 3.9 Hz), 133.6 (d, 3JCF = 4.3 Hz), 131.7 (d, 4JCF = 2.3 Hz), 131.3 (d, 4JCF = 3.2 Hz),
31.2, 131.1, 129.0, 127.1, 122.9, 122.1, 122.0, 103.9 (d, 2JCF = 22.3 Hz), 90.7 (d, 4JCF = 1.5 Hz),
19
FN
O [M]+:
4.6 ; F NMR (376 MHz, CDCl
3
) δ –89.0 (s, 1F) ; HRMS (EI): calc. for C24
H17Br
2
2
27.9671, found: 527.9677.
.3.6.
3fa)
5-((1-Fluoro-2,2-bis(3-(trifluoromethyl)phenyl)vinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole
(
9

1
Oil (yellow); H NMR (400 MHz, CDCl
3
) δ 7.58–7.45 (m, 5 H), 7.41–7.27 (m, 8 H), 5.89 (d, J =
.6 Hz, 1H), 2.29 (s, 3H) ; C NMR (100 MHz, CDCl
) δ 151.3 (d, 1JCF = 293.0 Hz), 149.0, 147.7
d, 3JCF = 1.9 Hz), 137.4, 135.4 (d, 3JCF = 3.9 Hz), 135.3 (d, 3JCF = 4.2 Hz), 133.0 (d, 4JCF = 1.5 Hz),
13
1
3
(
1
1
32.8 (d, 4JCF = 2.8 Hz), 131.1 (q, 2JCF = 32.0 Hz), 131.1 (q, 2JCF = 32.2 Hz), 129.2, 129.1, 129.0,
27.2, 126.5–126.3 (m), 126.3–126.1 (m), 125.0–124.9 (m), 124.8–124.7 (m), 123.9 (q, 1JCF = 271.3
Hz), 123.8 (q, 1JCF = 270.8 Hz), 122.9, 103.4 (d, 2JCF = 22.5 Hz), 90.9 (d, 4JCF = 1.6 Hz), 14.5 ; 19F
NMR (376 MHz, CDCl ) δ –62.7 (s, 3F), –62.7 (s, 3F), –88.1 (s, 1F) ; HRMS (EI): calc. for
3
+
C
26
H
17
F
7
N
2
O [M] : 506.1229, found: 506.1230.
4
.3.7. 5-((1-Fluoro-2,2-di-p-tolylvinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (3ga)
1
Oil (grey); H NMR (400 MHz, CDCl
3
) δ 7.31–7.22 (m, 4H), 7.17–6.96 (m, 9H), 5.77 (d, J = 2.0
1
3
) δ 150.2 (d, 1JCF
89.8 Hz), 149.2 (d, 3JCF = 3.1 Hz), 149.0, 137.7, 137.5, 137.4, 132.5 (d, 3JCF = 3.7 Hz), 132.4 (d, 3JCF
4.2 Hz), 129.53, 129.50, 129.46, 129.0, 128.8, 126.8, 122.7, 105.8 (d, 2JCF = 21.6 Hz), 90.2 (d, 4JCF
Hz, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 2.20 (s, 3H) ; C NMR (100 MHz, CDCl
3
=
2
=
=
C
1
9
1.3 Hz), 21.24, 21.23, 14.6 ; F NMR (376 MHz, CDCl ) δ –92.1 (s, 1F) ; HRMS (EI): calc. for
3
+
26
H23FN
2
O [M] : 398.1794, found: 398.1795.
4
.3.8. 5-((1-Fluoro-2,2-diphenylvinyl)oxy)-1,3-diphenyl-1H-pyrazole (3ab)
1
Yellow solid, mp: 110.2–112.7 °C; H NMR (400 MHz, CDCl
3
) δ 7.86–7.84 (m, 2H), 7.47–7.23
) δ 150.9, 150.5 (d, 1JCF = 291.2 Hz),
49.6 (d, 3JCF = 3.0 Hz), 137.8, 135.3 (d, 3JCF = 3.6 Hz), 135.1 (d, 3JCF = 4.2 Hz), 132.9, 129.66,
13
(
m, 18H), 6.38 (d, J = 2.8 Hz, 1H); C NMR (100 MHz, CDCl
3
1
1
29.70 (d, 4JCF = 3.1 Hz), 129.66, 129.0, 128.7, 128.5, 128.4, 127.9, 127.8, 127.2, 125.6, 123.0, 106.2
d, 2JCF = 21.2 Hz), 87.9 (d, 4JCF = 1.6 Hz) ; F NMR (376 MHz, CDCl
19
(
3
) δ –91.2 (s, 1F) ; HRMS
+
(EI): calc. for C29
H21FN
2
O [M] : 432.1638, found: 432.1640.
4
.3.9. 5-((1-Fluoro-2,2-bis(4-fluorophenyl)vinyl)oxy)-1,3-diphenyl-1H-pyrazole (3bb)
10

1
Light yellow solid, mp: 120.3–121.2 °C; H NMR (400 MHz, CDCl
3
) δ 7.84 (d, J = 7.2 Hz, 2H),
7
1
1
1
2
1
4
4
.49–7.23 (m, 10H), 7.18–7.15 (m, 2H), 7.07–7.03 (m, 2H), 6.96–6.91 (m, 2H), 6.37 (d, J = 2.4 Hz,
1
3
) δ 162.3 (d, 1JCF = 246.5 Hz), 162.2 (d, 1JCF = 246.9 Hz), 150.9,
H) ; C NMR (100 MHz, CDCl
3
50.5 (d, 1JCF = 290.4 Hz), 149.3 (d, 3JCF = 2.9 Hz), 137.7, 132.7, 131.4–131.3 (m), 131.0–130.9 (m),
30.9–130.8 (m), 129.0, 128.7, 128.5, 127.4, 125.6, 123.0, 115.6 (d, 2JCF = 21.5 Hz), 115.5 (d, 2JCF
=
1.5 Hz), 104.4 (d, 2JCF = 22.1 Hz), 88.0 (d, 4JCF = 1.2 Hz) ; F NMR (376 MHz, CDCl
19
) δ –91.1 (s,
3
+
F), –113.38 to –113.39 (m, 2F) ; HRMS (EI): calc. for C29
H
19
F
3
N
2
O [M] : 468.1449, found:
68.1451.
.3.10. 5-((2,2-Bis(4-chlorophenyl)-1-fluorovinyl)oxy)-1,3-diphenyl-1H-pyrazole (3db)
1
Yellow solid, mp: 82.6–83.3 °C; H NMR (400 MHz, CDCl
3
) δ 7.85–7.83 (m, 2H), 7.48–7.29 (m,
1
3
1
0H), 7.22–7.19 (m, 4H), 7.12–7.10 (m, 2H), 6.37 (d, J = 2.8 Hz, 1H) ; C NMR (100 MHz, CDCl )
3
δ 151.0, 150.7 (d, 1JCF = 292.3 Hz), 148.9 (d, 3JCF = 2.6 Hz), 137.6, 134.0, 133.9, 133.2 (d, 3JCF = 3.8
Hz), 133.1 (d, 3JCF = 4.4 Hz), 132.7, 131.0 (d, 4JCF = 3.2 Hz), 130.9 (d, 4JCF = 4.6 Hz), 129.1, 128.81,
28.76, 128.7, 128.6, 127.5, 125.6, 123.1, 104.2 (d, 2JCF = 21.9 Hz), 88.3 (d, 4JCF = 1.6 Hz) ; F NMR
19
1
+
(
376 MHz, CDCl
3
) δ –89.4 (s, 1F) ; HRMS (EI): calc. for C29
H19Cl
2
FN
2
O [M] : 500.0858, found:
5
4
00.0857.
.3.11. 5-((2,2-Bis(4-bromophenyl)-1-fluorovinyl)oxy)-1,3-diphenyl-1H-pyrazole (3eb)
1
White solid, mp: 150.5–153.3 °C; H NMR (400 MHz, CDCl
3
) δ 7.85–7.82 (m, 2H), 7.48–7.29
1
3
(
m, 12H), 7.15–7.10 (m, 2H), 7.05–7.03 (m, 2H), 6.36 (d, J = 2.8 Hz, 1H) ; C NMR (100 MHz,
CDCl
) δ 150.9, 150.5 (d, 1JCF = 292.5 Hz), 148.8 (d, 3JCF = 2.6 Hz), 137.5, 133.5 (d, 3JCF = 3.8 Hz),
33.4 (d, 3JCF = 4.3 Hz), 132.6, 131.7, 131.6, 131.2 (d, 4JCF = 3.2 Hz), 131.1 (d, 4JCF = 4.5 Hz), 129.0,
3
1
1
28.6, 128.4, 127.4, 125.5, 123.0, 122.2, 122.0, 104.1 (d, 2JCF = 22.0 Hz), 88.2 (d, 4JCF = 1.7 Hz) ; 19F
+
3
NMR (376 MHz, CDCl ) δ –89.2 (s, 1F) ; HRMS (EI): calc. for C29
H19Br
2
FN
2
O [M] : 589.9828,
11

found: 589.9833.
4
.3.12. 5-((1-Fluoro-2,2-bis(3-(trifluoromethyl)phenyl)vinyl)oxy)-1,3-diphenyl-1H-pyrazole (3fb)
1
Oil (yellow); H NMR (400 MHz, CDCl
3
) δ 7.84 (d, J = 7.6 Hz, 2H), 7.61–7.32 (m, 16H), 6.39
) δ 151.2 (d, 1JCF = 293.4 Hz), 151.0, 148.3 (d, 3JCF
1.9 Hz), 137.5, 135.3 (d, 3JCF = 3.9 Hz), 135.2 (d, 3JCF = 4.2 Hz), 133.0 (d, 4JCF = 1.4 Hz), 132.9 (d,
4JCF = 2.9 Hz), 132.7, 131.23 (q, 2JCF = 32.3 Hz), 131.21 (q, 2JCF = 32.3 Hz), 129.3, 129.2, 129.1,
1
3
(
d, J =2.4 Hz, 1H ) ; C NMR (100 MHz, CDCl
3
=
1
1
1
28.7, 128.5, 123.9 (q, 1JCF = 270.9 Hz), 123.8 (q, 1JCF = 270.9 Hz), 127.6, 126.5–126.4 (m), 126.3–
26.1 (m), 125.6, 125.2–125.0 (m), 124.9–124.8 (m), 123.1, 103.6 (d, 2JCF = 22.2 Hz), 88.5 (d, J =
4
19
.8 Hz) ; F NMR (376 MHz, CDCl ) δ –62.7 (s, 3F), –62.7 (s, 3F), –88.3 (s, 1F) ; HRMS (EI): calc.
3
+
for C31
H
19
F
7
N
2
O [M] : 568.1386, found: 568.1389.
4
.3.13. 5-((1-Fluoro-2,2-diphenylvinyl)oxy)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole (3ac)
1
Yellow solid, mp: 75.8–77.4 °C; H NMR (400 MHz, CDCl
3
) δ 7.35–7.26 (m, 13H), 7.20–7.18
) δ 150.1 (d, 1JCF = 291.6 Hz), 149.2
d, 3JCF = 2.8 Hz), 142.2 (q, 2JCF = 38.8 Hz), 136.8, 134.9 (d, 3JCF = 3.6 Hz), 134.6 (d, 3JCF = 4.3 Hz),
1
3
(
m, 2H), 6.32 (d, J = 2.4 Hz, 1H) ; C NMR (100 MHz, CDCl
3
(
1
1
–
4
29.7 (d, 4JCF = 3.1 Hz), 129.6 (d, 4JCF = 4.5 Hz), 129.2, 128.6, 128.50, 128.46, 128.1, 128.0, 123.6,
20.8 (q, 1JCF = 267.6 Hz), 106.8 (d, 2JCF = 20.2 Hz), 89.1–89.0 (m) ; F NMR (376 MHz, CDCl
19
) δ
3
+
63.0 (s, 3F), –92.5 (s, 1F) ; HRMS (EI): calc. for C24
H
16
F
4
N
2
O [M] : 424.1199, found: 424.1198.
.3.14.
3bc)
5-((1-Fluoro-2,2-bis(4-fluorophenyl)vinyl)oxy)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole
(
1
Oil (yellow); H NMR (400 MHz, CDCl
3
) δ 7.42–7.34 (m, 5H), 7.26–7.22 (m, 2H), 7.14–7.11 (m,
13
2
H), 7.06–7.00 (m, 2H), 6.97–6.92 (m, 2H), 6.31 (d, J = 2.4 Hz, 1H ) ; C NMR (100 MHz, CDCl
δ 162.4 (d, 1JCF = 246.9 Hz), 162.3 (d, 1JCF = 246.9 Hz), 150.1 (d, 1JCF = 291.5 Hz), 148.8 (d, 3JCF
.7 Hz), 142.1 (q, 2JCF = 38.9 Hz), 136.6, 132.4–132.1 (m), 131.4–131.2 (m), 130.6–130.5 (m), 130.4–
3
)
=
2
12

1
30.3 (m), 129.2, 128.6, 123.5, 120.7 (q, 1JCF = 267.6 Hz), 115.65 (d, 2JCF = 21.6 Hz), 115.57 (d,2JCF
21.6 Hz), 104.9 (d, 2JCF = 21.1 Hz), 89.21–89.18 (m) ; F NMR (376 MHz, CDCl
19
) δ –63.2 (s, 3F),
=
3
+
–
4
4
92.3 (s, 1F), –113.0 to –113.1 (m, 2F) ; HRMS (EI): calc. for C24
60.1012.
.3.15. 5-((1-Fluoro-2,2-bis(3-(trifluoromethyl)phenyl)vinyl)oxy)-1-phenyl-3-(trifluoromethyl)-1H-
H
14
F
6
N
2
O [M] : 460.1010, found:
pyrazole (3fc)
1
Oil; H NMR (400 MHz, CDCl
3
) δ 7.61–7.57 (m, 2H), 7.52–7.48 (m, 3H), 7.42–7.35 (m, 8H),
) δ 150.7 (d, 1JCF = 293.9 Hz), 147.8 (d, 3JCF
.6 Hz), 142.2 (q, 2JCF = 39.2 Hz), 136.4, 134.9 (d, 3JCF = 4.8 Hz), 134.7 (d, 3JCF = 4.2 Hz), 132.9 (d,
1
3
8
1
.35 (d, J = 2.8 Hz, 1H) ; C NMR (100 MHz, CDCl
3
=
4JCF = 1.5 Hz), 132.73–132.69 (m), 131.3 (q, 2JCF = 32.4 Hz), 131.2 (q, 2JCF = 32.4 Hz), 129.3, 129.2,
1
1
28.8, 123.8 (q, 1JCF = 238.4 Hz), 123.7 (q, 1JCF = 270.9 Hz), 126.4–126.3 (m), 126.2–126.0 (m),
25.3–125.2 (m), 125.1–125.0 (m), 120.5 (q, 1JCF = 267.7 Hz), 104.1 (d, 2JCF = 21.2 Hz), 89.7–89.6
19
(
m) ; F NMR (376 MHz, CDCl ) δ –62.7 (s, 6F), –63.3 (s, 3F), –89.5 (s, 1F) ; HRMS (EI): calc. for
3
+
C
26
H
14
F
10
N
2
O [M] : 560.0946, found: 560.0947.
4
.3.16. (E/Z)-5-((1-Fluoro-2-(4-fluorophenyl)-2-phenylvinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole
(E/Z-3ia)
1
Oil; H NMR (400 MHz, CDCl
3
) δ 7.40–7.14 (m, 12H), 7.06–7.00 (m, 0.65 × 2H), 6.95–6.90 (m,
13
) δ 162.2 (d, 1JCF = 246.1
0
.35 × 2H), 5.87–5.86 (m, 1H), 2.29 (s, 3H) ; C NMR (100 MHz, CDCl
3
Hz), 162.1 (d, 1JCF = 246.4 Hz), 151.9, 150.6 (d, 1JCF = 290.6 Hz), 150.6 (d, 1JCF = 290.9 Hz), 149.11,
1
1
1
49.10, 149.0, 148.8–148.7 (m), 137.7, 135.1 (d, 3JCF = 3.6 Hz), 135.0 (d, 3JCF = 4.2 Hz), 131.4–
31.3 (m), 131.2–131.1 (m), 129.7 (d, 4JCF = 3.1 Hz), 129.6, 129.5, 128.93, 128.91, 128.5, 128.4,
27.9, 127.8, 127.0, 126.9, 122.8, 115.4 (d, 2JCF = 21.5 Hz), 105.1 (d, 2JCF = 21.7 Hz), 105.0 (d, 2JCF
13

22.4 Hz), 90.4 (d, 4JCF = 1.6 Hz), 90.3 (d, 4JCF = 1.5 Hz), 14.6 ; F NMR (376 MHz, CDCl
19
) δ –
=
3
9
0.9 (s, 0.35 × 1F), –91.4 (s, 0.65 × 1F), –113.7 to –113.8 (m, 1F) ; HRMS (EI): calc. for C24
H
18
F
2
2
N O
+
[
M] : 388.1387, found: 388.1389.
4
.3.17. 5-((9H-Fluoren-9-ylidene)fluoromethoxy)-3-methyl-1-phenyl-1H-pyrazole (3ha)
1
Grey solid, mp: 96.9–98.4 °C; H NMR (400 MHz, CDCl
3
) δ 7.81–7.74 (m, 5H), 7.56 (d, J = 7.6
Hz, 1H), 7.50–7.46 (m, 2H), 7.40–7.31 (m, 4H), 7.20–7.16 (m, 1H), 5.91 (d, J = 2.0 Hz, 1H), 2.30 (s,
1
3
) δ 151.3 (d, 1JCF = 301.5 Hz), 149.3, 147.1, 139.3 (d, 3JCF = 5.2
3
H) ; C NMR (100 MHz, CDCl
3
Hz), 139.0, 137.7, 134.6 (d, 3JCF = 6.3 Hz), 134.3 (d, 3JCF = 7.0 Hz), 129.3, 127.9 (d, 5JCF = 1.9 Hz),
1
1
1
4
27.8 (d, 5JCF = 2.1 Hz), 127.44, 127.42, 127.3, 124.4, 124.2, 123.6 (d, 4JCF = 1.9 Hz), 123.0, 120.1,
20.0, 102.6 (d, 2JCF = 23.1 Hz), 91.8 (d, 4JCF = 1.4 Hz), ; F NMR (376 MHz, CDCl
19
) δ –77.7 (s,
3
+
F) ; HRMS (EI): calc. for C24
H17FN
2
O [M] : 138.1325, found: 368.1327.
.3.18. 5,5'-(((9H-Fluoren-9-ylidene)methylene)bis(oxy))bis(3-methyl-1-phenyl-1H-pyrazole) (3ha')
1
White solid, mp: 197.0–198.5 °C; H NMR (400 MHz, CDCl
3
) δ 7.69–7.64 (m, 4H), 7.38–7.36
1
3
(
m, 4H), 7.29–7.23 (m, 6H), 7.19–7.12 (m, 4H), 5.48 (s, 2H), 1.96 (s, 6H) ; C NMR (100 MHz,
CDCl
3
) δ 148.9, 147.8, 147.1, 139.5, 137.5, 134.9, 129.0, 128.1, 127.5, 127.1, 124.3, 122.7, 120.1,
+
1
09.5, 92.3, 14.5 ; HRMS (EI): calc. for C34
H
26
N
4
O
2
[M] : 522.2056, found: 522.2057.
4
.3.19. 5-((9H-Fluoren-9-ylidene)fluoromethoxy)-1,3-diphenyl-1H-pyrazole (3hb)
1
Yellow solid, mp: 101.3–103.4 °C; H NMR (400 MHz, CDCl
3
) δ 7.87–7.81 (m, 5H), 7.78–7.72
(m, 2H), 7.60–7.58 (m, 1H), 7.53–7.49 (m, 2H), 7.40–2.29 (m, 7H), 7.20–7.15 (m, 1H), 6.41 (d, J =
.0 Hz, 1H) ; C NMR (100 MHz, CDCl
) δ 151.3 (d, 1JCF = 301.6 Hz), 151.2, 147.8 (d, 4JCF = 2.0
1
3
2
3
Hz), 139.4 (d, 3JCF = 5.2 Hz), 139.1, 137.8, 134.6 (d, 3JCF = 6.3 Hz), 134.3 (d, 3JCF = 6.9 Hz), 132.7
14

1
1
29.4, 128.7, 128.6, 128.1 (d, 5JCF = 2.0 Hz), 128.0 (d, 5JCF = 1.9 Hz), 127.8, 127.5, 127.4, 125.6,
24.5, 124.3, 123.7 (d, 4JCF = 1.9 Hz), 123.3, 120.2, 103.0 (d, 2JCF = 22.9 Hz), 89.5 (d, 4JCF3 = 1.3
1
9
+
Hz) ; F NMR (376 MHz, CDCl
3
) δ –77.8 (s, 1F) ; HRMS (EI): calc. for C29
H
19FN O[M] : 430.1481,
2
found: 430.1487.
4
.3.20. 5,5'-(((9H-Fluoren-9-ylidene)methylene)bis(oxy))bis(1,3-diphenyl-1H-pyrazole) (3hb')
1
White solid, mp: 177.6–188.5 °C; H NMR (400 MHz, CDCl
3
) δ 7.84 (d, J = 7.6 Hz, 2H ), 7.78
(d, J = 7.6 Hz, 2H ), 7.62–7.60 (m, 4H), 7.53–7.51 (m, 4H), 7.39–7.20 (m, 14H), 7.15–7.12 (m, 2H),
1
3
6
1
.14 (s, 2H) ; C NMR (100 MHz, CDCl ) δ 150.9, 147.8, 147.6, 139.6, 137.4, 134.8, 132.6, 129.1,
3
28.5, 128.39, 128.36, 127.7, 127.6, 125.6, 124.5, 123.0, 120.2, 110.1, 89.8 ; HRMS (EI): calc. for
+
C
44
H
30
N
4
O
2
[M] : 646.2369, found: 646.2366.
4
.3.21. (E)-5-((2-(4-Chlorophenyl)-1-fluorovinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (E-3ja)
1
Oil (yellow); H NMR (400 MHz, CDCl
3
) δ 7.62 (d, J = 8.0 Hz, 2H), 7.46–7.42 (m, 2H), 7.36–
1
3
7
.32 (m, 1H), 7.22–7.17 (m, 4H), 5.82 (d, J = 2.0 Hz, 1H), 5.58 (d, J = 5.6 Hz, 1H), 2.28 (s, 3H) ; C
) δ 152.3 (d, 1JCF = 285.8 Hz), 149.1, 147.4 (d, 3JCF = 1.9 Hz), 137.7, 132.9
d, 4JCF = 2.1 Hz), 129.4 (d, 3JCF = 7.7 Hz), 129.1, 129.0 (d, 4JCF = 3.6 Hz), 128.8, 127.3 123.1, 91.0
NMR (100 MHz, CDCl
3
(
(
d, 4JCF = 2.6 Hz), 90.6 (d, 2JCF = 34.9 Hz), 14.5 ; F NMR (376 MHz, CDCl
19
) δ –85.3 (dd, J = 5.6
3
+
Hz, J = 2.0 Hz, 1F) ; HRMS (EI): calc. for C18
H14ClFN
2
O [M] : 328.0779, found: 328.0782.
4
.3.22. (Z)-5-((2-(4-Chlorophenyl)-1-fluorovinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (Z-3ja)
1
Oil; H NMR (400 MHz, CDCl
3
) δ 7.63 (d, J = 8.0 Hz, 2H), 7.47–7.43 (m, 2H), 7.34–7.29 (m,
1
3
5
H), 5.87 (s, 1H), 5.36 (d, J = 28.0 Hz, 1H), 2.31 (s, 3H) ; C NMR (100 MHz, CDCl ) δ 154.5 (d,
3
1JCF = 287.6 Hz), 149.0, 148.1, 137.7 132.9 (d,4JCF = 3.1 Hz), 129.7 (d,3JCF = 6.2 Hz), 129.13, 129.06,
28.9, 127.2, 122.6, 91.7, 88.9 (d, 2JCF = 16.5 Hz), 14.5 ; F NMR (376 MHz, CDCl
19
) δ –85.1 (d, J
1
3
15

+
=
27.8 Hz, 1F) ; HRMS (EI): calc. for C18
H
14ClFN O [M] : 328.0779, found: 328.0777.
2
4
.3.23. (E)-5-((2-(3-Bromophenyl)-1-fluorovinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (E-3ka)
1
Oil (yellow); H NMR (400 MHz, CDCl
3
) δ 7.62 (d, J = 7.6 Hz, 2H), 7.47–7.43 (m, 3H), 7.36–
7
1
1
1
.31 (m, 2H), 7.22–7.20 (m, 1H), 7.11–7.07 (m, 1H), 5.83 (d, J = 2.4 Hz, 1H), 5.56 (d, J = 6.0 Hz,
H), 2.29 (s, 3H) ; C NMR (100 MHz, CDCl =
) δ 153.5 (d, 1JCF = 286.8 Hz), 149.1, 147.2 (d, 3JCF
1
3
3
.3 Hz), 137.6, 133.1 (d, 3JCF = 7.9 Hz), 130.6 (d, 4JCF = 3.5 Hz), 130.2 (d, 5JCF = 1.8 Hz), 130.1, 129.2,
27.4, 126.3 (d, 4JCF = 3.5 Hz), 123.2, 122.7, 91.1 (d, 4JCF = 1.8 Hz), 90.2 (d, 2JCF = 25.0 Hz), 14.5 ;
19F NMR (376 MHz, CDCl
) δ –84.6 (dd, J = 6.0 Hz, J = 2.3 Hz, 1F) ; HRMS (EI): calc. for
3
+
C
18
H
14BrFN
2
O [M] : 374.0253, found: 374.0255.
4
.3.24. (Z)-5-((2-(3-Bromophenyl)-1-fluorovinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (Z-3ka)
1
Oil (yellow); H NMR (400 MHz, CDCl
3
) δ 7.62 (d, J = 8.0 Hz, 2H), 7.52–7.52 (m, 1H), 7.47–
7
3
6
9
.44 (m, 2H), 3.37–7.26 (m, 3H), 7.21–7.17 (m, 1H), 5.88 (s, 1H), 5.33 (d, J = 27.6 Hz, 1H), 2.32 (s,
H) ; C NMR (100 MHz, CDCl =
) δ 154.9 (d, 1JCF = 287.7 Hz), 149.1, 147.9, 137.9, 133.3 (d,4JCF
1
3
3
.3 Hz), 130.6 (d, 3JCF = 7.4 Hz), 130.12, 130.09, 129.1, 127.2, 126.4 (d, 4JCF = 6.9 Hz), 122.8, 122.7,
1.9, 88.4 (d, 2JCF = 16.2 Hz), 14.6 ; F NMR (376 MHz, CDCl
19
) δ –84.0 (d, J = 27.8 Hz, 1F) ;
3
+
HRMS (EI): calc. for C18
H
14BrFN
2
O [M] : 374.0253, found: 374.0255.
4
.3.25. (E/Z)-5-((1-Fluoro-2-(4-methoxyphenyl)vinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (E/Z-3la)
1
Oil (grey); H NMR (400 MHz, CDCl
3
) δ 7.67–7.64 (m, 2H), 7.47–7.42 (m, 2H), 7.34–7.31 (m,
1
6
0
H + 0.25 × 2H, Z-isomer), 7.25–7.21 (m, 0.75 × 2H, E-isomer), 6.89–6.86 (m, 0.25 × 2H, Z-isomer),
.78–6.76 (m, 0.75× 2H, E-isomer), 5.85 (d, J = 1.2 Hz, 0.25 × 1H, Z-isomer), 5.81 (d, J = 1.6 Hz,
.75 × 1H, E-isomer), 5.61 (d, J = 6.0 Hz, 0.75 × 1H, E-isomer), 5.40 (d, J = 28.0 Hz, 0.25 × 1H, Z-
isomer), 3.80 (s, 0.25 × 3H, Z-isomer), 3.76 (s, 0.75× 3H, E-isomer), 2.30 (s, 0.25 × 3H, Z-isomer),
.28 (s, 0.75× 3H, E-isomer) ; C NMR (100 MHz, CDCl
) δ 158.8–158.7 (m), 153.8, 153.3 (d, 1JCF
1
3
2
3
16

=
287.3 Hz), 151.0, 149.1, 149.0 (d, 3JCF = 1.8 Hz), 148.1 (d, 3JCF = 2.6 Hz), 137.8, 137.8, 129.2,
29.2, 129.1, 129.5, 127.1, 127.0, 123.5 (d, 3JCF = 6.1 Hz), 123.1 (d, 3JCF = 7.1 Hz), 122.9, 122.6,
14.2, 114.1, 91.5 (d, 2JCF = 34.3 Hz), 91.2, 90.7 (d, 4JCF = 1.2 Hz), 90.1 (d, 2JCF = 17.2 Hz), 55.3,
1
1
5
19
5.3, 14.6, 14.5 ; F NMR (376 MHz, CDCl
3
) δ –88.1 (d, J = 27.8 Hz, 0.25 × 1F, Z-isomer), –88.5
+
(
dd, J = 5.6 Hz, J = 1.5 Hz, 0.75× 1F, E-isomer) ; HRMS (EI): calc. for C19
H
17FN
2
O
2
[M] : 324.1274,
found: 324.1273.
4
.3.26. (E/Z)-5-((1-Fluoro-2-(4-(methylthio)phenyl)vinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (E/Z-
3
ma)
1
Oil (brown); H NMR (400 MHz, CDCl
3
) δ 7.65–7.63 (m, 2H), 7.45–7.40 (m, 2H), 7.32–7.29 (m,
0
2
5
3
.62 × 3H, Z-isomer), 7.28–7.26 (m, 0.38 × 1H, E-isomer), 7.21–7.14 (m, 2H), 7.09–7.07 (m, 0.38 ×
H, E-isomer), 5.85 (d, J = 0.8 Hz, 0.62 × 1H, Z-isomer), 5.81 (d, J = 1.0 Hz, 0.38 × 1H, E-isomer),
.58 (d, J = 5.6 Hz, 0.38 × 1H, E-isomer), 5.37 (d, J = 28.4 Hz, 0.62 × 1H, Z-isomer), 2.44 (s, 0.62 ×
H, Z-isomer), 2.41 (s, 0.38 × 3H, E-isomer), 2.29 (s, 0.62 × 3H, Z-isomer), 2.27 (s, 0.38 × 3H, E-
1
3
) δ 154.1 (d, 1JCF = 288.6 Hz), 153.0 (d, 1JCF = 284.8 Hz), 149.1,
49.0, 148.6, 147.8 (d, 3JCF = 2.3 Hz), 137.8, 137.8, 137.7 (d, 5JCF = 2.0 Hz), 137.7 (d, 5JCF = 2.5 Hz),
29.1, 128.3 (d, 3JCF = 6.9 Hz), 128.2 (d, 4JCF = 3.6 Hz), 127.8 (d, 4JCF = 6.2 Hz), 127.5 (d, 3JCF = 7.3
isomer) ; C NMR (100 MHz, CDCl
3
1
1
Hz), 127.2, 127.1, 126.6, 126.5, 122.9, 122.6, 91.5, 91.5, 90.9 (d, 4JCF = 1.2 Hz), 89.8 (d, 2JCF = 16.6
1
9
Hz), 15.6, 15.6, 14.6,14.6 ; F NMR (376 MHz, CDCl
3
) δ –85.7 (d, J = 27.8 Hz, 0.62 × 1F, Z-isomer),
86.4 (dd, J = 5.6 Hz, J = 1.1 Hz, 0.38 × 1F, E-isomer) ; HRMS (EI): calc. for C19
OS [M]+:
40.1046, found: 340.1047.
–
3
4
H17FN
2
.3.27. (E/Z)-5-((1-Fuoro-2-(naphthalen-2-yl)vinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (E/Z-3na)
1
Oil (brown); H NMR (400 MHz, CDCl
3
) δ 7.93–7.91 (m, 0.36 × 1H, E-isomer), 7.80–7.69 (m,
4
H), 7.62–7.60 (m, 0.64 × 1H, Z-isomer), 7.49–7.40 (m, 5H), 7.32–7.27 (m, 0.64 × 2H, Z-isomer),
17

7
1
.27–7.25 (m, 0.36 × 1H, E-isomer), 7.21–7.17 (m, 0.36 × 1H, E-isomer), 6.19 (d, J = 5.2 Hz, 0.36 ×
H, E-isomer), 6.00–5.94 (m, 0.64 × 2H, Z-isomer), 5.82 (d, J = 2.4 Hz, 0.36 × 1H, E-isomer), 2.32
1
3
(
s, 0.64 × 3H, Z-isomer), 2.23 (s, 0.36 × 3H, E-isomer) ; C NMR (100 MHz, CDCl
1JCF = 285.2 Hz), 153.9 (d, 1JCF = 277.1 Hz), 149.2, 149.0, 148.5, 148.1 (d, 3JCF = 1.9 Hz), 138.0,
37.7, 133.7, 133.6, 131.6 (d, 3JCF = 3.4 Hz), 131.4, 129.3, 129.0, 128.8, 128.7, 128.2, 128.1, 127.4
d, 3JCF = 4.5 Hz), 127.3, 127.2, 127.0, 126.8 (d, 3JCF = 7.3 Hz), 126.5 (d, 5JCF = 2.0 Hz), 126.4 (d,
3
) δ 154.9 (d,
1
(
4JCF = 3.8 Hz) 126.0, 126.0, 125.6, 125.5, 123.9, 123.8, 122.9, 122.8, 91.9, 91.0 (d, 4JCF = 1.3 Hz),
8.4 (d, 2JCF = 33.8 Hz), 86.4 (d, 2JCF = 18.3 Hz), 14.7, 14.6 ; F NMR (376 MHz, CDCl
19
) δ –85.4
8
3
to –85.4 (m, 0.36 × 1F, E-isomer), –88.3 (d, J = 26.3 Hz, 0.64 × 1F, Z-isomer) ; HRMS (EI): calc. for
+
C
22
H17FN
2
O [M] : 344.1325, found: 344.1328.
4
.3.28. (E/Z)-5-((2-(3,4-Dimethylphenyl)-1-fluorovinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (E/Z-
3
oa)
1
Oil (grey); H NMR (400 MHz, CDCl
3
) δ 7.68–7.64 (m, 2H), 7.46–7.42 (m, 2H), 7.34–7.30 (m,
1
H), 7.15–6.98 (m, 3H), 5.85 (d, J = 1.2 Hz, 0.25 × 1H, Z-isomer), 5.81 (d, J = 2.4 Hz, 0.75 × 1H, E-
isomer), 5.60 (d, J = 6.0 Hz, 0.75 × 1H, E-isomer), 5.38 (d, J = 28.4 Hz, 0.25 × 1H, Z-isomer), 2.30
(s, 0.25 × 3H, Z-isomer), 2.27 (s, 0.75 × 3H, E-isomer), 2.24 (s, 0.25 × 6H, Z-isomer), 2.19 (s, 0.75
3H, E-isomer), 2.10 (s, 0.75 × 3H, E-isomer) ; C NMR (100 MHz, CDCl =
) δ 153.8 (d, 1JCF
1
3
×
3
2
1
3
1
87.8 Hz), 152.8 (d, 1JCF = 283.7 Hz), 149.1, 149.0, 148.9, 148.1 (d, 3JCF = 2.6 Hz), 137.9, 136.9,
36.8, 135.9 (d, 5JCF = 1.8 Hz), 135.9 (d, 5JCF = 2.3 Hz), 130.0, 129.9, 129.2, 129.1, 129.0 (d, 4JCF
=
.4 Hz), 128.6 (d, 4JCF = 6.1 Hz), 128.2 (d, 3JCF = 7.1 Hz), 127.1, 127.0, 125.4 (d, 3JCF = 7.0 Hz),
25.3 (d, 4JCF = 3.5 Hz), 122.9, 122.6, 91.8 (d, 2JCF = 33.8 Hz), 91.3, 90.6 (d, 4JCF = 1.4 Hz), 90.3 (d,
2JCF = 16.8 Hz), 19.8, 19.7, 19.5, 19.5, 14.6, 14.6 ; F NMR (376 MHz, CDCl
19
) δ –86.7 (d, J = 28.6
3
Hz, 0.25 × 1F, Z-isomer), –87.3 (d, J = 6.0 Hz, 0.75 × 1F, E-isomer) ; HRMS (EI): calc. for
18

+
C
20
H
19FN O [M] : 322.1481, found: 322.1484.
2
4
.3.29. 5-((1-Fluoro-2,2-diphenylvinyl)thio)-3-methyl-1-phenyl-1H-pyrazole (3ad)
1
Oil; H NMR (400 MHz, CDCl
3
) δ 7.44–7.42 (m, 2H), 7.39–7.34 (m, 3H), 7.32–7.22 (m, 6H),
1
3
7
1
.12–7.10 (m, 2H), 7.06–7.04 (m, 2H), 6.46 (s, 1H), 2.34 (s, 3H) ; C NMR (100 MHz, CDCl
3
) δ
49.7, 147.8 (d, 1JCF = 304.0 Hz), 139.2, 137.4 (d, 3JCF = 4.1 Hz), 136.5 (d, 3JCF = 2.6 Hz), 130.3 (d,
4JCF = 3.1 Hz), 129.6, 129.5, 128.9, 128.7, 128.3, 128.1, 127.93, 127.86, 127.7, 125.4, 113.9, 13.7 ;
19F NMR (376 MHz, CDCl
found: 386.1257.
) δ –91.2 (s, 1F) ; HRMS (EI): calc. for C24
H19FN
S [M] : 386.1253,
+
3
2
4
.3.30. 5-((1-Fluoro-2,2-bis(3-(trifluoromethyl)phenyl)vinyl)thio)-3-methyl-1-phenyl-1H-pyrazole
3fd)
Oil (yellow); H NMR (400 MHz, CDCl
.34 (m, 7H), 7.29–7.27 (m, 2H), 7.19 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.45 (s, 1H), 2,33
(
1
3
) δ 7.61 (d, J = 7.6 Hz, 1H), 7.51–7.49 (m, 1H), 7.45–
7
1
3
) δ 150.1 (d, 1JCF = 306.2 Hz), 149.8, 139.1, 137.3 (d, 3JCF = 4.4
(
s, 3H) ; C NMR (100 MHz, CDCl
Hz), 136.4 (d, 3JCF = 2.4 Hz), 133.7, 132.6 (d, 4JCF = 3.3 Hz), 131.0 (q, 2JCF = 32.3 Hz), 130.7 (q, 2JCF
32.2 Hz), 129.1, 129.0, 128.8, 128.3, 123.84 (q, 1JCF = 272.5 Hz), 123.81 (q, 1JCF = 270.9 Hz),
3
=
1
1
27.1–127.0 (m), 126.7, 126.2–126.1 (m), 125.4, 125.3–125.2 (m), 124.9–124.8 (m), 124.4 (d, 2JCF
=
1
9
5.8 Hz), 114.8, 13.7 ; F NMR (376 MHz, CDCl
3
) δ –62.5 (s, 3F), –62.7 (s, 3F), –88.0 (s, 1F) ;
+
HRMS (EI): calc. for C26
H
17
F
7
N
2
S [M] : 522.1001, found: 522.1002.
4
.3.31. 5-((1-Fluoro-2,2-di-p-tolylvinyl)thio)-3-methyl-1-phenyl-1H-pyrazole (3gd)
1
Oil (yellow); H NMR (400 MHz, CDCl
3
) δ 7.44–7.32 (m, 5H), 7.11–7.00 (m, 6H), 6.95–6.93 (m,
1
3
2
1
1
H), 6.45 (s, 1H), 2.36 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H) ; C NMR (100 MHz, CDCl ) δ 149.7,
3
47.1 (d, 1JCF = 303.1 Hz), 139.3, 137.9, 137.7, 134.7 (d, 3JCF = 4.2 Hz), 133.8 (d, 4JCF = 2.7 Hz),
30.2 (d, 4JCF = 3.1 Hz), 129.5 (d, 3JCF = 5.3 Hz), 129.2, 128.9, 128.8, 128.7, 127.8, 125.3, 125.1,
19

1
13.7, 21.3, 21.2, 13.7 ; 19F NMR (376 MHz, CDCl
) δ –92.0 (s, 1F) ; HRMS (EI): calc. for
3
+
C
26
H
23FN S [M] : 414.1566, found: 414.1572.
2
4
.3.32. 5-((1-Fluoro-2,2-bis(3-(trifluoromethyl)phenyl)vinyl)thio)-1,3-diphenyl-1H-pyrazole (3fe)
1
Oil (yellow); H NMR (400 MHz, CDCl
3
) δ 7.86–7.84 (m, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.54–
1
3
7
.30 (m, 13H), 7.22–7.19 (m, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H) ; C NMR (100 MHz,
) δ 152.3, 149.9 (d, 1JCF = 306.4 Hz), 139.2, 137.2 (d, 3JCF = 4.4 Hz), 136.4 (d, 3JCF = 2.4 Hz),
33.7, 132.6 (d, 3JCF = 3.4 Hz), 132.3, 131.0 (q, 2JCF = 32.3 Hz), 130.8 (q, 2JCF = 32.2 Hz), 129.1,
29.1, 128.9, 128.8, 128.6, 128.5, 127.9, 127.1–127.0 (m), 126.3–126.1 (m), 125.74, 125.65, 125.5–
CDCl
3
1
1
1
2
25.3 (m), 125.0–124.9 (m), 124.6 (d, 2JCF = 15.5 Hz), 123.9 (q, 1JCF = 270.8 Hz), 123.1 (q, 1JCF
=
19
70.9 Hz), 112.3 ; F NMR (376 MHz, CDCl
3
) δ –62.5 (s, 3F), –62.6 (s, 3F), –87.9 (s, 1F) ; HRMS
+
(EI): calc. for C31
H
19
F
7
N
2
S [M] : 584.1157, found: 584.1161.
4
.3.33. (E/Z)-5-((1-Fluoro-2-(4-methoxyphenyl)vinyl)oxy)-3-methyl-1-phenyl-1H-pyrazole (E/Z-3jd)
1
Oil (yellow); H NMR (400 MHz, CDCl
3
) δ 7.56–7.15 (m, 9H), 6.49 (s, 1H), 6.42 (d, J = 16.0
1
3
Hz, 0.82 × 1H, E-isomer), 5.82 (d, J = 32.4 Hz, 0.18 × 1H, Z-isomer), 2.33 (s, 3H) ; C NMR (100
MHz, CDCl
) δ 151.2 (d, 1JCF = 297.4 Hz), 151.1 (d, 1JCF = 308.1 Hz), 149.8, 139.2, 139.0, 133.7 (d,
4JCF = 1.5 Hz), 130.2 (d, 3JCF = 9.0 Hz), 130.0 (d, 3JCF = 3.2 Hz), 129.9, 128.9, 128.8, 128.5, 128.2,
3
1
28.1, 127.6, 127.2 (d, 4JCF = 1.5 Hz), 125.7, 125.6, 125.1, 115.2 (d, 2JCF = 30.0 Hz), 114.8 (d, 2JCF
=
1
9
1
1.1 Hz), 114.4, 113.7, 110.4, 14.4, 13.7 ; F NMR (376 MHz, CDCl
3
) δ –82.2 (d, J = 16.2 Hz, 0.82
×
1F, E-isomer), –87.1 (d, J = 32.3 Hz, 0.18 × 1F, Z-isomer) ; HRMS (EI): calc. for C18
H
14ClFN S
2
+
[
M] : 344.0550, found: 344.0551.
Acknowledgments
We are grateful for financial supports from the National Natural Science Foundation of China (Grant
Nos. 21472043, 21272070).
20

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23

Fig. 1. Examples of bioactive O-pyrazole derivatives.
24

Table 1. Optimization of reaction conditions.a, b
Entry 2a (equiv) Base
Temp. (°C) Solvent
Yield of 3aa (%)b
(equiv)
1
2
3
4
5
6
2.0
2.0
2.0
2.0
2.0
2.0
t-BuOK
60
60
60
60
60
60
1,4-Dioxane 0
(
2.0)
t-BuOK
2.0)
t-BuOK
2.0)
t-BuOK
2.0)
t-BuOK
2.0)
t-BuOK
2.0)
THF
0
(
CH
3
CN
23
30
61
94
(
NMP
(
DMF
(
DMSO
(
7
8
2.0
2.0
None
60
60
DMSO
DMSO
0
t-BuOLi
47
(
2.0)
PO
2.0)
9
1
2.0
2.0
K
3
4
60
60
DMSO
DMSO
50
56
(
0
Cs
2
CO
3
(2.0)
1
1
2.0
2.0
2.0
NaOH (2.0) 60
DMSO
DMSO
DMSO
83
80
90
1
1
2
3
KOH (2.0)
60
60
t-BuOK
(2.5)
25

1
1
1
1
1
4
5
6
7
8
2.0
2.0
2.0
2.0
1.5
t-BuOK
1.5)
t-BuOK
2.0)
t-BuOK
2.0)
t-BuOK
2.0)
t-BuOK
2.0)
60
25
45
75
60
DMSO
DMSO
DMSO
DMSO
DMSO
75
71
89
92
67
(
(
(
(
(
a
Reaction conditions: 1a (0.25 mmol), solvent (2 mL), 24 h.
Yields were determined by GC-MS analysis and based on 1a.
b
26

Table 2. Reaction of various symmetrical gem-difluoroalkenes with pyrazolones.a, b
a
Reaction conditions: 1a–g, 1i (0.5 mmol), 2a–c (1.0 mmol), t-BuOK (1.0 mmol), DMSO (4 mL),
6
0 °C, 24 h.
b
Isolated yields.
c
Reaction conditions: 1h (0.5 mmol); 2a, 2b (0.5 mmol), MeCN (4 mL), RT, 2 h.
Reaction conditions: 1h (0.5 mmol); 2a, 2b (1.0 mmol), MeCN (4 mL), RT, 4 h.
d
27

Table 3. Reaction of various umsymmetrical gem-difluoroalkenes with pyrazolones.a,b,c
a
Reaction conditions: 1j–o (0.5 mmol), 2a (1.0 mmol), t-BuOK (1.0 mmol), DMSO (4 mL), 60 °C,
2
4 h.
b
Isolated yields of pure isomer or inseparable E/Z mixture of the products.
c
19
E/Z selectivity was determined by F NMR spectra. The configurations of E- and Z-isomers were
determined by their 3JHF coupling constants in H NMR spectra.
1
28

Table 4. Reaction of various gem-difluoroalkenes with pyrazol-5-thiones.a, b, c
a
Reaction conditions: 1a, 1f, 1g, 1j (0.5 mmol), 2d, 2e (1.0 mmol), t-BuOK (1.0 mmol), DMSO (4
mL), 60 °C, 24 h.
b
Isolated yields.
c
19
E/Z selectivity was determined by F NMR spectra. The configurations of E- and Z-isomers were
determined by their 3JHF coupling constants in H NMR spectra.
1
29