Copper-catalyzed regioselective synthesis of (E)-β-fluorovinyl sulfones

Article abstract of DOI:10.3390/molecules24081569

Organofluorine compounds are finding increasing application in a variety of fields such as pharmaceutical, agrochemical, and material sciences. However, given the scarcity of fluorine-containing natural products, advancement in this area depends almost entirely on the development of new synthetic methodologies. In this article, we present the synthesis of a series of previously undescribed (E)-β-fluorovinyl sulfones via a simple copper-catalyzed addition of hydrogen fluoride to alkynyl sulfone starting materials in varying yields and E/Z selectivities. The hydrogenation of these products was also explored and compared with the hydrogenation of the related Z isomers. These new products may find interesting applications, given the versatility of vinyl sulfones in chemical synthesis and the unique properties of vinyl fluorides in biological settings.

Full text of DOI:10.3390/molecules24081569

molecules
Article
Copper-Catalyzed Regioselective Synthesis of
(E)-β-Fluorovinyl Sulfones
Raquel Román 1, Pablo Barrio 2, Natalia Mateu 3, Daniel M. Sedgwick 1,* and Santos Fustero 1,3,
*
1
Departamento de Química Orgánica, Universitat de València, 46100 Burjassot, Spain;
raquel.roman@uv.es
2
Departamento de Química Orgánica e Inorgánica, Avda. Julián Clavería nº 8, 33006 Oviedo, Spain;
barriopablo@uniovi.es
3
Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain;
natalia.mateu@uv.es
*
Correspondence: dased@uv.es (D.M.S.); santos.fustero@uv.es (S.F.);
Tel.: +34-96-354-4940 (D.M.S.); +34-96-354-4279 (S.F.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 4 April 2019; Accepted: 19 April 2019; Published: 20 April 2019
Abstract: Organofluorine compounds are finding increasing application in a variety of fields
such as pharmaceutical, agrochemical, and material sciences. However, given the scarcity of
fluorine-containing natural products, advancement in this area depends almost entirely on the
development of new synthetic methodologies. In this article, we present the synthesis of a series of
previously undescribed (E)-β-fluorovinyl sulfones via a simple copper-catalyzed addition of hydrogen
fluoride to alkynyl sulfone starting materials in varying yields and E/Z selectivities. The hydrogenation
of these products was also explored and compared with the hydrogenation of the related Z isomers.
These new products may find interesting applications, given the versatility of vinyl sulfones in
chemical synthesis and the unique properties of vinyl fluorides in biological settings.
Keywords: β-fluorovinyl sulfone; regioselectivity; organofluorine chemistry; copper catalysis; alkynyl
sulfones; hydrogenation
1. Introduction
Vinyl sulfones and related compounds are versatile intermediates that lend themselves to a wide
variety of processes such as cycloadditions, hydrogenations, and Michael additions [1–3]. Fluorovinyl
sulfones and derivatives, therefore, possess strong potential as fluorinated building blocks towards
more complex fluorinated organic molecules.
Research into such areas represents a key goal in the synthetic community given the scarcity of
fluorine-containing molecules in nature, and the prevalence of this capricious element in pharmaceutical,
agrochemical and material sciences [4].
Although the synthesis of
the corresponding isomers is much less so, and very few examples exist for the synthesis of such
compounds. The first of these was reported just last year when Hammond and co-workers described a
gold-catalyzed addition of HF pyridine to alkynyl sulfone starting materials towards (Z)- -fluorovinyl
α-fluorovinyl sulfones is well-documented [5–13], the synthesis of
β
·
β
sulfones (Scheme 1a) [14]. Almost simultaneously, Berkowitz and co-workers described the use of
phenyl 2,2-difluorovinyl sulfone as an electrophile in the synthesis of amino acid derivatives containing
a (Z)-
downstream chemistry using these products. We then described a metal-free and practical synthesis
of (Z)- -fluorovinyl sulfones via the addition of TBAF to alkynyl sulfones, and their subsequent
chemoselective hydrogenation to saturated β-fluoroalkyl sulfones (Scheme 1c) [16].
β-fluorovinyl sulfone moiety (Scheme 1b) [15]. This report also contained the first example of
β
Molecules 2019, 24, 1569; doi:10.3390/molecules24081569
www.mdpi.com/journal/molecules

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Following our interest in this field, herein we report the synthesis of the related (E)-
β-fluorovinyl
sulfones which, to the best of our knowledge, remain undescribed in the chemical literature (Scheme 1).
Scheme 1. Comparison of past examples dealing with the synthesis of (Z)-
in this work, the synthesis of related E isomers.
β-fluorovinyl sulfones and
2. Results and Discussion
We first began this study looking at the metal-catalyzed addition of a variety of fluoride sources
to the alkynyl sulfone starting materials used in our previous publication dealing with the synthesis
of the Z isomers [16]. We were surprised to observe small amounts of the elusive E isomers in
our crude reaction mixtures, although in most cases with standard gold and silver-based catalysts,
the major product was the expected Z isomer (Table 1). We then decided to explore the use of
copper-based (Ph3P)3CuF 2MeOH, after Zhu and co-workers described a switch in regioselectivity
·
in the hydrofluorination of ynamides when using this catalyst [17]. To our delight, the E isomer was
formed to a higher degree when using this catalyst, which we prepared via the method described by
Chaudhuri and co-workers [18]. During a short optimization of the reaction conditions, we found that
heating the reagents to 70 ◦C in toluene gave the best results in terms of conversion and selectivity
(Entry 7, Table 1). It is worth noting that the conversion was important in this procedure since the
starting alkynyl sulfones and the resulting (E)-β-fluorovinyl sulfones were somewhat difficult to
separate via simple column chromatography. The E and Z isomers, however, could be separated
without any difficulties. A stoichiometric amount of the copper complex could also be used to
effectively carry out the reaction (Entry 8, Table 1). Oddly, we found that the commercially available
catalyst (Ph3P)3CuF free of any coordinated methanol was catalytically inactive under the same reaction
conditions (Entry 9, Table 1), even though the same copper complex could be used stoichiometrically,
albeit with lower stereoselectivity (Entry 10, Table 1). These results suggested that the methanol plays
an important role in the stereoselectivity and the regeneration of the catalytically active copper species.
The coordinated methanol has also been observed to exert important effects in other reactions catalyzed
by this copper complex [19], as well as in other metal-mediated transformations of alkynes [20].

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Table 1. Optimization of the syn-hydrofluorination procedure towards (E)-β-fluorovinyl sulfones 1.
◦
Entry
[cat.]
[F]
Solvent
T C
Conv.% 2
E:Z 3
1
2
3
Ph3PAuMe
JohnPhosAuCl
AgNTf2
HF
·
DMPU
DMPU
DCE
DCE
DMF
THF
THF
70
55
70
70
70
70
70
70
70
70
70
44
58
55
73
79
<1:20
1:9
1:5
1:1
2:1
HF
3HF
·
·
Et3N
4 4
5 4
6 4
7 4
8 4,5
9 6
10 5,6
11 8
(Ph3P)3CuF·2MeOH
(Ph3P)3CuF·2MeOH
(Ph3P)3CuF·2MeOH
(Ph3P)3CuF·2MeOH
(Ph3P)3CuF·2MeOH
(Ph3P)3CuF
HF DMPU
·
3HF
3HF
3HF
·
·
·
Et3N
Et3N Dioxane
Et3N Toluene
90
3:1
4:1
>95
>95
<10
>95
>95
-
Toluene
Et3N Toluene
Toluene
Et3N Toluene
3:1
7
3HF
·
-
(Ph3P)3CuF
(Ph3P)3CuF
-
1:1
3:1
3HF
·
1
Typical reaction conditions:
1
(0.1 mmol), [cat.] (0.01 mmol), [F] (0.3 mmol), solvent (2 mL). 2 Determined by
1H-NMR of the crude reaction mixture. Determined by 19F-NMR of the crude reaction mixture. Catalyst
synthesized as described by Chaudhuri and co-workers [
used. Commercial catalyst was used as supplied. Ratio not determined. A mixture of toluene:methanol (20:1)
was used as the solvent.
3
4
5
8
]. 100 mol% of the corresponding copper species was
6
7
8
In terms of the reaction mechanism, we propose the E selectivity is principally governed by an
interaction between the copper metal center and the oxygen atoms in the sulfone group (Scheme 2). In
this first step, the active copper complex
a four-membered chelate ring in intermediate II. From there, the fluorine is delivered in the
leaving vinyl cuprate intermediate III. From there, one of the two pathways could be acting. Pathway
A involves the direct protodemetallation and regeneration of active species through the addition of
HF. Pathway B involves the formation of copper species IV via methanol-mediated protodemetallation
and subsequent regeneration of through the reaction with hydrogen fluoride. We suspect the second
pathway is more likely, given that the only slightly acidic 3HF Et3N is used as the hydrogen fluoride
I
coordinates to the triple bond and the sulfone oxygen, forming
β
position,
I
I
·
source; methanol, therefore, could be preferred for the protodemetallation step. Secondly, this would
explain the role of the coordinated methanol in the catalyst, given that the commercially available
complex—which contains no methanol—was catalytically inactive, yet successful when a stoichiometric
amount was used.
Scheme 2. Proposed reaction mechanism.

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This mechanistic hypothesis was found to be plausible after carrying out the reaction with the
catalytically inactive commercial species in a solvent mixture of toluene:methanol (20:1) (Entry 11,
Table 1). To our delight, we found that the reaction proceeded to completion, proving that the
methanol was indeed necessary for the catalytic reaction to take place and suggesting that the
reaction was occurring via pathway B. Furthermore, using deuterated methanol in the same
experiment, we saw an incorporation of roughly 50% deuterium into the vinylic position of the
product (see supporting information).
We then proceeded to explore the scope of this reaction (Scheme 3). Substrates bearing
electron-neutral and electron-rich aromatic rings were found to be suitable substrates and gave
rise to the desired (E)-β-fluorovinyl sulfones in moderate to good yields (products 2a–j, Scheme 3).
However, substituents in the ortho position prevented the reaction from taking place, most likely
due to the steric factors given that substrate 1g bears an electronically favorable methoxy group,
and even so the reaction failed to take place. Conversely, alkynyl sulfones bearing aromatic rings
containing electron-withdrawing substituents proved less suitable in this procedure, resulting in lower
E selectivity—or even slight Z selectivity—and therefore lower yields (products 2k–m, Scheme 3).
Thiophenyl derivative 1n was also a successful substrate and afforded the desired 2n in good selectivity
and yield. Furthermore, we found that aromatic groups at the triple bond were required for the reaction
to proceed successfully; substrate 1o featuring a cyclohexyl-substituted alkynyl sulfone was found to
be unsuitable for this reaction and resulted in a complex mixture of products.
1
2
Scheme 3. Reaction scope of our syn-hydrofluorination procedure. Isolated yield. Determined by
19F-NMR of the crude mixture.
We observed a clear trend between the electronic properties of the substrate and the E:Z selectivity;
substrates featuring more electron-rich aromatic rings favored the formation of the desired E isomers,
whereas the opposite was true for substrates featuring more electron-poor aromatic rings (Figure 1).

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Figure 1. Correlation between the electronic properties of the alkynyl sulfone starting material and the
E:Z selectivity of copper-catalyzed fluoride addition.
We then explored the use of the resulting (E)-fluorovinyl sulfones in hydrogenation reactions,
given our previous experience in this field [16]. Unfortunately, we found that the Z isomers were
far more suitable for use in our hydrogenation procedure towards the same saturated fluoroalkyl
sulfone products. The E isomers described herein were found to be much less reactive and required
far longer reaction times to achieve similar rates of conversion, as well as resulting in higher rates of
hydrodefluorination (Table 2). This is somewhat different from what one would expect from this type
of reaction. Generally speaking, the reaction rate of catalytic heterogeneous hydrogenation correlates
directly to the stability of the olefin in question—which in turn usually means the less sterically
hindered isomer should react faster [21]. In our case, this would suggest that the (E)-β-fluorovinyl
sulfones should react faster, which is not what we observed experimentally. Therefore, we could
expect the differences to be due to electronic rather than steric factors. These results also reinforced our
previous observation that the loss of fluorine during the hydrogenation of fluorovinyl sulfones takes
place via the saturated fluoroalkyl sulfone product [16].
Table 2. A comparison of the hydrogenation of both (E)- and (Z)-fluorovinyl sulfones.
Entry
Substrate
Time, h
Conv.% 1
3:4 1
(Z)-2a 2
(E)-2a
(E)-2a
(E)-2a
1
2
3
4
2
2
4
>98
-
10
95
12:1
-
1:1
2:3
20
1
2
Determined by 1H-NMR of the crude reaction mixture. Synthesized as described in our previous report [16].

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3. Materials and Methods
3.1. General Information
All reactions were carried out under a nitrogen atmosphere unless otherwise indicated. Solvents
were purified prior to use: THF and toluene were distilled from sodium and DCM from calcium
hydride. Reagents were used as received from the suppliers without further purification unless stated
otherwise. The reactions were monitored by TLC on 0.25mm precoated silica-gel plates, which were
revealed with UV light and aqueous ceric ammonium molybdate or potassium permanganate stains.
Flash column chromatography was performed with the indicated solvents on silica gel 60 (particle size:
1
0.040
−
0.063 mm). H-, 13C- and 19F-NMR spectra were recorded by a 300 MHz spectrometer. Chemical
shifts are given in ppm (δ), referenced to the residual proton resonances of the solvents. Coupling
constants (J) are given in Hertz (Hz). The letters s, d, t, q and m stand for singlet, doublet, triplet,
quartet and multiplet respectively. The letters br indicate that the signal is broad. A QTOF mass
analysis system was used for the HRMS measurements.
See Supplementary Materials for the spectra of all new compounds as well as the synthetic
procedures used to prepare the alkynyl sulfone starting materials.
3.2. General Method for the Synthesis of (E)-Fluorovinyl Sulfones
A screw-top eppendorf tube was charged with alkynyl sulfone (1 equiv) and (Ph3P)3CuF
(10 mol%), and purged with nitrogen. Toluene (0.05 M) was then added, followed by 3HF
(3 equiv), and the resulting mixture was heated at 70 ◦C for 20 h in an oil bath. When the reaction was
complete, the crude mixture was concentrated and purified by the flash column chromatography using
mixtures of hexane and ethyl acetate as the eluent (assuming the reaction was complete; if not, mixtures
of hexane and DCM were used to separate the product from the alkynyl sulfone starting material).
·
2MeOH
·Et3N
3.3. Characterization of (E)-Fluorovinyl Sulfones 2a–2n
(E)-1-((2-Fluoro-2-phenylvinyl)sulfonyl)-4-methylbenzene ((E)-2a). Flash chromatography of the crude
reaction product [n-hexane:EtOAc (4:1)] afforded (E)-2a as a colorless oil (35%, 65 mg). 1H-NMR
(CDCl3, 300 MHz):
δ 2.33 (s, 3H), 6.38 (d, J = 18.4 Hz, 1H), 7.16–7.19 (m, 2H), 7.36–7.38 (m, 2H), 7.38–7.43
(m, 1H), 7.54–7.59 (m, 4H) ppm. 13C-NMR (CDCl3, 75.5 MHz): 21.6, 114.5 (d, J = 31.8 Hz), 127.4, 128.1
(d, J = 16.3 Hz), 128.3, 129.5 (d, J = 5.0 Hz), 129.6, 129.7 (d, J = 2.2 Hz), 132.0, 138.5 (d, J = 2.9 Hz), 138.6,
144.5, 167.7 (d, J = 276.4 Hz) ppm. 19F-NMR (CDCl3, 282.4 MHz):
δ -71.74 (d, J = 18.4 Hz, 1F) ppm.
HRMS (EI) calcd. for C15H14FO2S [M + H+]: 277.0693, found: 277.0698.
(E)-2-(1-Fluoro-2-tosylvinyl)naphthalene ((E)-2b). Flash chromatography of the crude reaction product
[n-hexane:EtOAc (5:1)] afforded (E)-2b as a pale yellow solid (38%, 16 mg) with a melting point of
◦
1
42–43 C. H-NMR (CDCl3, 300 MHz):
δ
2.29 (s, 3H), 6.47 (d, J = 18.4 Hz, 1H), 7.10–7.13 (d, 2H),
21.6, 114.7 (d, J =
7.49–7.57 (m, 5H), 7.77–7.86 (m, 3H), 8.15 (s, 1H) ppm. 13C-NMR (CDCl3, 75.5 MHz):
δ
32.0 Hz), 124.9 (d, J = 3.8 Hz), 125.6 (d, J = 25.7 Hz), 126.9, 127.3, 127.4, 127.8 (d, J = 8.2 Hz), 128.3, 129.1,
129.7, 131.2 (d, J = 6.5 Hz), 132.0, 134.7, 138.5, 144.5, 167.7 (d, J = 276.6 Hz) ppm. 19F-NMR (CDCl3, 282.4
+
MHz): δ −71.93 (d, J = 18.4 Hz, 1F) ppm. HRMS (EI) calcd. for C19H19FNO2S [M + NH4
]: 344.1115,
found: 344.1120.
(E)-1-((2-Fluoro-2-(4-tolyl)vinyl)sulfonyl)-4-methylbenzene ((E)-2c). Flash chromatography of the crude
reaction product [n-hexane:EtOAc (4:1)] afforded (E)-2c as a colorless oil (43%, 18 mg). 1H-NMR
(CDCl3, 300 MHz):
δ
2.44 (s, 6H), 6.40 (d, J = 18.5 Hz, 1H), 7.25–7.30 (m, 4H), 7.58–7.60 (d, 2H), 7.67–7.69
21.6, 21.7, 113.7 (d, J = 32.6 Hz), 125.6 (d, J = 26.0 Hz),
(d, 2H) ppm. 13C-NMR (CDCl3, 75.5 MHz):
δ
127.3, 128.8, 129.6 (d, J = 5.6 Hz), 129.7, 138.7 (d, J = 2.7 Hz), 142.7, 144.4, 167.8 (d, J = 275.7 Hz) ppm.
19F-NMR (CDCl3, 282.4 MHz): δ −72.04 (d, J = 18.6 Hz, 1F) ppm. HRMS (EI) calcd. for C16H19FNO2S
[M + NH4+]: 308.1115, found: 308.1116.

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(E)-1-(tert-Butyl)-4-(1-fluoro-2-(phenylsulfonyl)vinyl)benzene ((E)-2d). Flash chromatography of the crude
reaction product [n-hexane:EtOAc (4:1)] afforded (E)-2d as a colorless oil (45%, 19 mg). 1H-NMR
(CDCl3, 300 MHz):
δ
1.36 (s, 9H), 6.45 (d, J = 18.4 Hz, 1H), 7.43–7.48 (m, 5H), 7.55–7.62 (m, 2H),
31.1, 35.1, 113.7 (d, J = 32.9 Hz), 125.1, 125.2,
7.76–7.79 (m, 2H) ppm. 13C-NMR (CDCl3, 75.5 MHz):
δ
127.4, 128.6 (d, J = 11.8 Hz), 129.0, 129.4 (d, J = 5.2 Hz), 133.3 (d, J = 10.3 Hz), 141.5, 155.8, 168.2
(d, J = 276.3 Hz) ppm. 19F-NMR (CDCl3, 282.4 MHz): δ −71.61 (d, J = 18.4 Hz, 1F) ppm. HRMS (EI)
calcd. for C18H23FNO2S [M + NH4+]: 336.1428, found: 336.1425.
(E)-1-((2-Fluoro-2-(4-methoxyphenyl)vinyl)sulfonyl)-4-methylbenzene ((E)-2e). Flash chromatography of the
1
crude reaction product [n-hexane:EtOAc (3:1)] afforded (E)-2e as a colorless oil (51%, 30 mg). H-NMR
(CDCl3, 300 MHz):
δ
2.33 (s, 3H), 3.79 (s, 3H), 6.26 (d, J = 18.8 Hz, 1H), 6.86 (dd, J = 9.1, 0.9 Hz, 2H),
21.6, 55.5,
7.17–7.20 (m, 2H), 7.65 (s, 2H), 7.58–7.61 (m, 4H) ppm. 13C-NMR (CDCl3, 75.5 MHz):
δ
112.7 (d, J = 33.5 Hz), 113.5, 120.6 (d, J = 26.7 Hz), 127.3, 128.5, 128.7, 129.7, 131.6 (d, J = 5.8 Hz), 133.8
(d, J = 19.4 Hz), 138.8 (d, J = 3.0 Hz), 144.4, 162.6 (d, J = 1.5 Hz), 167.4 (d, J = 274.4 Hz) ppm. 19F-NMR
(CDCl3, 282.4 MHz): δ −72.67 (d, J = 18.8 Hz, 1F) ppm. HRMS (EI) calcd. for C16H15FO3S [M + H+]:
307.0799, found: 307.0803.
(E)-1-(1-Fluoro-2-(phenylsulfonyl)vinyl)-4-methoxybenzene ((E)-2f). Flash chromatography of the crude
reaction product [n-hexane:EtOAc (3:1)] afforded (E)-2f as a colorless oil (56%, 40 mg). 1H-NMR
(CDCl3, 300 MHz):
δ 3.86 (s, 3H), 6.35 (d, J = 18.6 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 7.38–7.50 (m, 2H),
7.51–7.61 (m, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.78 (dd, J = 5.3, 3.3 Hz, 2H) ppm. 13C-NMR (CDCl3,
75.5 MHz):
δ 55.5, 112.4 (d, J = 33.6 Hz), 113.6, 120.5 (d, J = 26.6 Hz), 127.2, 129.1, 131.5 (d, J = 5.6 Hz),
133.4, 141.7 (d, J = 2.5 Hz), 162.7, 167.8 (d, J = 275.1 Hz) ppm. 19F-NMR (CDCl3, 282.4 MHz): δ −71.77
(d, J = 18.6 Hz, 1F) ppm. HRMS (EI) calcd. for C15H17FNO3S [M + NH4+]: 310.0908, found: 310.0911.
(E)-4-(1-Fluoro-2-(phenylsulfonyl)vinyl)-1,2-dimethoxybenzene ((E)-2h). Flash chromatography of the
crude reaction product [n-hexane:EtOAc (2:1)] afforded (E)-2h as a white solid (60%, 24 mg) with a
melting point of 51–53 ◦C. 1H-NMR (CDCl3, 300 MHz):
δ
3.91 (s, 3H), 3.95 (s, 3H), 6.39 (d, J = 18.8 Hz
1H), 6.92 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.34 (ddd, J = 8.4, 2.0, 0.6 Hz, 1H), 7.45–7.50
(m, 2H), 7.56–7.58 (m, 1H), 7.78–7.81 (m, 2H) ppm. 13C-NMR (CDCl3, 75.5 MHz):
56.0, 110.3, 112.2
,
δ
(d, J = 5.4 Hz), 112.7 (d, J = 33.7 Hz), 120.5 (d, J = 26.8 Hz), 123.7 (d, J = 6.5 Hz), 127.2, 129.1, 133.4,
141.6 (d, J = 2.5 Hz), 148.4, 152.4, 167.5 (d, J = 275.0 Hz) ppm. 19F-NMR (CDCl3, 282.4 MHz): δ −72.68
(d, J = 18.9 Hz, 1F) ppm. HRMS (EI) calcd. for C16H19FNO4S [M + NH4+]: 340.1013, found: 340.1019.
(E)-6-(1-Fluoro-2-(phenylsulfonyl)vinyl)-2,3-dihydrobenzo[b][1,4]dioxine ((E)-2i). Flash chromatography
of the crude reaction product [n-hexane:EtOAc (2:1)] afforded (E)-2i as a colorless oil (53%, 19 mg).
1H-NMR (CDCl3, 300 MHz):
δ
4.22 (dqd, J = 7.0, 3.3, 1.5 Hz, 4H), 6.28 (d, J = 18.6 Hz, 1H), 6.82
(dd, J = 8.4, 0.8 Hz, 1H), 7.12–7.14 (m, 2H), 7.40–7.43 (m, 2H), 7.49–7.51 (m, 1H), 7.72–7.75 (m, 2H) ppm.
13C-NMR (CDCl3, 75.5 MHz):
64.1, 64.6, 112.8 (d, J = 33.5 Hz), 117.1, 118.8 (d, J = 5.5 Hz), 121.2
δ
(d, J = 26.6 Hz), 123.6 (d, J = 5.9 Hz), 127.4, 129.1, 133.4, 141.6, 143.0, 147.1, 167.3 (d, J = 275.8 Hz) ppm.
19F-NMR (CDCl3, 282.4 MHz): δ −71.81 (d, J = 18.6 Hz, 1F) ppm. HRMS (EI) calcd. for C16H17FNO4S
[M + NH4+]: 338.0857, found: 338.0866.
(E)-5-(1-Fluoro-2-(phenylsulfonyl)vinyl)-1,2,3-trimethoxybenzene ((E)-2j). Flash chromatography of the
1
crude reaction product [n-hexane:EtOAc (2:1)] afforded (E)-2j as a colorless oil (58%, 23 mg). H-NMR
(CDCl3, 300 MHz):
δ
3.88 (s, 6H), 3.93 (s, 3H), 6.46 (d, J = 18.6 Hz, 1H), 6.96 (s, 2H), 7.45–7.50
56.3, 61.0, 107.1
(m, 2H), 7.56–7.59 (m, 1H), 7.76–7.80 (m, 2H) ppm. 13C-NMR (CDCl3, 75.5 MHz):
δ
(d, J = 5.6 Hz), 113.9 (d, J = 32.9 Hz), 123.0 (d, J = 26.8 Hz), 127.2, 128.6 (d, J = 8.2 Hz), 129.0, 133.4,
133.8 (d, J = 13.9 Hz), 141.4, 152.7, 167.4 (d, J = 276.5 Hz) ppm. 19F-NMR (CDCl3, 282.4 MHz): δ −73.03
(d, J = 18.6 Hz, 1F) ppm. HRMS (EI) calcd. for C17H21FNO5S [M + NH4+]: 370.1119, found: 370.1123.

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(E)-1-Bromo-4-(1-fluoro-2-tosylvinyl)benzene ((E)-2m). Flash chromatography of the crude reaction
product [n-hexane:EtOAc (5:1)] afforded (E)-2m as a colorless oil (27%, 13mg). 1H-NMR (CDCl3,
300 MHz):
(CDCl3, 75.5 MHz):
δ
2.42 (s, 3H), 6.45 (d, J = 18.5 Hz, 1H), 7.26–7.30 (m, 2H), 7.52–7.66 (m, 6H) ppm. 13C-NMR
δ
21.6, 114.9 (d, J = 31.3 Hz), 127.0, 127.1, 127.4, 129.8, 131.0 (d, J = 4.9 Hz), 131.4,
138.3, 144.8, 166.27 (d, J = 275.7 Hz) ppm. 19F-NMR (CDCl3, 282.4 MHz): δ −73.51 (d, J = 18.5 Hz, 1F)
ppm. HRMS (EI) calcd. for C15H16BrFNO2S [M + NH4+]: 372.0064, found: 372.0068.
(E)-3-(1-Fluoro-2-tosylvinyl)thiophene ((E)-2n). Flash chromatography of the crude reaction product
1
[n-hexane:EtOAc (4:1)] afforded (E)-2n as a colorless oil (63%, 23 mg). H-NMR (CDCl3, 300 MHz):
δ
2.34 (s, 3H), 6.28 (d, J = 20.4 Hz, 1H), 7.22–7.25 (m, 3H), 7.43–7.45 (m, 1H), 7.63–7.65 (m, 2H), 8.12
(ddd, J = 3.0, 1.3, 0.7 Hz, 1H) ppm. 13C-NMR (CDCl3, 75.5 MHz):
δ
21.6, 112.7 (d, J = 33.1 Hz), 125.9,
127.2, 127.5 (d, J = 5.0 Hz), 129.8, 132.3 (d, J = 8.3 Hz), 138.7 (d, J = 2.8 Hz), 144.6, 162.4 (d, J = 269.0 Hz)
ppm. 19F-NMR (CDCl3, 282.4 MHz): δ −77.29 (dd, J = 20.5, 1.3 Hz, 1F) ppm. HRMS (EI) calcd. for
C15H13FO2S [M + H+]: 283.0257, found: 283.0257.
4. Conclusions
In conclusion, we have developed a copper-catalyzed procedure to synthesize the previously
undescribed (E)-β-fluorovinyl sulfones starting from the parent alkynyl sulfones. The hydrogenation
of these products was also explored, and unfortunately, the E isomers were much less suitable to
this transformation than the Z isomers. Further studies into the reactivity of this interesting class of
compounds are ongoing in our research group.
Supplementary Materials: Supplementary Materials are available online.
Author Contributions: S.F. and P.B. conceived the experiments; D.M.S., R.R. and N.M. carried out the experimental
work and analysis of results. D.M.S. wrote and edited the manuscript.
Funding: The authors are grateful for the financial support from the Spanish Ministerio de Economía y Competitividad
(CTQ-2013-43310-P and CTQ2017-84249-P) and the Generalitat Valenciana (GV/PrometeoII/2014/073). D.M.S. wishes to
thank the Spanish Ministerio de Educación, Cultura y Deporte for his predoctoral fellowship (FPU15/01485).
Acknowledgments: The authors are also grateful to Alberto Llobat, Cristina Morales and Daniel Dávila for
assistance in the synthesis of certain starting materials.
Conflicts of Interest: The authors declare no conflict of interest.
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