Convergent Synthesis of Fluoroalkenes Using a Dual-Reactive Unit

Article abstract of DOI:10.1021/acs.joc.0c02474

Fluoroalkenes have shown importance as a metabolically stable isostere of amide compounds. To expedite the synthesis of diverse fluoroalkenes, we have developed a dual-reactive C2-unit, (Z)-1-boryl-1-fluoro-2-tosyloxyethene, containing nucleophilic and electrophilic moieties. Consecutive palladium-catalyzed cross-coupling reactions of this unit with aryl bromides and aryl boronic acids allow for the convergent synthesis of diverse trans-1,2-diaryl-substituted fluoroethenes in a chemoselective and stereoretentive manner.

Full text of DOI:10.1021/acs.joc.0c02474

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Convergent Synthesis of Fluoroalkenes Using a Dual-Reactive Unit
Motoyuki Isoda, Yuta Uetake, Tadashi Takimoto, Junpei Tsuda, Takamitsu Hosoya,*
and Takashi Niwa*
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ABSTRACT: Fluoroalkenes have shown importance as a meta-
bolically stable isostere of amide compounds. To expedite the
synthesis of diverse fluoroalkenes, we have developed a dual-
reactive C2-unit, (Z)-1-boryl-1-fluoro-2-tosyloxyethene, containing
nucleophilic and electrophilic moieties. Consecutive palladium-
catalyzed cross-coupling reactions of this unit with aryl bromides
and aryl boronic acids allow for the convergent synthesis of diverse trans-1,2-diaryl-substituted fluoroethenes in a chemoselective and
stereoretentive manner.
electrophilic sites at the vicinal position (Nu/E-type), is an
attractive alternative because it can easily perform the
chemoselective reaction to introduce substituents in a
regioselective manner (Figure 1C).5 For example, Suzuki et
al. developed (E)-(2-bromoethenyl)dibromo-borane as a dual-
reactive C2-unit and used it for the preparation of (E)-1,2-
disubstituted alkenes via consecutive palladium-catalyzed
cross-coupling reactions.6 Burke et al. updated this motif by
protecting the boryl group with N-methyliminodiacetic acid,7
which was applied to the iterative synthesis of a polyene
moiety in several natural products.8 These pioneering works
illustrated the synthetic utility of dual-reactive C2-ethene units
for alkene synthesis. However, only a few more examples have
been reported probably because it is difficult to prepare
ethenes with functional groups at adjacent positions that can
react with each other. To facilitate convergent synthesis of
complex alkenes, the development of various C2-units easily
available at a large scale is required. Herein, we report a
fluorine-substituted dual-reactive C2-unit for facile synthesis of
fluoroalkenes.
INTRODUCTION
■
Alkenes represent a most fundamental class of organic
compounds, and their selective synthesis is a longstanding
issue in organic synthesis.1 Among the various methods,
consecutive functionalization of a bisreactive C2-ethene unit is
a straightforward method for the synthesis of alkenes (Figure
1A). This convergent approach using the C2-unit as a platform
Fluoroalkenes have attracted considerable attention from
medicinal chemists as one of the promising metabolically
stable mimics of amide compounds (Figure 2A).9 This
isosterism is explained by the several unique properties of
fluoroethene, such as the planar structure, the dipole moment
of the C(sp2)−F bond, and the ability to accept hydrogen
bonding, which are all physically similar to that of the amide
group. This homology enables the replacement of amide bonds
of bioactive compounds with a fluoroethene to improve
Figure 1. Convergent synthesis of alkenes using C2-units.
molecule is suitable for diversity-oriented synthesis of alkenes.2
This approach also enables stereoselective preparation of
desired isomers by the stereoretentive introduction of
substituents through preinstalled transformable groups. In
this context, various 1,2-difunctionalized ethenes have been
developed as a C2-unit for the preparation of 1,2-disubstituted
alkenes. Conventionally, 1,2-dimetalethenes with two nucleo-
philic sites (Nu/Nu-type)3 and 1,2-dihaloethenes with two
electrophilic sites (E/E-type)4 have been used for the
construction of alkene moieties of complex molecules (Figure
1B). Dual-reactive ethene, bearing both nucleophilic and
Received: October 19, 2020
Published: January 5, 2021
https://dx.doi.org/10.1021/acs.joc.0c02474
© 2021 American Chemical Society
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Table 1. Optimization for Defluoroborylation of 2
Cu
yield of 1a
a
entry complex
ligand
PCy3
PPh3
base
solvent
THF
THF
THF
THF
THF
THF
THF
THF
(%)
1
2
3
4
5
6
7
8
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
CuOAc
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
LiOAc
NaOAc
CsOAc
CsF
33
61
62
55
35
10
10
45
60
67
73
82
67
77
38
5
PCy2Ph
PCyPh2
P(n-Bu)3
b
Figure 2. Our synthetic approach for fluoroalkenes.
dppf
b
DPEphos
PPh3
PPh3
metabolic stability without significant losses of their original
bioactivities. Indeed, drug candidates having a fluoroethene
moiety have been developed based on this concept.10 Although
considerable efforts have been made to develop hopeful drug
candidates possessing a fluoroethene moiety, the number of
such examples is limited, most likely because of the lack of
practical synthetic methods for fluoroalkenes. To the best of
our knowledge, all of fluoroalkenes have been prepared via
linear synthetic routes.11 This approach is suitable for target-
oriented synthesis but often decreases the overall yield of the
desired product and can be difficult to apply to the synthesis of
other analogs. We have considered a convergent approach
using a dual-reactive fluoroethene unit offering the higher
synthetic efficiency for the preparation of diverse fluoroalkenes
and facilitating the development of drug candidates.
To realize this idea, we designed a fluoroethene unit bearing
both nucleophilic and electrophilic moieties, which would
allow the convergent synthesis of fluoroalkenes by the
consecutive connection of substituents through cross-coupling
reactions (Figure 2B). Challenges include the preparation of
the trisubstituted C2-unit and establishment of the conditions
for the cross-coupling reactions using the unit without
undesired homocoupling. We anticipated that (Z)-1-boryl-1-
fluoro-2-tosyloxyethene 1 would suit this purpose. The lower
reactivity of the C−OTs bond compared to that of typical C−
halogen bonds is expected to be suitable for the prior
transformation of the nucleophilic boron moiety, which is in
inverse to that of known dual-reactive C2-units, where the first
bond connection occurs preferentially at the electrophilic
moiety.6−8 We planned to synthesize 1 by trans-selective
defluoroborylation from 1,1-difluoro-2-tosyloxyethene (2),
which was readily available from 2,2,2-trifluoroethanol in a
large scale.12 Among several reported methods for this
transformation,10d,13 we believe that our copper-catalyzed
conditions10d were preferable because of excellent tolerance
to various functional groups, including leaving groups such as a
tosyloxy group.
9
THF
THF
THF
10
11
12
13
14
15
16
17
18
19
20
21
22
PPh3
c
PPh3
c
PPh3
toluene
n-hexane
CPME
1,4-dioxane
DMF
toluene
toluene
toluene
toluene
toluene
c
PPh3
c
PPh3
c
PPh3
c
PPh3
c
PPh3
77
70
51
7
0
40
c
PPh3
c
PPh3
c
PPh3
c
PPh3
K2CO3
none
c
PPh3
toluene
a
b
1
Yields were determined by H NMR analysis. 5 mol % of ligands
c
were used. 15 mol % of ligands were used.
the replacement of CuCl with copper(I) thiophenecarboxylate
(CuTC) (entries 2 and 8−10) gave superior results. The yield
of 1a was slightly improved by increasing the amount of PPh3
to 15 mol % (entry 11). Performing the reaction in various
solvents revealed that the use of nonpolar solvents, such as
toluene, were preferable, providing 1a in high yields (entries
11−16). Screening of the base revealed that the addition of
alkaline acetates was preferable, and, among them, potassium
acetate (KOAc) gave the best result (entries 12 and 17−22).
Other boron sources, such as bis(neopentyl glycolato)diboron
or bis(catecolato)diboron, were not employable, resulting in
low yields (Table S5). As expected, throughout the
investigation, cleavage of the C−OTs bond was not observed.
However, cis-1-fluoro-2-tosyloxyethene (3) was formed as a
byproduct, particularly when the yield of 1a was low, indicating
that protodeborylation of 1a proceeded under these con-
ditions. The purification of 1a by typical column chromatog-
raphy lowered the yield as was also the case for the isolation of
defluoroborylated products synthesized from 2-(2,2-
difluorovinyl)arenes.10d For the sake of easy purification, 1a
was converted to the corresponding potassium trifluoroborate
1b by treating the crude mixture with aqueous KHF2, and the
resulting precipitate was isolated by simple filtration to afford
an analytically pure colorless solid (Scheme 1). In combination
with the large-scale synthesis of 2 from 2,2,2-trifluoroethanol,12
this method allowed a scale-up synthesis with 50 mmol of 2 to
give more than 10 g of 1b after filtration.
RESULTS AND DISCUSSION
■
We began our investigation from the synthesis of 1 by the
copper-catalyzed defluoroborylation of 2. Our first attempt
using the previously defined optimal conditions10d afforded the
desired product 1a via trans-selective C−F bond cleavage,
albeit in low yield (Table 1, entry 1). To improve the yield, we
reoptimized the reaction conditions (for details, see Tables
S1−S4). We found that the use of triarylphosphines, such as
triphenylphosphine (PPh3), instead of PCy3 (entries 1−7), and
With the dual-reactive fluoroalkene unit in hand, we
examined the first cross-coupling via C−B bond-selective
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Scheme 1. Large-Scale Synthesis of Potassium (Z)-(1-Fluoro-2-tosyloxy)ethen-1-yl(trifluoro)borate (1b) from 2,2,2-
Trifluoroethanol
transformation of 1b. Unfortunately, typical conditions for the
cross-coupling reactions of organotrifluoroborates with aryl
halides in hydrous solvents, such as a mixture of
dimethylformamide (DMF) and water, did not give the
desired product but did provide protodeborylated product 3
(Table S6).14 Therefore, we screened for the reaction
conditions using 1b and 4-bromotoluene (4a) as a model
substrate. Extensive screening revealed that the choice of
solvent significantly affected the efficiency of the cross-
coupling reaction (Table 2, entries 1−7 and Table S7 for
of 2 equiv of ethylene glycol in tetrahydrofuran (THF) was
sluggish (entry 7). We also found that the use of CsF gave the
best result, while alkali metal acetates were also available.
Further screening of palladium salts and ligands did not
improve the efficiencies (Tables S9 and S10).
A possible reaction mechanism was estimated based on the
conventional cross-coupling mechanism involving oxidative
addition of aryl bromide 4 to palladium(0), transmetalation
with an alkenylboron compound, and reductive elimination of
5 (Scheme 2).16 In the presence of cesium fluoride (CsF),
halogen exchange of B occurred to give arylpalladium(II)
fluoride C, facilitating the following transmetalation.17 Ethyl-
ene glycol reacts with 1b to generate alkenylboron ethylene
glycol ester D reversibly, which is sufficiently active for the
transmetalation with C because of the sterically less hindered
environment around the boron center compared with other
typical boronic esters, such as pinacol or neopentyl glycolato
ester.18 Further reaction of D with ethylene glycol under basic
conditions may occur to form trialkoxyborate G, which has
been proposed as an intermediate of protodeborylation of
arylboronic acids under basic conditions.19 We anticipated that
this step (D to G) is slower in ethylene glycol than that in
other protic solvents, such as methanol or water, because of
instability of G caused by the more sterically congested
environment of tri(ethylene glycoxy)borate compared with
that of the trimethoxy- or trihydroxyborate (Table 2, entries
4−6). We tentatively assumed that the slow formation of
trialkoxyborate G prevented the protodeborylation pathway,
leading to the high yields of the desired product 5.
Table 2. Solvent Effects on the Palladium-Catalyzed
Arylation of 1b
a
a
entry
base
CsF
CsF
CsF
CsF
CsF
CsF
CsF
solvent
toluene
MeCN
DMF
MeOH
H2O
ethylene glycol
THF
yield of 5a (%) yield of 3 (μmol)
1
2
3
4
5
6
0
0
0
0
22
32
11
71
0
41
61
97 (82)
1
b
c
7
3
Optimized conditions (Table 2, entry 6) were applicable to
the arylation of 1b with a wide range of aryl bromides 4 to
afford products 5 (Scheme 3). Arylation with electron-neutral
and -rich aryl bromides, such as 4b−g, smoothly proceeded to
afford cross-coupling products 5b−g in high yields. Aryl
bromides bearing an electron-withdrawing group at the para-
position, such as an ester moiety (5h) and a trifluoromethyl
group (5i), were found to be less favorable for this
transformation. Chloro- and fluoro-substituted aryl bromides
afforded arylated products 5j and 5k, respectively, leaving these
halogeno groups untouched. Sterically hindered aryl bromides
did not impede the reaction, as reactions using 2-tolyl- or 2-
mesityl bromide gave products 5l and 5m, respectively.
Substrates containing heterocycles, such as pyridine (4n),
benzo[b]thiophene (4o), and indole (4p), participated in the
reaction to afford the cross-coupling products 5n−p. The
applicability of the method to prepare monofluoroalkene
derivatives of bioactive compounds was demonstrated in the
synthesis of acetaminophen conjugate 5q from N-acetyl-4-
bromoaniline (4q) in high yield. Unfortunately, chlorobenzene
and phenyl triflate were not suitable substrates for the coupling
with 1b under the same conditions, affording a trace amount of
5b. This method was scalable, as demonstrated in the reaction
8
9
KF
ethylene glycol
ethylene glycol
ethylene glycol
ethylene glycol
ethylene glycol
ethylene glycol
ethylene glycol
ethylene glycol
79
82
84
80
6
5
17
11
0
0
69
46
16
0
CsOAc
KOAc
NaOAc
K2CO3
t-BuOK
KOH
Et3N
10
11
12
13
14
15
<1
92
a
b
Yields were determined by 1H NMR analysis. Isolated yield is
shown in parentheses. Ethylene glycol (2 equiv) was added.
c
details). No reaction proceeded in nonpolar solvents, such as
toluene, probably because of the low solubility of 1b (entry 1).
In polar aprotic solvents able to dissolve 1b, such as MeCN or
DMF, protodeborylation of 1b predominantly occurred to
form 3 (entries 2 and 3). Meanwhile, the use of protic solvents,
such as methanol or water, provided desired product 5a in
moderate yields (entries 4 and 5). We finally found that
ethylene glycol was the most effective solvent for the reaction
to afford 5a in 97% yield (entry 6). Notably, neither
protodeborylation nor C−OTs bond cleavage15 of 1b was
observed under the conditions. The quantity of ethylene glycol
used was essential, and the reaction performed in the presence
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Scheme 2. Plausible Reaction Mechanism of Pd-Catalyzed Cross-Coupling Reaction of 1b with Aryl Bromide 4 in Ethylene
Glycol
a
Next, we examined the second cross-coupling via catalytic
transformation of the tosyloxy group of 5 with arylboronic
acids. The reported conditions for the arylation of (E)-(2-
fluoroethenyl)tosylate12 were not applicable. The catalyst
optimization study using 4-biphenyl substituted fluoro-
(tosyloxy)ethene 5c and phenylboronic acid (6a) revealed
that various palladacycle precatalysts having a biaryl-
substituted phosphine ligand20 effectively promoted the
arylation (Table 3). Among them, CPhos Pd G4 precatalyst
exhibited the best catalytic activity to afford the desired cross-
coupling product 7a, while the isolated yield slightly decreased.
One of the possible reasons is the poor solubility of 7a, which
resulted in loss of the product during column chromatographic
purification. This prompted us to use phenyl-substituted 5b as
Scheme 3. Palladium-Catalyzed Arylation of 1b
Table 3. Optimization of the Palladium Precatalyst for
Arylation of 5c
a
entry
Pd source
yield of 7a (%)
1
2
3
4
5
6
7
8
9
APhos Pd G4
CyJohnPhos Pd G4
SPhos Pd G4
RuPhos Pd G4
DavePhos Pd G4
CPhos Pd G4
BrettPhos Pd G4
XPhos Pd G3
0
68
83
66
70
b
98 (73)
87
87
21
DPPF Pd G4
a
b
Yields were determined by 19F NMR analysis. Isolated yield is
shown in parentheses.
a
b
Isolated yields are shown. 3.1 mmol (1.3 equiv) of 1b and 2.4 mmol
c
of 4c were used. 0.3 mmol (1.5 equiv) of 1b and 0.2 mmol of 4l were
used. 0.45 mmol (1.5 equiv) of 1b and 0.3 mmol of 4m were used.
d
using 2.4 mmol of 4c, affording desired product 5c in excellent
yield.
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a substrate for the scope investigation. Although slight Z- to E-
isomerization of the product 7a was observed when the
reaction was performed under the usual light illumination, it
was avoidable by performing the reaction protected from
light.21 The addition of methanol as a cosolvent was effective
in dissolving arylboronic acid and increased product yields
(Table S12). The use of arylboronic acid esters, such as
pinacol or neopentyl glycolato esters, as coupling partners were
less favorable under these reaction conditions (Scheme S1).
Optimized conditions were applicable for cross-coupling of
5b with various arylboronic acids bearing electron-donating or
-withdrawing groups to afford diverse trans-diaryl-substituted
fluoroalkenes (Scheme 4, 7b−h). The tolerance of a
CONCLUSIONS
■
We developed a dual-reactive fluoroethene unit 1b having
nucleophilic boryl and electrophilic tosyloxy moieties and
demonstrated its utility for the convergent synthesis of diverse
trans-1,2-diaryl-substituted fluoroalkenes by consecutive palla-
dium-catalyzed cross-coupling reactions. Unit 1b was prepar-
able in a decagram-scale by the copper-catalyzed defluorobor-
ylation under reoptimized conditions, enhancing the synthetic
utility of the method. We also found an intriguing solvent
effect of ethylene glycol in the first cross-coupling reaction
between fluoroethenyl(trifluoro)borate and aryl bromides. We
believe that advanced cross-coupling chemistry would further
improve the utility of the fluoroethene unit for the convergent
synthesis of fluoroalkenes and contribute to the development
of fluoroalkene drug candidates.
Scheme 4. Palladium-Catalyzed Arylation of
a
Tosyloxyethene 5b with Arylboronic Acids 6
EXPERIMENTAL SECTION
■
General Experiments. All reactions were performed under an
argon atmosphere, unless otherwise indicated. All manipulations of
air- and/or moisture-sensitive compounds were performed either
using standard Schlenk techniques or in a MIWA DBO-1KH-NYWS
glovebox under an atmosphere of argon. Unless otherwise noted, all
reactions were conducted in a 4 mL (15 × 45 mm) screw-thread clear
vial (Thermo Fisher Scientific, cat. no. C4015-1) with a cap
assembled with a septum (Thermo Fisher Scientific, cat. no.
C4015-75A). Analytical thin-layer chromatography (TLC) was
performed on precoated (0.25 mm) silica-gel plates (Merck, Merck
Silica Gel 60 F254). Column chromatography was conducted by hand
using silica-gel (SiliCycle Inc., SiliaFlash) or on a Yamazen automated
flash chromatography system that consists of AI-580 and Parallel Frac
FR-360 with silica-gel-packed column (Shoko scientific, Purif-Pack).
Recycling preparative high-performance liquid chromatography
(HPLC) was performed by LC-Forte/R (YMC Co., Ltd.) with
high-resolution gel permeation chromatography column (Japan
Analytical Industry Co., Ltd., JAIGEL-1H). Melting points (mp)
were measured with an OptiMelt automated melting point apparatus
1
(Stanford Research Systems, Inc.) and were uncorrected. H NMR
(400 MHz), 13C NMR (100 MHz), 19F NMR (373 MHz), and 11B
NMR (127 MHz) spectra were obtained from measurements at
ambient temperature on a JEOL ESC-400 spectrometer. 19F-
1
decoupled H NMR (400 MHz) spectra of compounds 5l and 5m
were obtained from measurements at ambient temperature on a JEOL
ECZ-400R spectrometer equipped with a JEOL Royal Probe HFX.
Chloroform-d1 (CDCl3) containing 0.05% tetramethylsilane (TMS)
(99.8% D, Cambridge Isotope Laboratories, Inc.), acetone-d6 (99.5%
D, Cambridge Isotope Laboratories, Inc.), or methanol-d4 (99.8%D,
Cambridge Isotope Laboratories, Inc.) was used as a solvent for NMR
measurements at room temperature. Chemical shifts (δ) are given in
parts per million (ppm) relative to the signal of TMS (δ 0.00 ppm for
1H NMR), residual acetone (δ 2.09 ppm for 1H NMR), residual
a
b
Isolated yields are shown, unless otherwise noted. Yield was
estimated by 19F NMR analysis.
1
methanol (δ 3.31 ppm for H NMR), CDCl3 (δ 77.2 ppm for 13C
nonprotected amino group (7f) was noteworthy. 4-Fluoro-
phenylboronic acid (6g) participated in the reaction to afford
7g, whereas the use of 4-chlorophenylboronic acid (6i)
resulted in low yields likely because of the competitive
cleavage of the C−Cl bond. The sterically hindered
arylboronic acid was employable, as demonstrated in the
reaction of mesitylboronic acid (6j) to afford 7j. Hetero-
aromatic boronic acids (6k−m) also participated in this
reaction to afford benzo[b]furan-2-yl- (7k), benzo[b]thiophen-
2-yl- (7l), and 3-thienyl(fluoro)ethenes (7m), respectively.
When 4-acetoxyphenyl boronic acid (6n) was used, depro-
tection of the acetyl group simultaneously occurred to afford
(Z)-4′-hydroxy-1-fluorostilbene (7n). Throughout the inves-
tigation, cleavage of the C−F bond was not observed.22
NMR), acetone-d6 (δ 30.6 ppm for 13C NMR), methanol-d4 (δ 49.0
ppm for 13C NMR), (trifluoromethyl)benzene (δ −63.0 ppm for 19F
NMR), or BF3·OEt2 (δ 0.00 ppm for 11B NMR) with coupling
constants (J) in hertz (Hz). The abbreviations s, d, t, q, m, and br
signify singlet, doublet, triplet, quartet, multiplet, and broad,
respectively. Infrared (IR) absorption spectra were measured by
attenuated total reflection (ATR) method on a Shimadzu IRPrestige-
21 spectrometer equipped with a PIKE Technologies MIRacle single
reflection ATR optical attachment and a ZnSe crystal plate. The
absorption bands are given in wavenumber (cm−1). High-resolution
mass spectra (HRMS) were measured on a Thermo Fisher Scientific
Exactive Plus Orbitrap mass spectrometer under positive or negative
electrospray ionization (ESI+ or ESI−) conditions. Unless otherwise
noted, materials obtained from commercial suppliers were used
without further purification. 2,2-Difluoroethenyl 4-methylbenzenesul-
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fonate (2) was prepared in a 100 mmol scale according to the
literature.23
(Z)-2-Fluoro-2-(4-methylphenyl)ethenyl 4-Methylbenzenesulfo-
nate (5a, Table 2, Entry 6). Prepared with 4-bromotoluene (4a,
12.3 μL, 0.100 mmol); eluent for column chromatographic
purification: n-hexane/EtOAc = 4:1; yield: 81.9% (25.0 mg, 81.6
μmol); yellow oil; TLC Rf = 0.39 (n-hexane/EtOAc = 4:1); 1H NMR
(CDCl3): δ 7.87−7.84 (m, 2H), 7.36−7.34 (m, 2H), 7.27−7.25 (m,
2H), 7.17−7.15 (m, 2H), 6.71 (d, JH−F = 19.4 Hz, 1H), 2.45 (s, 3H),
2.35 (s, 3H); 13C{1H} NMR (CDCl3): δ 151.9 (d, 1JC−F = 254.6 Hz,
1C), 145.8 (1C), 140.4 (1C), 132.3 (1C), 130.1 (2C), 129.6 (2C),
128.2 (2C), 126.1 (d, 2JC−F = 24.8 Hz, 1C), 124.2 (d, 3JC−F = 5.7 Hz,
2C), 117.7 (d, 2JC−F = 14.3 Hz, 1C), 21.9 (1C), 21.5 (1C); 19F NMR
Procedure for Large-Scale Synthesis of Potassium (Z)-(1-
Fluoro-2-tosyloxy)ethen-1-yl(trifluoro)borate (1b, Scheme 1).
Caution. The water bath temperature must be kept below 40 °C
during the concentration of reaction mixtures containing the
defluoroborylated product, such as 1a or 1b. We observed that
protodeborylation was promoted at the temperature over 40 °C to
reduce the yield of 1b.
To a 1 L round-bottom flask equipped with a magnetic stir bar
were added CuTC (477 mg, 2.50 mmol, 0.05 equiv), PPh3 (1.97 g,
7.51 mmol, 0.15 equiv), (Bpin)2 (19.1 g, 75.2 mmol, 1.5 equiv),
KOAc (5.89 g, 60.0 mmol, 1.2 equiv), and toluene (200 mL). After
stirring for 30 min at room temperature, to this, was added a solution
of (2,2-difluoroethenyl) 4-methylbenzenesulfonate (2) (11.7 g, 50.0
mmol, 1 equiv) in toluene (50 mL), and the suspension was stirred
for 72 h at 40 °C with an oil bath. After cooling with an ice-water
bath, to the reaction mixture, was added saturated aqueous
ammonium chloride (ca. 250 mL). The mixture was extracted with
EtOAc (ca. 100 mL × 3). The combined organic extract was washed
with brine (ca. 100 mL) and dried over Na2SO4. After filtration, the
filtrate was concentrated under reduced pressure, keeping the water
bath temperature at 35 °C. The residue that contained 1a was
dissolved with MeOH (375 mL) in a 2 L round-bottom flask
equipped with a magnetic stir bar, and the mixture was cooled to 0
°C. To this, was slowly added an aqueous KHF2 solution (4.5 mol/L,
170 mL, 765 mmol, 15.3 equiv) with a dropping funnel over 30 min.
After finishing addition, the mixture was warmed up to room
temperature and stirred for 24 h at the same temperature. The
solvents were removed under reduced pressure, keeping the
temperature of the water bath at 35 °C, and the residue was dried
under vacuum. The residue was suspended in acetone (ca. 500 mL)
and irradiated with an ultrasonic wave for 1 min. After passing the
mixture through a pad of Celite and washing with acetone, the filtrate
was concentrated under reduced pressure until a precipitate was
observed. To this suspension, was added Et2O (1 L) to promote the
precipitation. The precipitate was collected by filtration, washed with
Et2O, and dried under vacuum to give a crude solid (11.0 g)
containing 1b and a small amount of an unidentified byproduct
3
(CDCl3): δ −129.0 (d, JF−H = 19.4 Hz); IR (ZnSe, cm−1) 1371,
1192, 866, 736, 663; HRMS (ESI) m/z: [M + H]+ calcd for
C16H16O3FS+, 307.0799; found, 307.0789.
(Z)-2-Fluoro-2-phenylethenyl 4-Methylbenzenesulfonate (5b).
Prepared with bromobenzene (4b, 10.5 μL, 0.100 mmol); eluent
for column chromatographic purification: n-hexane/EtOAc = 4:1;
yield: 70.1% (20.5 mg, 70.1 μmol); colorless solid; mp: 54−56 °C;
TLC Rf = 0.38 (n-hexane/EtOAc = 4:1); 1H NMR (CDCl3): δ 7.88−
3
7.84 (m, 2H), 7.41−7.35 (m, 7H), 6.77 (d, JH−F = 19.9 Hz, 1H),
2.45 (s, 3H); 13C{1H} NMR (CDCl3): δ 151.5 (d, 1JC−F = 259.4 Hz,
1C), 145.9 (1C), 132.3 (1C), 130.2 (2C), 130.1 (1C), 129.0 (1C),
128.9 (2C), 128.4 (2C), 124.2 (d, 3JC−F = 6.7 Hz, 2C), 118.3 (d, 2JC−F
= 13.4 Hz, 1C), 21.9 (1C); 19F NMR (CDCl3): δ −129.4 (d, 3JF−H
=
19.9 Hz); IR (ZnSe, cm−1) 1371, 1182, 866, 754, 667; HRMS (ESI)
m/z: [M + H]+ calcd for C15H14O3FS+, 293.0642; found, 293.0634.
(Z)-2-(Biphenyl-4-yl)-2-fluoroethenyl 4-Methylbenzenesulfonate
(5c). Prepared with 1b (1.01 g, 3.14 mmol, 1.3 equiv) and 4-
bromobiphenyl (4c, 560 mg, 2.40 mmol); eluent for column
chromatographic purification: n-hexane/EtOAc = 4:1; yield: 91.6%
(810 mg, 2.20 mmol); colorless solid; mp: 139−140 °C; TLC Rf =
1
0.41 (n-hexane/EtOAc = 4:1); H NMR (acetone-d6): δ 8.00−7.96
(m, 2H), 7.78−7.75 (m, 2H), 7.74−7.71 (m, 2H), 7.69−7.66 (m,
2H), 7.59−7.57 (m, 2H), 7.54−7.49 (m, 2H), 7.43 (tt, JH−H = 7.1, 1.2
Hz, 1H), 7.25 (d, 3JH−F = 19.8 Hz, 1H), 2.51 (s, 3H); 13C{1H} NMR
1
(acetone-d6): δ 152.8 (d, JC−F = 251.7 Hz, 1C), 147.8 (1C), 144.1
(1C), 141.3 (1C), 133.8 (1C), 131.9 (2C), 130.6 (2C), 129.8 (2C),
129.6 (1C), 129.2 (d, 2JC−F = 23.8 Hz, 1C), 128.9 (2C), 128.5 (2C),
3
2
126.1 (d, JC−F = 5.7 Hz, 2C), 120.6 (d, JC−F = 13.3 Hz, 1C), 22.4
(1C); 19F NMR (CDCl3): δ −129.7 (d, 3JF−H = 19.8 Hz); IR (ZnSe,
cm−1) 1388, 1190, 867, 763, 661; HRMS (ESI) m/z: [M + H]+ calcd
for C21H18FO3S+, 369.0955; found, 369.0955.
1
observable by H NMR spectroscopy. To the solid, was added 1,2-
dichloroethane (55 mL), and the suspension was irradiated with an
ultrasonic wave for 1 min. The insoluble solid was collected by
filtration, washed with Et2O, and dried under vacuum to give 1b (10.1
(Z)-2-Fluoro-2-(4-methoxyphenyl)ethenyl 4-Methylbenzenesul-
fonate (5d). Prepared with 4-bromoanisole (4d, 12.5 μL, 0.100
mmol); eluent for column chromatographic purification: n-hexane/
EtOAc = 7:3; yield: 72.0% (23.2 mg, 72.0 μmol); yellow oil; TLC Rf
= 0.39 (n-hexane/EtOAc = 7:3); 1H NMR (CDCl3): δ 7.88−7.84 (m,
2H), 7.36−7.34 (m, 2H), 7.32−7.28 (m, 2H), 6.89−6.85 (m, 2H),
1
g, 31.4 mmol, 62.7%); mp: 140−143 °C; H NMR (acetone-d6): δ
3
7.81−7.77 (m, 2H), 7.46−7.44 (m, 2H), 5.98 (d, JH−F = 25.3 Hz,
1H), 2.45 (s, 3H); 13C{1H} NMR (acetone-d6): δ 145.9 (1C), 134.1
(1C), 130.7 (2C), 128.7 (2C), 122.8 (br s, 1C), 21.5 (1C) (the signal
for the carbon that is attached to the boron atom was not observed);
3
6.63 (d, JH−F = 19.0 Hz, 1H), 3.81 (s, 3H), 2.45 (s, 3H); 13C{1H}
3
2
19F NMR (acetone-d6): δ −139.0 (dq, JF−H = 25.3 Hz, JF−B = 28.7
NMR (CDCl3): δ 161.1 (1C), 151.9 (d, 1JC−F = 254.6 Hz, 1C), 145.7
(1C), 132.3 (1C), 130.1 (2C), 128.4 (2C), 125.9 (d, 3JC−F = 6.7 Hz,
2C), 121.3 (d, 2JC−F = 24.8 Hz, 1C), 116.9 (d, 2JC−F = 14.3 Hz, 1C),
114.3 (2C), 55.5 (1C), 21.9 (1C); 19F NMR (CDCl3): δ −127.9 (d,
3JF−H = 19.0 Hz); IR (ZnSe, cm−1) 1608, 1371, 1251, 1176, 840, 736;
Hz, 1F), −147.5 (q, JF−B = 40.9 Hz, 3F); 11B NMR (acetone-d6): δ
1
−0.9 (qd, JB−F = 40.9 Hz, JB−F = 28.7 Hz); IR (ZnSe, cm−1) 1373,
945, 862, 750, 665; HRMS (ESI) m/z: [M − K]− calcd for
C9H8BF4O3S−, 283.0218; found, 283.0218.
1
2
HRMS (ESI) m/z: [M + H]+ calcd for C16H16FO4S+, 323.0748;
found, 323.0737.
General Procedure for Palladium-Catalyzed Arylation of 1b
with Aryl Bromides (Scheme 3). To a capped vial equipped with a
magnetic stir bar, were added PdCl2(amphos)2 (3.5 mg, 4.9 μmol,
0.05 equiv), potassium (Z)-1-fluoro-2-tosyloxyethenyl(trifluoro)-
borate (1b) (48.3 mg, 0.150 mmol, 1.5 equiv), aryl bromide (4,
0.100 mmol, 1 equiv), CsF (45.6 mg, 0.300 mmol, 3.0 equiv), and
ethylene glycol (1 mL) in a glovebox filled with argon gas, and the
mixture was stirred for 24 h at 80 °C with an aluminum heat block.
After cooling to room temperature, the reaction vial was taken out
from the glovebox. To the reaction mixture, was added saturated
aqueous ammonium chloride (ca. 1 mL), and the mixture was
extracted with EtOAc (ca. 1 mL × 3). The combined organic extract
was dried over Na2SO4. After filtration, the filtrate was concentrated
under reduced pressure. The residue was purified by silica-gel column
chromatography to give the corresponding (Z)-2-aryl-2-fluoroethenyl
4-methylbenzenesulfonate 5.
(Z)-2-Fluoro-2-(4-hydroxyphenyl)ethenyl 4-Methylbenzenesulfo-
nate (5e). Prepared with 4-bromophenol (4e, 17.3 mg, 0.100 mmol);
eluent for column chromatographic purification: n-hexane/EtOAc =
2:3; yield: 65.5% (20.2 mg, 65.5 μmol); yellow oil; TLC Rf = 0.14 (n-
1
hexane/EtOAc = 7:3); H NMR (CDCl3): δ 7.86−7.84 (m, 2H),
7.36−7.34 (m, 2H), 7.24−7.22 (m, 2H), 6.83−6.81 (m, 2H), 6.60 (d,
3JH−F = 19.0 Hz, 1H), 2.45 (s, 3H) (the signal corresponding to the
phenolic proton was not observed); 13C{1H} NMR (CDCl3): δ 157.5
(1C), 152.1 (d, 1JC−F = 254.6 Hz, 1C), 145.9 (1C), 132.1 (1C), 130.1
3
2
(2C), 128.3 (2C), 126.1 (d, JC−F = 21.5 Hz, 2C), 121.2 (d, JC−F
=
25.8 Hz, 1C), 116.7 (d, 2JC−F = 14.3 Hz, 1C), 115.9 (2C), 21.9 (1C);
19F NMR (CDCl3): δ −127.5 (d, 3JF−H = 19.0 Hz); IR (ZnSe, cm−1)
3315, 1361, 1192, 744, 659; HRMS (ESI) m/z: [M + H]+ calcd for
C15H14FO4S+, 309.0591; found, 309.0580.
1627
https://dx.doi.org/10.1021/acs.joc.0c02474
J. Org. Chem. 2021, 86, 1622−1632

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(Z)-2-(Benzo[d][1,3]dioxol-5-yl)-2-fluoroethenyl 4-Methylbenze-
nesulfonate (5f). Prepared with 4-bromo-1,2-methylenedioxybenzene
(4f, 12.0 μL, 0.100 mmol); eluent for column chromatographic
purification: n-hexane/EtOAc = 3:2; yield: 76.1% (25.6 mg, 76.1
μmol); colorless solid; mp: 83−84 °C; TLC Rf = 0.34 (n-hexane/
19F NMR (CDCl3): δ −129.7 (d, 3JF−H = 19.8 Hz); IR (ZnSe, cm−1)
1377, 1192, 1083, 866, 661; HRMS (ESI) m/z: [M + Na]+ calcd for
C15H12ClFO3SNa+, 349.0072; found, 349.0063.
(Z)-2-Fluoro-(4-fluorophenyl)ethenyl 4-Methylbenzenesulfonate
(5k). Prepared with 1-bromo-4-fluorobenzene (4k, 10.9 μL, 0.100
mmol); eluent for column chromatographic purification: n-hexane/
EtOAc = 9:1; yield: 71.5% (22.2 mg, 71.5 μmol); colorless solid; mp:
70−73 °C; TLC Rf = 0.42 (n-hexane/EtOAc = 4:1); 1H NMR
(CDCl3): δ 7.87−7.84 (m, 2H), 7.38−7.35 (m, 4H), 7.08−7.03 (m,
1
EtOAc = 7:3); H NMR (CDCl3): δ 7.86−7.83 (m, 2H), 7.37−7.35
3
(m, 2H), 6.91−6.88 (m, 1H), 6.80−6.77 (m, 2H), 6.61 (d, JH−F
=
19.4 Hz, 1H), 5.98 (s, 2H), 2.46 (s, 3H); 13C{1H} NMR (CDCl3): δ
151.7 (d, 1JC−F = 245.6 Hz, 1C), 149.3 (1C), 148.3 (1C), 145.8 (1C),
132.3 (1C), 130.1 (2C), 128.4 (2C), 122.8 (d, 2JC−F = 24.8 Hz, 1C),
3
2H), 6.71 (d, JH−(alkenyl)F = 19.0 Hz, 1H), 2.46 (s, 3H); 13C{1H}
3
2
NMR (CDCl3): δ 163.7 (d, 1JC−F = 250.8 Hz, 1C), 150.9 (d, 1JC−F
=
118.9 (d, JC−F = 5.7 Hz, 1C), 117.3 (d, JC−F = 14.3 Hz, 1C), 108.7
(1C), 104.7 (d, JC−F = 6.7 Hz, 1C), 101.8 (1C), 21.9 (1C); 19F
3
254.6 Hz, 1C), 145.9 (1C), 132.3 (1C), 130.2 (2C), 128.3 (2C),
NMR (CDCl3): δ −127.9 (d, JF−H = 19.4 Hz); IR (ZnSe, cm−1)
3
3
3
126.3 (dd, J(aryl)C−F = 8.6 Hz, J(alkenyl)C−F = 5.8 Hz, 2C), 125.2 (dd,
1705, 1344, 1172, 813, 744; HRMS (ESI) m/z: [M + H]+ calcd for
C16H14FO5S+, 337.0540; found, 337.0529.
2J(alkenyl)C−F = 24.8 Hz, J(aryl)C−F = 2.9 Hz, 1C), 118.0 (d, J(alkenyl)C−F
4
2
= 12.3 Hz, 1C), 116.2 (d, J(aryl)C−F = 22.0 Hz, 2C), 21.9 (1C); 19F
2
NMR (CDCl3): δ −109.8 (m, 1F), −128.3 (d, 3JF−(alkenyl)H = 19.0 Hz,
1F); IR (ZnSe, cm−1) 1371, 1190, 866, 734, 665; HRMS (ESI) m/z:
[M + Na]+ calcd for C15H12F2O3SNa+, 333.0367; found, 333.0359.
(Z)-2-Fluoro-2-(2-methylphenyl)ethenyl 4-Methylbenzenesulfo-
nate (5l). Prepared with 2-bromotoluene (4l, 24.0 μL, 0.199
mmol); eluent for column chromatographic purification: n-hexane/
EtOAc = 19:1; yield: 66.8% (40.7 mg, 0.132 mmol); yellow oil; TLC
(Z)-2-Fluoro-2-(4-morpholinylphenyl)ethenyl 4-Methylbenzene-
sulfonate (5g). Prepared with 4-(4-bromophenyl)morpholine (4g,
24.3 mg, 0.100 mmol); eluent for column chromatographic
purification: n-hexane/EtOAc = 4:1; yield: 64.1% (24.2 mg, 64.1
μmol); colorless solid; mp: 108−111 °C; TLC Rf = 0.75 (n-hexane/
1
EtOAc = 2:1); H NMR (CDCl3): δ 7.86−7.84 (m, 2H), 7.36−7.33
3
(m, 2H), 7.28−7.26 (m, 2H), 6.85−6.83 (m, 2H), 6.62 (d, JH−F
=
1
19.0 Hz, 1H), 3.86−3.83 (m, 4H), 3.20−3.18 (m, 4H), 2.45 (s, 3H);
Rf = 0.40 (n-hexane/EtOAc = 9:1); H NMR (CDCl3): δ 7.89−7.87
13C{1H} NMR (CDCl3): δ 152.3 (1C), 152.2 (d, JC−F = 254.6 Hz,
1
(m, 2H), 7.38−7.36 (m, 2H), 7.30 (dd, JH−H = 7.7, 7.7 Hz, 1H),
1C), 145.7 (1C), 132.4 (1C), 130.1 (2C), 128.4 (2C), 125.5 (d, 3JC−F
= 6.7 Hz, 2C), 119.6 (d, 2JC−F = 24.8 Hz, 1C), 116.5 (d, 2JC−F = 14.3
Hz, 1C), 115.0 (2C), 66.8 (2C), 48.5 (2C), 21.9 (1C); 19F NMR
7.21−7.16 (m, 3H), 6.36 (d, 3JH−F = 18.4 Hz, 1H), 2.46 (s, 3H), 2.20
(d, JH−F = 3.2 Hz, 3H) (the long range coupling (5JH−F) was
5
confirmed by the observation of the corresponding singlet signal in
(CDCl3): δ −120.6 (d, JF−H = 19.0 Hz); IR (ZnSe, cm−1) 1610,
3
1
the H{19F} NMR spectrum); 13C{1H} NMR (CDCl3): δ 152.9 (d,
1371, 1242, 817, 671; HRMS (ESI) m/z: [M + H]+ calcd for
C19H21FNO4S+, 378.1170; found, 378.1163.
1JC−F = 260.4 Hz, 1C), 145.8 (1C), 137.7 (1C), 131.0 (1C), 130.7
2
(1C), 130.1 (2C), 129.2 (d, JC−F = 4.8 Hz, 1C), 128.5 (2C), 128.2
(d, 2JC−F = 21.9 Hz, 1C), 126.0 (1C), 120.3 (d, 3JC−F = 16.1 Hz, 2C),
21.9 (1C), 20.1 (d, JC−F = 2.9 Hz, 1C); 19F NMR (CDCl3): δ −112.4
(Z)-2-Fluoro-2-(4-methoxycarbonylphenyl)ethenyl 4-Methylben-
zenesulfonate (5h). Prepared with methyl 4-bromobenzoate (4h,
21.5 mg, 0.100 mmol); eluent for column chromatographic
purification: n-hexane/EtOAc = 4:1; yield: 51.9% (18.2 mg, 51.9
μmol); colorless solid; mp: 120−123 °C; TLC Rf = 0.42 (n-hexane/
3
(d, JF−H = 18.4 Hz); IR (ZnSe, cm−1) 1375, 1179, 1082, 1009, 808,
738, 667; HRMS (ESI) m/z: [M + Na]+ calcd for C16H15FNaO3S+,
329.0618; found, 329.0614.
1
EtOAc = 7:3); H NMR (CDCl3): δ 8.03−8.01 (m, 2H), 7.88−7.85
(Z)-2-Fluoro-2-(2,4,6-trimethylphenyl)ethenyl 4-Methylbenzene-
sulfonate (5m). Prepared with 2-bromo-1,3,5-trimethylbenzene (4m,
45.9 μL, 0.300 mmol); eluent for column chromatographic
purification: n-hexane/EtOAc = 9:1; yield: 74.5% (74.7 mg, 0.223
mmol); yellow oil; TLC Rf = 0.34 (n-hexane/EtOAc = 9:1); 1H NMR
(CDCl3): δ 7.90−7.87 (m, 2H), 7.39−7.36 (m, 2H), 6.84 (s, 2H),
3
(m, 2H), 7.47−7.44 (m, 2H), 7.39−7.37 (m, 2H), 6.92 (d, JH−F
=
19.0 Hz, 1H), 3.93 (s, 3H), 2.46 (s, 3H); 13C{1H} NMR (CDCl3): δ
1
166.4 (1C), 150.2 (d, JC−F = 254.6 Hz, 1C), 146.1 (1C), 133.3 (d,
2JC−F = 23.8 Hz, 1C), 132.2 (1C), 131.3 (1C), 130.3 (2C), 130.2
3
2
(2C), 128.3 (2C), 123.8 (d, JC−F = 6.7 Hz, 2C), 119.9 (d, JC−F
=
13.4 Hz, 1C), 52.5 (1C), 22.0 (1C); 19F NMR (CDCl3): δ −127.9 (d,
3JF−H = 19.0 Hz); IR (ZnSe, cm−1) 1715, 1379, 1287, 1179, 1086,
7
6.12 (d, 3JH−F = 18.6 Hz, 1H), 2.46 (s, 3H), 2.26 (d, JH−F = 2.3 Hz,
5
3H), 2.11 (d, JH−F = 2.3 Hz, 6H) (the long range couplings (5JH−F
856, 756, 687; HRMS (ESI) m/z: [M + H]+ calcd for C17H16FO5S+,
351.0697; found, 351.0697.
7
and JH−F) were confirmed by the observation of the corresponding
singlet signals in the 1H{19F} NMR spectrum); 13C{1H} NMR
(CDCl3): δ 149.8 (d, 1JC−F = 263.2 Hz, 1C), 145.8 (1C), 140.7 (1C),
(Z)-2-Fluoro-2-(4-(trifluoromethyl)phenyl)ethenyl 4-Methylben-
zenesulfonate (5i). Prepared with 1-bromo-4-(trifluoromethyl)-
benzene (4i, 13.8 μL, 0.100 mmol); eluent for column chromato-
graphic purification: n-hexane/EtOAc = 4:1; yield: 42.2% (15.2 mg,
42.2 μmol); colorless solid; mp: 93−94 °C; TLC Rf = 0.42 (n-
2
138.9 (2C), 132.5 (1C), 130.1 (2C), 128.6 (2C), 128.2 (d, JC−F
=
2
3
5.8 Hz, 1C), 125.0 (d, JC−F = 21.0 Hz, 1C), 121.4 (d, JC−F = 16.1
Hz, 2C), 21.9 (1C), 21.3 (1C), 19.8 (2C); 19F NMR (CDCl3): δ
−106.4 (d, 3JF−H = 18.6 Hz); IR (ZnSe, cm−1) 1373, 1178, 1001, 849,
754; HRMS (ESI) m/z: [M + H]+ calcd for C18H20FO3S+, 335.1112;
found, 335.1103.
1
hexane/EtOAc = 4:1); H NMR (CDCl3): δ 7.88−7.85 (m, 2H),
7.63−7.61 (m, 2H), 7.51−7.49 (m, 2H), 7.39−7.37 (m, 2H), 6.90 (d,
3JH−F = 19.0 Hz, 1H), 2.46 (s, 3H); 13C{1H} NMR (CDCl3): δ 149.8
(Z)-2-Fluoro-2-(3-pyridyl)ethenyl 4-Methylbenzenesulfonate
(5n). Prepared with 3-bromopyridine (4n, 9.7 μL, 0.10 mmol);
eluent for column chromatographic purification: n-hexane/EtOAc =
3:2; yield: 51.5% (15.1 mg, 51.5 μmol); colorless solid; mp: 90−93
1
2
(d, JC−F = 254.6 Hz, 1C), 146.2 (1C), 132.6 (d, JC−F = 24.8 Hz,
3
1C), 132.2 (1C), 131.8 (q, JC−F = 32.5 Hz, 2C), 130.3 (2C), 128.3
(2C), 126.0−125.8 (m, 2C), 124.3 (d, 2JC−F = 6.7 Hz, 1C), 123.8 (q,
1
1JC−F = 272.8 Hz, 1C), 119.9 (d, 2JC−F = 13.3 Hz, 1C), 22.0 (1C); 19
F
°C; TLC Rf = 0.22 (n-hexane/EtOAc = 3:2); H NMR (CDCl3): δ
NMR (CDCl3): δ −62.9 (s, 3F), −129.0 (d, 3JF−H = 19.0 Hz, 1F); IR
(ZnSe, cm−1) 1375, 1109, 860, 742, 673; HRMS (ESI) m/z: [M +
H]+ calcd for C16H13F4O3S+, 361.0516; found, 361.0507.
8.64 (d, JH−H = 2.0 Hz, 1H), 8.61 (dd, JH−H = 5.1, 2.0 Hz, 1H), 7.89−
7.85 (m, 2H), 7.69 (ddd, JH−H = 8.3, 2.0, 2.0 Hz, 1H), 7.39−7.37 (m,
2H), 7.33−7.30 (m, 1H), 6.83 (d, 3JH−F = 19.0 Hz, 1H), 2.47 (s, 3H);
1
13C{1H} NMR (CDCl3): δ 150.9 (1C), 148.9 (d, JC−F = 255.6 Hz,
(Z)-2-(4-Chlorophenyl)-2-fluoroethenyl 4-Methylbenzenesulfo-
nate (5j). Prepared with 1-bromo-4-chlorobenzene (4j, 19.1 mg,
0.100 mmol); eluent for column chromatographic purification: n-
hexane/EtOAc = 9:1; yield: 41.3% (13.5 mg, 41.3 μmol); colorless
1C), 146.2 (1C), 145.4 (d, 3JC−F = 5.7 Hz, 1C), 132.1 (1C), 131.6 (d,
2
3JC−F = 5.7 Hz, 1C), 130.3 (2C), 128.3 (2C), 125.5 (d, JC−F = 23.8
2
Hz, 1C), 123.6 (1C), 119.3 (d, JC−F = 13.4 Hz, 1C), 22.0 (1C); 19F
1
3
NMR (CDCl3): δ −131.6 (d, JF−H = 19.0 Hz); IR (ZnSe, cm−1)
solid; mp: 97−100 °C; TLC Rf = 0.31 (n-hexane/EtOAc = 9:1); H
1691, 1384, 1180, 1012, 763; HRMS (ESI) m/z: [M + H]+ calcd for
C14H13FNO3S+, 294.0595; found, 294.0587.
NMR (CDCl3): δ 7.87−7.84 (m, 2H), 7.38−7.30 (m, 6H), 6.77 (d,
3JH−F = 19.8 Hz, 1H), 2.46 (s, 3H); 13C{1H} NMR (CDCl3): δ 150.6
(d, 1JC−F = 254.8 Hz, 1C), 146.0 (1C), 136.1 (1C), 132.2 (1C), 130.2
(2C), 129.2 (2C), 128.3 (2C), 127.5 (d, 2JC−F = 24.8 Hz, 1C), 125.4
(Z)-2-(Benzo[b]thiophen-3-yl)-2-fluoroethenyl 4-Methylbenzene-
sulfonate (5o). Prepared with 3-bromobenzo[b]thiophene (4o, 13.1
μL, 0.100 mmol); eluent for column chromatographic purification: n-
3
2
(d, JC−F = 5.8 Hz, 2C), 118.6 (d, JC−F = 13.3 Hz, 1C), 22.0 (1C);
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hexane/EtOAc = 4:1; yield: 83.5% (29.1 mg, 83.5 μmol); yellow oil;
TLC Rf = 0.68 (n-hexane/EtOAc = 2:1); 1H NMR (CDCl3): δ 7.91−
7.88 (m, 2H), 7.87−7.85 (m, 1H), 7.74−7.71 (m, 1H), 7.59 (s, 1H),
1JC−F = 257.5 Hz, 1C), 141.9 (1C), 140.4 (1C), 133.9 (d, 4JC−F = 2.8
2
3
Hz, 2C), 131.9 (d, JC−F = 27.7 Hz, 1C), 129.2 (d, JC−F = 8.6 Hz,
4
2C), 129.1 (2C), 128.8 (2C), 127.9 (1C), 127.5 (d, JC−F = 2.9 Hz,
3
2C), 127.4 (d, 3JC−F = 1.9 Hz, 1C), 127.2 (2C), 124.9 (d, 2JC−F = 7.6
7.45−7.37 (m, 4H), 6.75 (d, JH−F = 19.0 Hz, 1H), 2.47 (s, 3H);
1
13C{1H} NMR (CDCl3): δ 148.3 (d, JC−F = 254.6 Hz, 1C), 146.0
2
Hz, 1C), 106.1 (d, JC−F = 10.5 Hz, 1C); 19F NMR (CDCl3): δ
−114.2 (d, JF−H = 40.0 Hz); IR (ZnSe, cm−1) 3736, 1747, 833, 761,
684; HRMS (ESI) m/z: [M + H]+ calcd for C20H16F+, 275.1231;
found, 275.1224. The NMR spectra of the purified compound by
using HPLC are shown in the Supporting Information.
(1C), 140.4 (1C), 135.5 (1C), 132.2 (1C), 130.2 (2C), 128.5 (2C),
127.4 (d, 3JC−F = 6.8 Hz, 1C), 125.4 (1C), 125.3 (1C), 125.1 (d, 2JC−F
= 25.8 Hz, 1C), 123.2 (1C), 122.9 (d, 3JC−F = 1.9 Hz, 1C), 119.7 (d,
2JC−F = 13.3 Hz, 1C), 21.9 (1C); 19F NMR (CDCl3): δ −120.6 (d,
3JF−H = 19.0 Hz); IR (ZnSe, cm−1) 1373, 1179, 1080, 957, 828, 754,
(Z)-1-Fluoro-1,2-diphenylethene (7b). Prepared with phenyl-
boronic acid (6a, 18.3 mg, 0.150 mmol); eluent for column
chromatographic purification: n-hexane/EtOAc = 30:1; yield: 85.3%
(16.9 mg, 85.3 μmol); colorless solid; mp: 92−94 °C; TLC Rf = 0.55
+
689, 656; HRMS (ESI) m/z: [M + H]+ calcd for C17H14FO3S2 ,
349.0363; found, 349.0355.
(Z)-2-(1-Benzenesulfonylindol-5-yl)-2-fluoroethenyl 4-Methyl-
benzenesulfonate (5p). Prepared with 3-bromo-(1-phenylsulfonyl)-
1H-indole (4p, 33.6 mg, 0.100 mmol); eluent for column chromato-
graphic purification: n-hexane/EtOAc = 7:3; yield: 76.3% (36.0 mg,
76.3 μmol); colorless solid; mp: 135−138 °C; TLC Rf = 0.18 (n-
hexane/EtOAc = 4:1); 1H NMR (CDCl3): δ 8.00 (d, 4JH−H = 8.7 Hz,
1H), 7.92−7.86 (m, 4H), 7.74 (s, 1H), 7.61−7.56 (m, 1H), 7.50−
7.46 (m, 3H), 7.41−7.36 (m, 3H), 7.33−7.29 (m, 1H), 6.74 (d, 3JH−F
= 19.8 Hz, 1H), 2.46 (s, 3H); 13C{1H} NMR (CDCl3): δ 146.9 (d,
1JC−F = 247.0 Hz, 1C), 146.0 (1C), 137.9 (1C), 135.2 (1C), 134.6
1
(n-hexane/EtOAc = 9:1); H NMR (CDCl3): δ 7.68−7.60 (m, 4H),
3
7.41−7.33 (m, 5H), 7.27−7.23 (m, 1H), 6.30 (d, JH−F = 40.0 Hz,
1
1H); 13C{1H} NMR (CDCl3): δ 157.4 (d, JC−F = 258.4 Hz, 1C),
3
2
133.8 (d, JC−F = 2.9 Hz, 1C), 133.0 (d, JC−F = 27.7 Hz, 1C), 129.2
2
(2C), 129.1 (1C), 128.8 (2C + 2C), 127.5 (d, JC−F = 2.9 Hz, 1C),
3
124.5 (d, JC−F = 7.7 Hz, 2C), 106.0 (d, JC−F = 10.5 Hz, 1C); 19F
NMR (CDCl3): δ −114.1 (d, JF−H = 40.0 Hz). The chemical shifts
were consistent with those reported in the literature.24
(Z)-1-Fluoro-2-(4-methoxyphenyl)-1-phenylethene (7c). Prepared
with 4-methoxyphenylboronic acid (6c, 22.8 mg, 0.150 mmol); eluent
for column chromatographic purification: n-hexane/EtOAc = 9:1;
total weight of the product: 20.6 mg (containing N-methylcarbazole,
96.3:3.7 in molar ratio); net yield: 88.0%; colorless solid; mp: 98−100
(1C), 132.2 (1C), 130.2 (2C), 129.7 (2C), 128.4 (2C), 127.1 (2C),
3
3
126.1 (d, JC−F = 4.8 Hz, 1C), 125.9 (1C), 125.0 (d, JC−F = 5.7 Hz,
2
1C), 124.4 (1C), 120.6 (1C), 119.1 (d, JC−F = 13.4 Hz, 1C), 114.1
(1C), 112.1 (d, 2JC−F = 26.7 Hz, 1C), 22.0 (1C); 19F NMR (CDCl3):
δ −125.3 (d, JF−H = 19.8 Hz); IR (ZnSe, cm−1) 1369, 1178, 1014,
3
1
°C; TLC Rf = 0.43 (n-hexane/EtOAc = 9:1); H NMR (CDCl3): δ
+
844, 723; HRMS (ESI) m/z: [M + H]+ calcd for C23H19FNO5S2 ,
7.66−7.57 (m, 4H), 7.43−7.38 (m, 2H), 7.36−7.33 (m, 1H), 6.94−
473.0683; found, 472.0677.
3
6.91 (m, 2H), 6.27 (d, JH−F = 40.0 Hz, 1H), 3.84 (s, 3H); 13C{1H}
(Z)-2-(4-Acetylaminophenyl)-2-fluoroethenyl 4-Methylbenze-
nensulfonate (5q). Prepared with N-acetyl-4-bromoaniline (4q,
42.8 mg, 0.200 mmol); eluent for column chromatographic
purification: n-hexane/EtOAc = 1:1; yield: 63.0% (44.0 mg, 0.126
mmol); colorless solid; mp: 163 °C (decomp); TLC Rf = 0.33 (n-
hexane/EtOAc = 1:2); 1H NMR (acetone-d6): δ 9.31 (s, 1H), 7.89−
7.91 (m, 2H), 7.68 (d, JH−H = 8.6 Hz, 2H), 7.50 (d, JH−H = 8.2 Hz,
2H), 7.42−7.45 (m, 2H), 7.01 (d, JH−F = 19.9 Hz, 1H), 2.45 (s, 3H),
2.07 (s, 3H); 13C{1H} NMR (acetone-d6): δ 169.1 (1C), 152.4 (d,
1JC−F = 251.8 Hz, 1C), 146.9 (1C), 142.1 (1C), 133.1 (1C), 131.0
6
1
NMR (CDCl3): δ 159.0 (d, JC−F = 2.9 Hz, 1C), 156.1 (d, JC−F
=
2
3
255.6 Hz, 1C), 133.3 (d, JC−F = 27.7 Hz, 1C), 130.4 (d, JC−F = 7.7
Hz, 2C), 128.8 (1C), 128.7 (d, 4JC−F = 1.9 Hz, 2C), 126.6 (d, 3JC−F
=
4
2.9 Hz, 1C), 124.2 (d, JC−F = 7.6 Hz, 2C), 114.2 (1C), 105.5 (d,
2JC−F = 11.4 Hz, 1C), 55.5 (1C); 19F NMR (CDCl3): δ −117.0 (d,
JF−H = 40.0 Hz). The NMR spectra of the purified compound by
using HPLC are shown in the Supporting Information. The chemical
shifts were consistent with those reported in the literature.25
(Z)-2-(4-(Dimethylamino)phenyl)-1-fluoro-1-phenylethene (7d).
Prepared with 4-(dimethylamino)phenylboronic acid (6d, 24.8 mg,
0.150 mmol); eluent for column chromatographic purification: n-
hexane/EtOAc = 7:1; total weight of product: 10.2 mg (containing N-
methylcarbazole, 92.2:7.8 in molar ratio); net yield: 39.8%; colorless
solid; mp: 136−138 °C; TLC Rf = 0.46 (n-hexane/EtOAc = 9:1); 1H
NMR (CDCl3): δ 7.63−7.59 (m, 2H), 7.58−7.53 (m, 2H), 7.40−
7.36 (m, 2H), 7.32−7.27 (m, 1H), 6.78−6.68 (m, 2H), 6.24 (d, 3JH−F
= 40.8 Hz, 1H), 2.99 (s, 6H); 13C{1H} NMR (CDCl3): δ 155.1 (d,
3
2
(2C), 129.0 (2C), 125.6 (d, JC−F = 6.7 Hz, 2C), 123.9 (d, JC−F
=
23.8 Hz, 1C), 119.8 (2C), 118.7 (d, 2JC−F = 12.4 Hz, 1C), 24.3 (1C),
21.6 (s, 1C); 19F NMR (acetone-d6): δ −113.3 (d, JF−H = 19.9 Hz,
3
1F); IR (ZnSe, cm−1) 1695, 1593, 1520, 1366, 1319, 1177, 1084,
1001, 750, 683; HRMS (ESI) m/z: [M − H]− calcd for
C17H15FNO4S−, 348.0711; found, 348.0716.
General Procedure for Palladium-Catalyzed Arylation of 5b
with Arylboronic Acids 6 (Scheme 4). To a capped vial equipped
with a magnetic stir bar, were added CPhos Pd G4 (4.1 mg, 5.0 μmol,
0.05 equiv), (Z)-2-fluoro-2-phenylethenyl 4-methylbenzenesulfonate
(5b, 29.3 mg, 0.100 mmol, 1 equiv), arylboronic acid (6, 1.5 equiv),
CsF (30.4 mg, 0.200 mmol, 2.0 equiv), cyclopentyl methyl ether
(CPME) (1.0 mL), and MeOH (0.1 mL) in a glovebox filled with
argon gas, and the suspension was stirred for 3 h at 80 °C with an
aluminum heat block under the shading condition by wrapping with
aluminum foil. After stirring the mixture, the reaction vial was taken
from the glovebox. To the reaction mixture, was added saturated
aqueous ammonium chloride (ca. 1 mL), and the mixture was
extracted with EtOAc (ca. 1 mL × 3). The combined organic extract
was dried over Na2SO4. After filtration, the filtrate was concentrated
under reduced pressure. The residue was purified by silica-gel column
chromatography to give the corresponding (Z)-fluorostilbene 7.
(Z)-1-(Biphenyl-4-yl)-1-fluoro-2-phenylethene (7a, Table S11,
Entry 6). Prepared with 5c (36.8 mg, 0.100 mmol) and 6a in the
absence of MeOH; eluent for column chromatographic purification:
n-hexane/EtOAc = 19:1; total weight of product: 20.8 mg (containing
N-methylcarbazole, 94.3:5.7 in molar ratio); net yield: 72.9%;
colorless solid; mp: 188−190 °C; TLC Rf = 0.55 (n-hexane/EtOAc
2
1JC−F = 253.6 Hz, 1C), 149.7 (1C), 133.7 (d, JC−F = 27.7 Hz, 1C),
3
4
130.2 (d, JC−F = 8.6 Hz, 2C), 128.7 (d, JC−F = 1.9 Hz, 2C), 128.2
4
(1C), 123.8 (d, JC−F = 7.6 Hz, 2C), 122.1 (1C), 112.5 (2C), 106.1
(d, 2JC−F = 10.6 Hz, 1C), 40.6 (2C); 19F NMR (CDCl3): δ −119.1 (d,
3JF−H = 40.8 Hz); IR (ZnSe, cm−1) 1360, 1005, 856, 812, 761, 689;
HRMS (ESI) m/z: [M + H]+ calcd for C16H17FN+, 242.1340; found,
242.1331. The NMR spectra of the purified compound by using
HPLC are shown in the Supporting Information.
(Z)-N-(4-(2-Fluoro-2-phenyl)ethenyl)phenylacetamide (7e). Pre-
pared with 4-(acetamido)phenylboronic acid (6e, 26.8 mg, 0.150
mmol); eluent for column chromatographic purification: n-hexane/
EtOAc = 1:3; yield: 81.9% (20.9 mg, 81.9 μmol); colorless solid; mp:
1
183−185 °C; TLC Rf = 0.25 (n-hexane/EtOAc = 1:1); H NMR
(CDCl3): δ 7.65−7.59 (m, 4H), 7.52−7.51 (m, 2H), 7.42−7.30 (m,
3
4H), 6.28 (d, JH−F = 39.2 Hz, 1H), 2.19 (s, 3H); 13C{1H} NMR
1
(CDCl3): δ 168.4 (1C), 157.0 (d, JC−F = 257.4 Hz, 1C), 137.1 (d,
4JC−F = 1.9 Hz, 1C), 133.0 (d, 2JC−F = 27.7 Hz, 1C), 129.9 (d, 3JC−F
=
3
2.8 Hz, 1C), 129.8 (d, JC−F = 8.6 Hz, 2C), 129.1 (1C), 128.8 (2C),
124.3 (d, 4JC−F = 7.6 Hz, 2C), 119.9 (2C), 105.4 (d, 2JC−F = 10.6 Hz,
3
1C), 24.9 (1C); 19F NMR (CDCl3): δ −115.1 (d, JF−H = 39.2 Hz);
1
= 9:1); H NMR (CDCl3): δ 7.74−7.72 (m, 2H), 7.67−7.62 (m,
IR (ZnSe, cm−1) 1319, 1011, 860, 758, 687; HRMS (ESI) m/z: [M +
6H), 7.49−7.45 (m, 2H), 7.41−7.36 (m, 3H), 7.29−7.26 (m, 1H),
3
6.37 (d, JF−H = 40.0 Hz, 1H); 13C{1H} NMR (CDCl3): δ 157.2 (d,
Na]+ calcd for C16H14FNONa+, 278.0952; found, 278.0943.
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(Z)-2-(3-Amino-4-methylphenyl)-1-fluoro-1-phenylethene (7f).
Prepared with 3-amino-4-methylphenylboronic acid (6f, 22.6 mg,
0.150 mmol); eluent for column chromatographic purification: n-
hexane/EtOAc = 3:2; yield: 83.2% (18.9 mg, 83.2 μmol); colorless
solid; mp: 127−129 °C; TLC Rf = 0.33 (n-hexane/EtOAc = 2:1); 1H
NMR (CDCl3): δ 7.64−7.60 (m, 2H), 7.42−7.36 (m, 2H), 7.36−
7.30 (m, 1H), 7.06−7.04 (m, 2H), 6.95 (dd, JH−H = 7.7, 1.4 Hz, 1H),
Hz, 1H); 13C{1H} NMR (CDCl3): δ 158.5 (d, 1JC−F = 261.3 Hz, 1C),
154.3 (1C), 151.1 (d, 4JC−F = 2.8 Hz, 1C), 131.8 (d, 2JC−F = 26.7 Hz,
4
1C), 129.8 (1C), 129.4 (1C), 128.9 (d, JC−F = 1.9 Hz, 2C), 124.6
3
(1C), 124.4 (d, JC−F = 7.6 Hz, 2C), 123.1 (1C), 121.1 (1C), 111.1
3
(1C), 106.7 (d, 2JC−F = 12.3 Hz, 1C), 96.4 (d, JC−F = 12.4 Hz, 1C);
3
19F NMR (CDCl3): δ −107.0 (d, JF−H = 37.6 Hz). The chemical
shifts were consistent with those reported in the literature.26
3
6.22 (d, JH−F = 40.0 Hz, 1H), 3.62 (br, 2H), 2.18 (s, 3H); 13C{1H}
(Z)-2-(2-Fluoro-2-phenylethenyl)benzo[b]thiophene (7l). Pre-
pared with benzo[b]thiophen-2-ylboronic acid (6l, 26.7 mg, 0.150
mmol); eluent for column chromatographic purification: n-hexane/
EtOAc = 10:1; yield: 65.3% (16.6 mg, 65.3 μmol); colorless solid;
mp: 105−107 °C; TLC Rf = 0.55 (n-hexane/EtOAc = 4:1); 1H NMR
(CDCl3): δ 7.82 (dd, JH−H = 7.1, 1.2 Hz, 1H), 7.75 (dd, JH−H = 6.5,
NMR (CDCl3): δ 156.7 (d, 1JC−F = 257.5 Hz, 1C), 144.8 (1C), 133.3
5
(d, 2JC−F = 27.7 Hz, 1C), 132.5 (d, JC−F = 2.9 Hz, 1C), 130.7 (1C),
4
3
128.9 (1C), 128.7 (d, JC−F = 1.9 Hz, 2C), 124.3 (d, JC−F = 7.6 Hz,
5
4
2C), 122.2 (d, JC−F = 1.9 Hz, 1C), 120.0 (d, JC−F = 7.7 Hz, 1C),
4
2
115.3 (d, JC−F = 8.7 Hz, 1C), 106.2 (d, JC−F = 9.6 Hz, 1C), 17.4
(1C); 19F NMR (CDCl3): δ −114.9 (d, 3JF−H = 40.0 Hz); IR (ZnSe,
cm−1) 1014, 870, 800, 762, 687; HRMS (ESI) m/z: [M + H]+ calcd
for C15H15FN+, 228.1183; found, 228.1176.
3
2.1 Hz, 1H), 7.68−7.64 (m, 2H), 7.45−7.29 (m, 6H), 6.71 (d, JH−F
1
= 38.4 Hz, 1H); 13C{1H} NMR (CDCl3): δ 157.4 (d, JC−F = 259.0
Hz, 1C), 140.6 (d, 3JC−F = 8.6 Hz, 1C), 139.5 (1C), 136.6 (d, 5JC−F
=
2
(Z)-1-Fluoro-2-(4-fluorophenyl)-1-phenylethene (7g). Prepared
with 4-fluorophenylboronic acid (6g, 21.0 mg, 0.150 mmol); eluent
for column chromatographic purification: n-hexane/EtOAc = 19:1;
yield: 83.7% (18.1 mg, 83.7 μmol); colorless solid; mp: 108−110 °C;
TLC Rf = 0.50 (n-hexane/EtOAc = 9:1); 1H NMR (CDCl3): δ 7.64−
4.8 Hz, 1C), 131.9 (d, JC−F = 26.7 Hz, 1C), 129.6 (1C), 128.9 (d,
3
4JC−F = 2.0 Hz, 2C), 124.7 (1C), 124.6 (1C), 124.4 (d, JC−F = 7.6
4
Hz, 2C), 123.9 (d, JC−F = 4.8 Hz, 1C), 123.5 (1C), 122.2 (1C),
2
101.0 (d, JC−F = 22.3 Hz, 1C); 19F NMR (CDCl3): δ −110.2 (d,
3JF−H = 39.9 Hz); IR (ZnSe, cm−1) 1219, 1005, 831, 740, 687; HRMS
(ESI) m/z: [M + H]+ calcd for C16H12FS+, 255.0638; found,
255.0637.
7.59 (m, 4H), 7.43−7.34 (m, 3H), 7.09−7.02 (m, 2H), 6.27 (d, 3JH−F
1
= 39.2 Hz, 1H); 13C{1H} NMR (CDCl3): δ 162.0 (dd, JC−(aryl)F
=
6
1
247.5 Hz, JC−(alkenyl)F = 3.3 Hz, 1C), 157.1 (dd, JC−(alkenyl)F = 257.4
Hz, JC−(aryl)F = 1.9 Hz, 1C), 132.9 (d, JC−(alkenyl)F = 28.7 Hz, 1C),
130.8 (d, JC−(aryl)F = 32.4 Hz, 1C), 130.7 (d, JC−(aryl)F = 28.2 Hz,
1C), 130.0 (dd, JC−(alkenyl)F = 3.3 Hz, JC−(aryl)F = 3.3 Hz, 1C), 129.2
(Z)-3-(2-Fluoro-2-phenylethenyl)thiophene (7m). Prepared with
3-thiopheneboronic acid (6m, 19.2 mg, 0.150 mmol); eluent for
column chromatographic purification: n-hexane/EtOAc = 19:1; total
weight of product: 16.5 mg (containing N-methylcarbazole, 96.2:3.8
in molar ratio); net yield: 78.1%; colorless solid; mp: 84−87 °C; TLC
6
2
2
2
3
4
4
3
(1C), 128.8 (d, JC−3(alkenyl)F = 1.9 Hz, 2C), 124.4 (d, JC−(aryl)F = 7.6
2
1
Hz, 2C), 115.7 (d, JC−(alkenyl)F = 22.0 Hz, 2C), 104.9 (d, JC−(alkenyl)F
Rf = 0.52 (n-hexane/EtOAc = 9:1); H NMR (CDCl3): δ 7.63−7.60
= 10.5 Hz, 1C); 19F NMR (CDCl3): δ −113.7 (s, 1F), −115.3 (d,
3JF−H = 39.2 Hz, 1F); IR (ZnSe, cm−1) 1227, 1011, 813, 760, 687;
(m, 2H), 7.50 (dd, JH−H = 3.0, 1.4 Hz, 1H), 7.42−7.32 (m, 5H), 6.42
(d, 3JH−F = 39.2 Hz, 1H); 13C{1H} NMR (CDCl3): δ 156.6 (d, 1JC−F
= 255.6 Hz, 1C), 134.5 (d, 5JC−F = 1.9 Hz, 1C), 132.7 (d, 2JC−F = 27.7
+
HRMS (ESI) m/z: [M + H]+ calcd for C14H11F2 , 217.0823; found,
Hz, 1C), 129.0 (1C), 128.8 (d, 4JC−F = 1.9 Hz, 2C), 128.5 (d, 4JC−F
=
217.0813.
3
(Z)-1-Fluoro-1-phenyl-2-(4-(trifluoromethyl)phenyl)ethene (7h).
Prepared with 4-triflurophenylboronic acid (6h, 28.5 mg, 0.150
mmol); eluent for column chromatographic purification: n-hexane/
EtOAc = 19:1; yield: 96.5% (25.7 mg, 96.5 μmol); colorless solid;
mp: 110−111 °C; TLC Rf = 0.48 (n-hexane/EtOAc = 9:1); 1H NMR
(CDCl3): δ 7.74−7.71 (m, 2H), 7.68−7.65 (m, 2H), 7.62−7.60 (m,
2H), 7.46−7.38 (m, 3H), 6.34 (d, JH−F = 38.8 Hz, 1H); 13C{1H}
NMR (CDCl3): δ 158.9 (d, 1JC−(alkenyl)F = 261.3 Hz, 1C), 137.4 (1C),
5.7 Hz, 1C), 125.6 (1C), 124.2 (d, JC−F = 6.7 Hz, 2C), 124.1 (d,
2
3JC−F = 8.7 Hz, 1C), 100.7 (d, JC−F = 12.4 Hz, 1C); 19F NMR
3
(CDCl3): δ −113.9 (d, JF−H = 39.2 Hz); IR (ZnSe, cm−1) 1157,
1010, 819, 759, 687; HRMS (ESI) m/z: [M + H]+ calcd for
C12H10FS+, 205.0482; found, 205.0480. The remaining N-methyl-
carbazole is indicated in NMR spectra shown in the Supporting
Information.
(Z)-1-Fluoro-2-(4-hydroxyphenyl)-1-phenylethene (7n). Prepared
with 4-acetoxyphenylboronic acid (6n, 27.0 mg, 0.150 mmol); eluent
for column chromatographic purification: n-hexane/EtOAc = 5:2;
yield: 69.5% (14.9 mg, 69.5 μmol); colorless solid; mp: 174−176 °C;
2
132.4 (d, JC−(alkenyl)F = 27.7 Hz, 1C), 129.8 (1C), 129.1 (d,
3JC−(alkenyl)F = 8.6 Hz, 2C), 129.0 (q, 2JC−(alkyl)F = 31.8 Hz, 1C), 128.9
4
3
(d, JC−(alkenyl)F = 1.9 Hz, 2C), 125.6 (q, JC−(alkyl)F = 3.8 Hz, 2C),
4
1
1
124.7 (d, JC−(alkenyl)F = 7.6 Hz, 2C), 124.3 (q, JC−(alkyl)F = 271.8 Hz,
TLC Rf = 0.43 (n-hexane/EtOAc = 2:1); H NMR (methanol-d4): δ
1C), 104.8 (d, JC−(alkenyl)F = 10.5 Hz, 1C); 19F NMR (CDCl3): δ
2
7.65−7.62 (m, 2H), 7.52−7.49 (m, 2H), 7.42−7.37 (m, 2H), 7.35−
−62.4 (s, 3F), −110.9 (d, JF−H = 38.8 Hz, 1F); IR (ZnSe, cm−1)
3
3
7.30 (m, 1H), 6.81−6.77 (m, 2H), 6.39 (d, JH−F = 41.2 Hz, 1H);
1323, 1109, 866, 766, 689; HRMS (ESI) m/z: [M]+ calcd for
13C{1H} NMR (methanol-d4): δ 158.1 (d, 6JC−F = 2.9 Hz, 1C), 156.7
+
1
2
C15H10F4 , 266.0713; found, 266.0710.
(d, JC−F = 256.0 Hz, 1C), 134.5 (d, JC−F = 27.7 Hz, 1C), 131.5 (d,
3JC−F = 7.7 Hz, 2C), 129.6 (d, 4JC−F = 1.9 Hz, 2C), 129.5 (1C), 126.6
(Z)-1-Fluoro-1-phenyl-2-(2,4,6-trimethylphenyl)ethene (7j). Pre-
pared with 2,4,6-trimethylphenylboronic acid (6j, 24.6 mg, 0.150
mmol); eluent for column chromatographic purification: n-hexane/
EtOAc = 49:1; yield: 55.8% (13.4 mg, 55.8 μmol); colorless solid;
4
3
(d, JC−F = 1.9 Hz, 2C), 124.7 (d, JC−F = 7.6 Hz, 1C), 116.4 (2C),
106.7 (d, JC−F = 10.4 Hz, 1C); 19F NMR (methanol-d4): δ −120.4
2
3
(d, JF−H = 41.2 Hz); IR (ZnSe, cm−1) 1510, 1010, 813, 758, 687;
1
HRMS (ESI) m/z: [M − H]− calcd for C14H10FO−, 213.0710; found,
mp: 97−99 °C; TLC Rf = 0.60 (n-hexane/EtOAc = 9:1); H NMR
(CDCl3): δ 7.68−7.65 (m, 2H), 7.44−7.36 (m, 3H), 6.92 (s, 2H),
213.0714.
3
6.34 (d, JH−F = 39.6 Hz, 1H), 2.30 (s, 3H), 2.28 (s, 6H); 13C{1H}
NMR (CDCl3): δ 156.2 (d, 1JC−F = 252.7 Hz, 1C), 137.1 (2C), 132.7
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02474.
3
(d, 2JC−F = 28.6 Hz, 1C), 129.2 (1C), 128.8 (d, JC−F = 6.7 Hz, 2C),
■
4
3
sı
128.7 (d, JC−F = 1.9 Hz, 2C), 128.3 (2C+1C), 124.7 (d, JC−F = 6.7
2
Hz, 1C), 103.8 (d, JC−F = 17.2 Hz, 1C), 21.2 (1C), 20.70 (1C),
20.68 (1C); 19F NMR (CDCl3): δ −112.2 (d, JF−H = 39.6 Hz); IR
3
(ZnSe, cm−1) 1277, 1008, 835, 760, 687; HRMS (ESI) m/z: [M +
Na]+ calcd for C17H17FNa+, 263.1207; found, 263.1199.
Experimental procedures for the optimization studies
and copies of NMR spectra of new compounds (PDF)
(Z)-2-(2-Fluoro-2-phenylethenyl)benzo[b]furan (7k). Prepared
with benzo[b]furan-2-ylboronic acid (6k, 29.2 mg, 0.150 mmol);
eluent for column chromatographic purification: n-hexane/EtOAc =
19:1; yield: 89.0% (21.2 mg, 89.0 μmol); colorless solid; mp: 161−
163 °C; TLC Rf = 0.52 (n-hexane/EtOAc = 9:1); 1H NMR (CDCl3):
δ 7.68−7.64 (m, 2H), 7.58 (ddd, JH−H = 8.3, 1.0, 1.0 Hz, 1H), 7.48−
7.37 (m, 4H), 7.30−7.21 (m, 2H), 7.07 (s, 1H), 6.51 (d, 3JH−F = 37.6
AUTHOR INFORMATION
Corresponding Authors
■
Takamitsu Hosoya − Laboratory for Chemical Biology,
RIKEN Center for Biosystems Dynamics Research (BDR),
1630
https://dx.doi.org/10.1021/acs.joc.0c02474
J. Org. Chem. 2021, 86, 1622−1632

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(3) For representative synthetic applications, see: (a) Nicolaou, K.
C.; Chakraborty, T. K.; Piscopio, A. D.; Minowa, N.; Bertinato, P.
Total synthesis of rapamycin. J. Am. Chem. Soc. 1993, 115, 4419−
4420. (b) Woerly, E. M.; Cherney, A. H.; Davis, E. K.; Burke, M. D.
Stereoretentive Suzuki−Miyaura Coupling of Haloallenes Enables
Fully Stereocontrolled Access to (−)-Peridinin. J. Am. Chem. Soc.
Kobe 650-0047, Japan; Chemical Biology Team, Division of
Bio-Function Imaging, RIKEN Center for Life Science
Technologies (CLST), Kobe 650-0047, Japan; Laboratory of
Chemical Bioscience, Institute of Biomaterials and
Bioengineering, Tokyo Medical and Dental University
(TMDU), Tokyo 101-0062, Japan; orcid.org/0000-
0002-7270-351X; Email: takamitsu.hosoya@riken.jp
Takashi Niwa − Laboratory for Chemical Biology, RIKEN
Center for Biosystems Dynamics Research (BDR), Kobe 650-
0047, Japan; Chemical Biology Team, Division of Bio-
Function Imaging, RIKEN Center for Life Science
̈
2010, 132, 6941−6943. (c) Wang, L. L.; Candito, D.; Drager, G.;
Herrmann, J.; Muller, R.; Kirschning, A. Harnessing ap-Quinone
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Methide Intermediate in the Biomimetic Total Synthesis of the
Highly Active Antibiotic 20-Deoxy-Elansolid B1. Chem.Eur. J.
2017, 23, 5291−5298. (d) Wang, L.-L.; Kirschning, A. Total synthesis
of elansolids B1 and B2. Beilstein J. Org. Chem. 2017, 13, 1280−1287.
(e) Haley, H. M. S.; Hill, A. G.; Greenwood, A. I.; Woerly, E. M.;
Rienstra, C. M.; Burke, M. D. Peridinin Is an Exceptionally Potent and
Membrane-Embedded Inhibitor of Bilayer Lipid Peroxidation. J. Am.
Chem. Soc. 2018, 140, 15227−15240.
Technologies (CLST), Kobe 650-0047, Japan; orcid.org/
0000-0002-6209-5362; Email: takashi.niwa@riken.jp
Authors
(4) For representative synthetic applications, see ref 3d and:
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tetraen-11-yn-4-one 1-Acetate. J. Org. Chem. 2004, 69, 695−700.
(5) For reviews, see: (a) Gillis, E. P.; Burke, M. D. Iterative Cross-
Coupling with MIDA Boronates: towards a General Strategy for
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Horst, B.; Feringa, B. L.; Minnaard, A. J. Iterative strategies for the
synthesis of deoxypropionates. Chem. Commun. 2010, 46, 2535−2547.
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molecules. Nat. Rev. Chem. 2018, 2, 0115.
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Motoyuki Isoda − Laboratory for Chemical Biology, RIKEN
Center for Biosystems Dynamics Research (BDR), Kobe 650-
0047, Japan; Chemical Biology Team, Division of Bio-
Function Imaging, RIKEN Center for Life Science
Technologies (CLST), Kobe 650-0047, Japan
Yuta Uetake − Chemical Biology Team, Division of Bio-
Function Imaging, RIKEN Center for Life Science
Technologies (CLST), Kobe 650-0047, Japan; orcid.org/
0000-0002-4742-8085
Tadashi Takimoto − Laboratory for Chemical Biology,
RIKEN Center for Biosystems Dynamics Research (BDR),
Kobe 650-0047, Japan
Junpei Tsuda − Laboratory for Chemical Biology, RIKEN
Center for Biosystems Dynamics Research (BDR), Kobe 650-
0047, Japan; Chemical Biology Team, Division of Bio-
Function Imaging, RIKEN Center for Life Science
Technologies (CLST), Kobe 650-0047, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02474
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Hiroyuki Koshino (RIKEN) for measuring 19F-
decoupled 1H NMR of 5l and 5m. This research was
supported by the Japan Agency for Medical Research and
Development (AMED) under grant no. JP20am0101098
(Platform Project for Supporting Drug Discovery and Life
Science Research, BINDS), JSPS KAKENHI grant nos.
JP19K16332 (Early-Career Scientists, M.I.) and JP20K05521
(C, T.N.), the Sasakawa Scientific Research Grant from The
Japan Science Society (Y.U.), the Research Grant from Hyogo
Science and Technology Association (T.N.), and the Pioneer-
ing Project “Chemical Probe” from RIKEN.
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