A metal-free and regioselective approach to (Z)-β-fluorovinyl sulfones and their chemoselective hydrogenation to β-fluoroalkyl sulfones

Article abstract of DOI:10.1016/j.jfluchem.2017.12.016

A highly regioselective, metal-free hydrofluorination reaction of alkynyl sulfones was developed using TBAF—one of the cheapest and most commonly available fluoride sources. In addition, the reactivity of the resulting β-fluorovinyl sulfones was studied, focusing on their selective hydrogenation reaction. Both β-fluorovinyl sulfones and their hydrogenation products β-fluoroalkyl sulfones may find applications in medicinal and agrochemical sciences.

Full text of DOI:10.1016/j.jfluchem.2017.12.016

JournalofFluorineChemistry206(2018)108–116
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
A metal-free and regioselective approach to (Z)-β-fluorovinyl sulfones and
their chemoselective hydrogenation to β-fluoroalkyl sulfones
⁎
Daniel M. Sedgwicka,b, Raquel Romána,b, Pablo Barrioa,⁎, Cristina Moralesa, Santos Fusteroa,b,
a
Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain
b
Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
A R T I C L E I N F O
A B S T R A C T
Keywords:
A highly regioselective, metal-free hydrofluorination reaction of alkynyl sulfones was developed using
Regioselectivity
Alkynyl sulfones
β-Fluorovinyl sulfones
Hydrogenation
Chemoselectivity
β-Fluoroalkyl sulfones
TBAF—one of the cheapest and most commonly available fluoride sources. In addition, the reactivity of the
resulting β-fluorovinyl sulfones was studied, focusing on their selective hydrogenation reaction. Both β-fluor-
ovinyl sulfones and their hydrogenation products β-fluoroalkyl sulfones may find applications in medicinal and
agrochemical sciences.
1. Introduction
scarce. Although there are several methods to synthesize the related α-
fluorovinyl sulfones [12,13], to the best of our knowledge only two
Fluorine is increasingly relevant in a variety of fields, such as
agrochemistry, materials science and medicinal chemistry. The fluorine
atom has become a routine addition in the search for new molecular
entities in drug development, due to the unique characteristics of the
CeF bond [1–3]. Being the most electronegative element, the carbon-
fluoride bond is among the most polarized in organic chemistry, al-
lowing chemists to modify certain features of bioactive molecules, in-
cluding metabolic stability, acidity/basicity, and lipophilicity. In cer-
tain cases, the effect of the fluorine atom on a functional group can be
significant. For example, due to their altered electronic arrangement,
vinyl fluorides might be used as bioisosteres for the peptide bond [4–6].
Vinyl fluorides, therefore, are increasingly important in organic and
medicinal chemistry due to new applications and their increasing ease
of preparation thanks to advances in synthetic fluorine chemistry [7].
Sulfones are similarly versatile synthetic building blocks [8–10].
Their strongly electron-withdrawing nature increases the acidity of the
adjacent hydrogen atoms and allows the α carbon to be used as a nu-
cleophile in CeC bond forming processes such as the Julia olefination
and the Ramberg-Bäcklund reaction. This same electron-withdrawing
character places vinyl sulfones among the most electron-deficient CeC
double bonds, making them viable electrophiles in Michael additions
and cycloaddition processes. For these reasons, fluorinated vinyl sul-
fones are expected to be not only useful in chemical synthesis, but also
have potential applications in medicinal and agrochemical sciences
[11]. However, methods to produce fluorinated vinylsulfones are
such reports deal with the synthesis of the β-fluoro analogs (Scheme 1a)
[14,15]. A recent report by Hammond and co-workers outlines a
strategy to produce the desired products, although their method re-
quires the use of an expensive gold catalyst [15]. Other reports on si-
milar substrates have presented problems with regioselectivity [16].
The selective hydrogenation of vinyl fluorides to alkyl fluorides
remains an underrepresented field; only a handful of studies have been
reported [17–22]. This could be due to the intrinsic difficulties asso-
ciated with the transformation: (1) only recently have new advances in
fluorine chemistry allowed the facile synthesis of the vinyl fluoride
precursors; and (2) the CeX bond has a tendency to undergo hydro-
dehalogenation, thus resulting in a mixture of the desired product and
the dehalogenated derivative. For this reason, vinyl halides are gen-
erally seen as poor substrates for hydrogenation reactions. However, of
the vinyl halides, fluorides are perhaps the most commonly used given
the relative strength of the C—F bond when compared to its chloride,
bromide and iodide counterparts. Nevertheless, no examples of hy-
drogenation of fluorovinyl sulfones have been previously reported.
Furthermore, in the vast majority of known examples of this transfor-
mation, the fluorine atom is adjacent to a carbonyl group, or a per-
fluorinated substrate is used. There are very few studies that include
substrates presenting the fluorine atom in the β-position [23], with the
exception of specific gem-difluorinated acrylic acids [24] and α,β-di-
fluoro-α,β-unsaturated carbonyl compounds [18] (Scheme 1b).
Herein we disclose
a metal-free and regioselective synthetic
⁎
Corresponding authors at: Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain.
E-mail addresses: pablo.barrio@uv.es (P. Barrio), santos.fustero@uv.es (S. Fustero).
https://doi.org/10.1016/j.jfluchem.2017.12.016
Received 27 November 2017; Received in revised form 20 December 2017; Accepted 21 December 2017
Availableonline23December2017
0022-1139/©2017ElsevierB.V.Allrightsreserved.

D.M. Sedgwick et al.
JournalofFluorineChemistry206(2018)108–116
Scheme 1. a) Previous examples of the synthesis of
β-fluorovinyl sulfones. b) Previous examples of hy-
drogenation of α- fluoro- α, β-unsaturated carbonyl
compounds with a heterogeneous palladium catalyst.
c) This work: metal-free synthesis of β-fluorovinyl
sulfones under mild conditions and their hydro-
genation to the corresponding β-fluoroalkyl sulfones.
procedure to afford (Z)-β-fluorovinyl sulfones using cheap and non-
toxic starting materials, and the first studies into the chemoselective
heterogeneous hydrogenation of these valuable building blocks
(Scheme 1c).
anhydrous THF, molecular sieves, lower temperatures and other less
hygroscopic fluoride sources (TBAT, TMAF, ZnF2, KHF2, NaF, TBAF@
SiO2) all failed to improve the yield of 2a. Therefore, we decided to run
several control experiments to understand how the reaction might
proceed (Scheme 3).
Alkynyl sulfone 1a and fluorovinyl sulfone 2a are both stable in a
mixture of THF/water, and 2a does not react further even in the pre-
sence of TBAF. However, the addition of 1 equivalent of LiOH to 2a
resulted in a 1:1:1 mixture of alkynyl sulfone 1a, unreacted 2a, and β-
keto sulfone 3a, suggesting that the slightly basic reaction conditions
were responsible for the formation of the undesired ketone.
Furthermore, given the stability of the fluorovinyl sulfone upon treat-
ment with TBAF in aqueous THF, we deduced that the hydroxide anion
may be formed upon protonation of intermediate 4 (Scheme 4).
In light of these results, we ran the reaction with the addition of one
equivalent NH4Cl to protonate intermediate 4 and hinder the in situ
formation of hydroxide, thereby reducing the formation of the ketone
side product. To our delight, the reaction proceeded with full conver-
sion and high selectivity, and the desired (Z)-fluorovinyl sulfones 2
were isolated in much higher yields (Table 1). The addition of more
equivalents of ammonium chloride—or the addition of a saturated
aqueous solution to the solvent mixture (THF:NH4Cl(aq) 10:1)—resulted
in much lower conversions, even after 24 h. Similarly, other acids such
as p-toluenesulfonic acid inhibited the reaction and no product was
detected.
We then investigated the scope of the reaction. Several aromatic
groups were well tolerated on the alkynyl sulfone starting materials,
including electron neutral substituents on the aromatic ring such as
alkyl and aryl groupings leading to 2a–e (Table 1) in good yields and
chemoselectivities. p-Methoxy and 3,5-dimethoxy substituents were
also compatible, affording to 2f–h in similarly good yields and che-
moselectivities (Table 1). Bromine-bearing products 2i,j—noteworthy
for their potential applicability to further transformations, such as
palladium-catalyzed cross-couplings—were also obtained in good
yields, albeit somewhat lower selectivities (Table 1). Unfortunately, the
use of alkynyl sulfones with electron-withdrawing substituents on the
aromatic ring, such as the trifluoromethyl- and 3,5-difluoro-substituted
2. Results and discussion
We first turned our attention to studying the regioselectivity of the
hydrofluorination of alkynyl sulfones 1, which were prepared according
to literature procedures [25]. Regarding the hydrofluorination of re-
lated substrates, Tatro and co-workers reported the selective fluorina-
tion of ethyl propiolate, achieving both the α and β regioisomers, albeit
in a low 38% yield for the β derivative [16]; Jiang and co-workers
reported the successful addition of fluoride solely to the β-position of
similar electron-deficient alkynes, although with slight E/Z selectivity
issues [26]; and Zhu and co-workers found that the addition of fluoride
to ynamides could be α- or β-selective depending on the metal catalyst
used [27]. We first attempted metal-catalyzed hydrofluorination using
HF as the fluoride source, and we were able to achieve the desired β-
fluorovinyl sulfones, albeit in moderate to low yields. Thus, we decided
to look for a simpler method and take advantage of the inherent elec-
trophilic character of the alkynyl sulfone.
In this sense, we observed that the treatment of alkynyl sulfone 1a
with TBAF at room temperature in THF gave the corresponding (Z)-β-
fluorovinyl sulfone 2a in moderate yield (43%) and complete se-
lectivity. The origin of this overwhelming preference for the Z geometry
may lie in the formation of a negative charge on the α carbon upon
nucleophilic addition. This negatively charged intermediate should
adopt the most stable conformation with the lone pair in anti to the
fluorine atom, in order to minimize electrostatic repulsion with the
fluorine’s lone pairs (see intermediate 4, Scheme 4). However, under
these conditions, we also observed the formation of a side product
identified as β-keto sulfone 3a [28] (40%) (2a:3a close to 1:1), which
we reasoned was due to residual water in the TBAF acting as a com-
peting nucleophile (Scheme 2) [29].
We attempted to minimize the formation of β-keto sulfone 3a by
avoiding water exposure. However, the use of freshly distilled
Scheme 2. Preliminary results towards the hydrofluorination of al-
kynyl sulfones.
109

D.M. Sedgwick et al.
JournalofFluorineChemistry206(2018)108–116
Scheme 3. Control experiments.
1k,1l, resulted in a drop in chemical yield and chemoselectivity (28%,
72:28 for 2k and 30%, 67:33 for 2l) (Table 1). In addition, the het-
eroaromatic thiophene-derived alkynyl sulfone 1m also worked well,
giving 2m in a good yield and selectivity (Table 1). Unfortunately, we
found that aliphatic derivatives such as 1n,o failed to give the desired
fluorovinyl sulfones 2n,o, both with and without the ammonium
chloride additive (Table 1), instead giving rise to the related allenyl
sulfones [30].
chemoselectivity was toluene (Table 2, entries 7–9). Given the slower
reaction rate in toluene, a careful reaction-time optimization could be
carried out to maximize conversion and chemoselectivity. Increasing
the reaction time to 1.5 h resulted in a significant improvement in
conversion with no noticeable effect on the degree of defluorination
(Table 2, entry 8). An extra 0.5 h reaction time increase resulted in full
conversion at the expense of a chemoselectivity (Table 2, entry 9).
Longer reaction times resulted in
a greater degree of hydrode-
With the desired β-fluorovinyl sulfones in hand, we then decided to
explore their reactivity. Reaction with a diverse range of nucleophiles,
including diethyl malonate, primary and secondary amines, ni-
tromethane, and boronic acids all resulted in the loss of fluorine via an
addition-elimination mechanism [14]. We then turned our attention to
the heterogeneous hydrogenation of the vinyl fluoride moiety, an am-
bitious transformation given the limited literature surrounding the
hydrogenation of fluorinated olefins [17–22]. The process would pro-
vide β-fluoroalkyl sulfones 5, which are similarly scarce in the litera-
ture. In this context, Liu and co-workers have recently developed a
racemic and regioselective Pd-catalyzed intermolecular fluor-
osulfonylation of styrenes under mild conditions [31]. Lectka and co-
workers have also applied their benzylic fluorination methodologies to
the synthesis of 5a [32,33].
After testing a variety of known heterogeneous hydrogenation sys-
tems—such as PtO2, Pd(OH)2, Pd/C, and NH4HCO2/Pd/C—using the
model substrate 2a we found palladium on activated charcoal to be the
most suitable. The transformation is highly sensitive to both solvent
effects and reaction time (Table 2). Methanol is widely used in hydro-
genation reactions, and has been used successfully in several past ex-
amples with vinyl fluorides [18,24]; however, we found that methanol
promoted the competing hydrodefluorination reaction and resulted in a
higher degree of the corresponding defluorinated alkyl sulfones 6
(Table 2, entry 5). Ultimately, we found that the best solvent in terms of
fluorinated product (Table 2, entry 10). The conditions shown in entry
9 resulted in the best-isolated yield and were used in the subsequent
study into the scope of the reaction.
There are three speculated mechanisms for the competing hydro-
defluorination reaction: (1) the hydrogenation of the CeC double bond
to give the desired 5, followed by the elimination of HF and the hy-
drogenation of the resulting defluorinated vinyl sulfone; (2) a concerted
mechanism as proposed by Hudlicky via a carbene intermediate [17];
and (3) direct cleavage of the CeF bond in 5 promoted by the palladium
catalyst. The intermediate defluorinated vinyl sulfone 7 was not ob-
served at any point (Scheme 5). Furthermore, in contrast to Andersson
[21] and Hudlicky’s [17] work with α-fluorovinyl carbonyls, we ob-
served that the resulting saturated β-fluoroalkyl sulfone 5 reacted fur-
ther in the reaction conditions to give 6. These observations lead us to
believe that the direct cleavage of the C(sp3)eF bond was responsible
for the hydrodefluorination of 5. Alternative reducing agents, such as
NaBH4 and Et3SiH, were also explored unsuccessfully.
For several substrates the reaction time had to be modified to
achieve the best yields of the desired products, but eventually we were
able to achieve high yields and acceptable selectivities for a range of
substrates (Table 3). Fluorovinyl sulfones with electron-neutral aro-
matic substituents such as 2a–e, along with electron-rich p-methoxy
bearing substrates 2f and 2g, all gave rise to the corresponding β-
fluoroalkyl sulfones 5a-g in good yields and chemoselectivities
Scheme 4. Proposed mechanism of reaction and formation of side
products.
110

D.M. Sedgwick et al.
JournalofFluorineChemistry206(2018)108–116
Table 1
Scope of the hydrofluorination reaction of alkynyl sulfones.
Table 2
Optimization for the selective heterogeneous hydrogenation of (Z)-β-fluorovinyl sulfones.
Entrya
Solvent
Time/h
Conversion (%)
5a:6a
1
2
3
4
5
6
7
8
9
MTBE
Et2O
EtOAc
Dioxane
MeOH
Acetone
Toluene
Toluene
Toluene
Toluene
1
1
1
1
1
1
1
1.5
2
> 98
> 98
> 98
> 98
> 98
> 98
30
80
> 98
> 98
86:14
75:25
50:50
87:13
75:25
25:75
> 98:2
> 98:2
92:8
10
18
66:34
a
Standard reaction conditions: 2a (0.05 mmol), Pd/C (10–15 mol%), solvent (1.5 mL), H2 (1 atm).
(Table 3, entries 1–7). Naphthyl-containing fluorovinyl sulfone 2b and
the related p-biphenyl derivative 2c resulted in slightly lower se-
lectivities (Table 3, entries 2–3). On the other hand, substrates 2 h and
2l, bearing electronegative atoms in the meta position, required sig-
nificantly longer reaction times (Table 3, entries 8, 11). This suggests
that the m-methoxy substituent behaves as an electron-withdrawing
group with respect to the vinyl fluoride moiety, in accordance with its
Hammett coefficient. Similarly, fluorovinyl sulfone 2k with an electron-
withdrawing trifluoromethyl group in the para position also required a
much longer reaction time, and unfortunately led to a higher degree of
defluorination (Table 3, entry 10). In the case of bromine-bearing 2i the
only product observed was 2a, arising from the cleavage of the
111

D.M. Sedgwick et al.
JournalofFluorineChemistry206(2018)108–116
Scheme 5. Control experiments towards the hydrodefluorination
mechanism.
aromatic CeBr bond; this was not observed with the related aromatic
CeF bonds in 5l. Thiophene-based 2m could also be hydrogenated in
good yields and chemoselectivities, although a stoichiometric amount
of Pd/C was needed, possibly due to catalyst poisoning by the desired
product 5m (Table 3, entry 12).
more susceptible to cleavage than in α, and that the aromatic ring plays
no role in the loss of fluorine in β.
3. Conclusion
We later sought to extend our methodologies to the synthesis of
other related compounds. Firstly, we attempted the hydrofluorination
of ethyl phenylpropiolate using our metal-free conditions (Scheme 6a).
This substrate proved somewhat less reactive than the alkynyl sulfones,
and it was necessary to heat the mixture. However, the reaction failed
to reach completion even after 16 h at 60 °C. Nevertheless, we obtained
the desired β-fluorovinyl ester 8 in a moderate 50% yield. We were
pleased to find that the subsequent hydrogenation of 8 to β-fluoro ester
9 (Scheme 6a) resulted in complete conversion after just 1.5 h with a
selectivity of 91:9 with respect to the corresponding defluorinated
product. Secondly, we validated our hydrogenation procedure with
other fluorovinyl sulfones such as the α-fluorinated and aliphatic ana-
logs 11 and 2n, which were synthesized according to the methods de-
scribed by Prakash [13] and Hammond [15], respectively. Both hy-
drogenations occurred uneventfully, giving rise to both high yields and
selectivities (Scheme 6b,c). It is worth noting that the hydrogenation of
α-fluorovinyl sulfone 11 was more selective than that of the β-fluori-
nated analogue 2a (96:4 vs 92:8), and that minor hydrodefluorination
occurred even with aliphatic derivative 2n (for 5n 93:7) (Scheme 6c).
These results suggest that the CeF bond in the β-position is inherently
In conclusion, we have developed a simple, inexpensive, metal-free,
and selective procedure for the synthesis of (Z)-β-fluorovinyl sulfo-
nes—a new class of compounds only recently introduced in the che-
mical literature—and investigated the reactivity of such compounds. In
this sense, we have described the first studies into the hydrogenation of
fluorovinyl sulfones, obtaining a range of hydrogenated products in
good yields and selectivities; a challenging reaction given the com-
peting hydrodehalogenation that has hindered the use of similar sub-
strates in hydrogenation processes. Further studies towards an en-
antioselective version are currently being carried out in our laboratory.
4. Experimental section
4.1. General methods
Reactions were carried out under a nitrogen atmosphere unless
otherwise indicated. Solvents were purified prior to use: THF was dis-
tilled from sodium. The reactions were monitored by TLC on 0.25 mm
precoated silica-gel plates. Visualization was carried out with UV light
and aqueous ceric ammonium molybdate solution or potassium
Table 3
β-Fluorovinyl sulfone hydrogenation scope.
Entry
Substrate 2a
R1
R2
Product 5
Time (h)
Conversion (%)
Yield 5 (%)b
5:6
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
C6H5
2-Naphthyl
p-PhC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
C6H5
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
5a
5b
5c
5d
5e
5f
5g
5h
5ic
5k
5l
2
2.5
3
2
3
> 98
> 98
> 98
> 98
95
> 98
> 98
> 98
41
96
97
94
92
96
95
96
95
0
92:8
87:13
89:11
97:3
96:4
96:4
93:7
95:5
–
p-MeC6H4
p-t-BuC6H4
p-MeOC6H4
p-MeOC6H4
3,5-diMeOC6H3
p-BrC6H4
p-CF3C6H4
3,5-diFC6H3
3-Thienyl
2
3
60
16
120
60
2.5
9
10
11
12e
2k
2l
2m
80
> 98
> 98
90d
94
85
78:22
92:8
93:7
5m
a
Standard reaction conditions: 2 (0.05 mmol), Pd/C (15 mol%), Toluene (1.5 mL), H2 (1 atm). Results shown are the average of a minimum 2–3 experiments.
In most cases, compounds 5 contain small amounts of inseparable defluorinated sulfones 6.
The only product observed was 2a.
Yield corresponds to the mixture of starting 2k, β-fluorovinyl sulfone 5k and defluorinated sulfone 6k.
Pd/C (100 mol%) was used.
b
c
d
e
112

D.M. Sedgwick et al.
JournalofFluorineChemistry206(2018)108–116
Scheme 6. Heterogeneous hydrogenation: other ap-
plications.
permanganate stain. Flash column chromatography was performed
with the indicated solvents on silica gel 60 (particle size:
0.040−0.063 mm). 1H, 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 m, s, d, t, and q stand for multiplet,
singlet, doublet, triplet, and quartet, respectively. The letters br in-
dicate that the signal is broad. A QTOF mass analyzer system has been
used for the HRMS measurements.
145.6 (C) ppm. HRMS (EI) calcd. for C15H11BrO2S [M+H+]: 334.9736,
found 334.9728.
4.2.3. 1,3-Difluoro-5-(tosylethynyl)benzene (1l)
Flash chromatography of the crude reaction product [n-hexane-
EtOAc (10:1)] afforded 1l as a white solid (67%, 150 mg). Mp
105–107 °C. 1H NMR (CDCl3, 300 MHz) δ 2.50 (s, 3H; CH3), 6.93–6.99
(m, 1H; CH), 7.04-7.08 (m, 2H; 2CH), 7.43 (dd, J = 9.0, 0.6 Hz, 2H;
2CH), 7.96 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz)
δ 21.8 (CH3), 86.9 (C), 89.2 (C), 107.8 (dd, 2J = 25.0, 25.0 Hz, CH),
115.7 (dd, 2J = 28.0 Hz, 4J = 9.0 Hz, 2CH), 120.0 (dd, 3J = 120,
12.0 Hz, C), 127.7 (2CH), 130.1 (2CH), 138.3 (C), 145.9 (C), 162.1 (d,
1J = 252.2 Hz, CF), 163.7 (d, 1J = 252.2, CF) ppm. 19F NMR (CDCl3,
282.4 MHz) δ −107.3-(-107.4) (m, 2F; 2CF) ppm. HRMS (EI) calcd. for
4.2. Synthesis of alkynylsulfones [25]: general procedure
Ceric ammonium nitrate (2.5 mmol) was added portion-wise to a
mixture of the corresponding acetylene (1 mmol), sodium p-toluene-
sulfinate (1.2 mmol) and NaI (1.2 mmol) in CH3CN (15 mL) under a
nitrogen atmosphere. After the completion of the reaction (1 h approx.),
the reaction mixture was hydrolyzed with H2O and extracted with
CH2Cl2. The organic layer was separated, washed with brine (50 mL)
and dried over Na2SO4. The solvent was removed and the residue was
heated at 60 °C with K2CO3 (3 mmol) in acetone (10 mL) for 16 h. After
the completion of the reaction, the reaction mixture was washed with
H2O (50 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts were washed with brine and dried over anhydrous
Na2SO4. The solvent was removed in vacuo using a rotary evaporator
and the residue was purified by column chromatography to afford the
desired product. Compounds 1d, 1f-g are described in reference [25];
compounds 1a and 1e in reference [34a]; compounds 1b, 1 h, 1i and 1k
in reference [34b]; compound 1 m in reference [34c]; and compound
1n in reference [15].
C
15H10F2O2S [M+H+]: 293.0442, found 293.0434.
4.3. Synthesis of (Z)-β-fluorovinyl sulfones 2: general procedure
A 1 M solution of TBAF (0.15 mmol) was added to a solution of the
corresponding alkynyl sulfone (0.1 mmol) and NH4Cl (0.1 mmol) in
THF (0.1 M) under a nitrogen atmosphere at room temperature. After
completion of the reaction (1–3 h), the reaction mixture was hydrolyzed
with aqueous NH4Cl and extracted with ethyl acetate. The organic layer
was separated and dried over Na2SO4. The solvent was removed in
vacuo and the residue was purified by flash chromatography affording
compounds 2. Compound 2a is described in reference [13].
4.3.1. (Z)-2-(1-Fluoro-2-tosylvinyl)naphthalene (2b)
Flash chromatography of the crude reaction product [n-hexane-
EtOAc (10:1)] afforded 2b as
a white solid (69%, 28 mg). Mp
130–132 °C. 1H NMR (CDCl3, 300 MHz) δ 2.46 (s, 3H; CH3), 6.69 (d,
J = 33.0 Hz, 1H; CH), 7.39 (d, J = 9.0 Hz, 2H; 2CH), 7.52 (d,
J = 9.0 Hz, 1H; CH), 7.57–7.62 (m, 2H; 2CH), 7.84–7.89 (m, 3H; 3CH),
8.00 (d, J = 9.0 Hz, 2H; 2CH), 8.12 (s, 1H; CH) ppm. 13C NMR (CDCl3,
4.2.1. 4-(Tosylethynyl)-1,1′-biphenyl (1c)
Flash chromatography of the crude reaction product [n-hexane-
EtOAc (10:1)] afforded 1c as a white solid (40%, 410 mg). Mp
132–134 °C. 1H NMR (CDCl3, 300 MHz) δ 2.50 (s, 3H; CH3), 7.41–7.50
(m, 5H; 5CH), 7.58–7.61 (m, 6H; 6CH), 8.00 (d, J = 9.0 Hz, 2H; 2CH)
ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 86.1 (C), 93.1 (C),
116.6 (C), 127.1 (2CH), 127.3 (2CH), 127.5 (2CH), 128.4 (CH), 129.0
(2CH), 130.0 (2CH), 133.2 (2CH), 139.0 (C), 139.5 (C), 144.3 (C),
145.3 (C) ppm. HRMS (EI) calcd. for C21H16O2S [M+H+]: 333.0944,
found 333.0941.
75.5 MHz)
δ 21.7 (CH3), 110.0 (d, J = 12.8 Hz, CH), 121.5 (d,
J = 7.6 Hz, CH), 125.8 (d, J = 25.7 Hz, C), 127.1 (d, J = 7.6 Hz, CH),
127.3 (CH), 127.7 (CH), 127.8 (CH), 128.5 (CH), 129.0 (CH), 129.8
(CH), 132.5 (C), 134.8 (C), 139.3 (C), 144.6 (C), 164.0 (d,
1J = 273.3 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −93.9 (d,
J = 31.0, 1F; CF) ppm. HRMS (EI) calcd. for C19H15FO2S [M+H+]:
327.0850, found 327.0852.
4.2.2. 1-Bromo-3-(tosylethynyl)benzene (1j)
Flash chromatography of the crude reaction product [n-hexane-
EtOAc (10:1)] afforded 1 j as a white solid (44%, 340 mg). Mp
130–132 °C. 1H NMR (CDCl3, 300 MHz) δ 2.5 (s, 3H; CH3), 7.26 (dd,
J = 9.9, 6.0 Hz, 1H; CH), 7.42 (d, J = 9.0 Hz, 2H; 2CH), 7.45–7.49 (m,
1H; CH), 7.59–7.63 (m, 1H; CH), 7.67 (dd, J = 3.0, 3.0 Hz, 1H; CH),
7.97 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.8
(CH3), 86.5 (C), 90.6 (C), 120.0 (C), 122.4 (C), 127.6 (2CH), 130.0
(2CH), 130.1 (CH), 131.2 (CH), 134.5 (CH), 135.2 (CH), 138.6 (C),
4.3.2. (Z)-4-(1-Fluoro-2-tosylvinyl)-1,1′-biphenyl (2c)
Flash chromatography of the crude reaction product [n-hexane-
EtOAc (10:1)] afforded 2c as
a white solid (72%, 27 mg). Mp
196–198 °C. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 6.60 (d,
J = 33.0 Hz, 1H; CH), 7.37–7.50 (m, 5H; 5CH), 7.59-7.65 (m, 6H; 6CH),
7.98 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7
(CH3), 109.5 (d, J = 13.6 Hz, CH), 126.4 (d, J = 8.3, 2CH), 127.1
(2CH), 127.2 (C), 127.7 (2CH), 128.4 (CH), 129.0 (2CH), 129.8 (2CH),
113

D.M. Sedgwick et al.
JournalofFluorineChemistry206(2018)108–116
139.3 (d, J = 8.3 Hz, C), 144.6 (C), 145.2 (C), 163.3 (d, 1J = 273.3 Hz,
CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −93.8 (d, J = 32.0 Hz, 1F;
CF) ppm. HRMS (EI) calcd. for C21H17FO2S [M+H+]: 353.1006, found
353.1003.
3J = 13.6 Hz, CH), 127.7 (2CH), 129.8 (2CH), 130.5 (d,
2J = 26.4 Hz, C), 139.1 (C), 144.6 (C), 161.1 (C), 163.7 (d,
1J = 274.0 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −92.3 (d,
J = 31.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C17H17FO4S [M+H+]:
337.0904, found 337.0895.
4.3.3. (Z)-1-((2-Fluoro-2-(4-tolyl)vinyl)sulfonyl)-4-methylbenzene (2d)
Flash chromatography of the crude reaction product [n-hexane-
4.3.8. (Z)-1-Bromo-4-(1-fluoro-2-tosylvinyl)benzene (2i)
EtOAc (10:1)] afforded 2d as
a
white solid (67%, 28 mg). Mp
Flash chromatography of the crude reaction product [n-hexane-
100–102 °C. 1H NMR (CDCl3, 300 MHz) δ 2.39 (s, 3H; CH3), 2.46 (s, 3H;
CH3), 6.52 (d, J = 33.0 Hz, 1H; CH), 7.23 (d, J = 9.0 Hz, 2H; 2CH),
7.37 (d, J = 9.0 Hz, 2H; 2CH), 7.46 (d, J = 9.0 Hz, 2H; 2CH), 7.95 (d,
J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.5 (CH3),
21.6 (CH3), 108.7 (d, J = 13.6 Hz, CH), 125.8 (2CH), 125.9 (2CH),
126.1 (C), 127.6 (2CH), 129.7 (2CH), 139.4 (C), 143.2 (C), 144.4 (C),
164.5 (d, 1J = 274.0 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ
−93.4 (d, J = 31.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C16H15FO2S
[M+H+]: 291.0850, found 291.0858.
EtOAc (10:1)] afforded 2i as a white solid (63%, 22 mg). Mp
145–147 °C. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 6.56 (d,
J = 33.0 Hz, 1H; CH), 7.38 (d, J = 9.0 Hz, 2H; 2CH), 7.42 (d,
J = 9.0 Hz, 2H; 2CH), 7.58 (d, J = 9.0 Hz, 2H; 2CH), 7.95 (d,
J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3),
110.3 (d, J = 13.6 Hz, CH), 127.2 (CH), 127.3 (CH), 127.6 (d,
J = 26.7 Hz, C), 127.7 (CH), 129.9 (CH), 132.3 (C), 144.8 (C), 163.5 (d,
J = 273.3 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −94.2 (d,
J = 31.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for C15H12BrFO2S [M
+H+]: 354.9798, found 354.9806.
4.3.4. (Z)-1-(tert-Butyl)-4-(1-fluoro-2-tosylvinyl)benzene (2e)
Flash chromatography of the crude reaction product [n-hexane-
4.3.9. (Z)-1-Bromo-3-(1-fluoro-2-tosylvinyl)benzene (2j)
EtOAc (15:1)] afforded 2e as
a
white solid (67%, 28 mg). Mp
Flash chromatography of the crude reaction product [n-hexane-
EtOAc (10:1)] afforded 2j as a white solid (60%, 20 mg). Mp 81–83 °C.
1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 6.57 (d, J = 30.0 Hz,
1H; CH), 7.33 (d, J = 9.0 Hz, 1H; CH), 7.38 (d, J = 6.0 Hz, 2H; 2CH),
7.50 (d, J = 9.0 Hz, 1H; CH), 7.61–7.64 (m, 1H; CH), 7.69-7.70 (m, 1H;
CH), 7.95 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ
21.7 (CH3), 111.2 (d, J = 13.6 Hz, CH), 123.1 (C), 124.4 (d, J = 7.5 Hz,
CH), 127.7 (2CH), 128.8 (d J = 8.3 Hz, CH), 129.9 (2CH), 130.5 (CH),
122–124 °C. 1H NMR (CDCl3, 300 MHz) δ 1.32 (s, 9H; 3CH3), 2.46 (s,
3H; CH3), 6.52 (d, J = 33 Hz, 1H; CH), 7.37 (d, J = 9.0 Hz, 2H; 2CH),
7.44 (d, J = 9.0 Hz, 2H; 2CH), 7.51 (d, J = 9.0 Hz, 2H; 2CH), 7.95 (d,
J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3),
30.9 (3CH3), 35.1 (C), 108.8 (d, 2J = 13.6 Hz, CH), 125.8 (d,
3J = 7.5 Hz, 2CH), 126.0 (d J = 2.3 Hz, 2CH), 127.6 (2CH), 129.7
(2CH), 139.4 (C), 144.4 (C); 156.3 (C), 164.2 (d, 1J = 273.3 Hz, CF)
ppm. 19F NMR (CDCl3, 282.4 MHz) δ −93.4 (d, J = 31.1 Hz, 1F; CF)
ppm. HRMS (EI) calcd. for C19H21FO2S [M+H+]: 333.1319, found
333.1327.
135.2 (CH), 138.8 (C), 144.8 (C), 162.0 (d, 1J = 274.0 Hz, CF) ppm. 19
F
NMR (CDCl3, 282.4 MHz) δ −94.1 (d, J = 31.1 Hz, 1F; CF) ppm. HRMS
(EI) calcd. for C15H12BrFO2S [M+H+]: 354.9798, found 354.9793.
4.3.5. (Z)-1-(1-Fluoro-2-(phenylsulfonyl)vinyl)-4-methoxybenzene (2f)
Flash chromatography of the crude reaction product [n-hexane-
EtOAc (10:1)] afforded 2f as a white solid (72%, 40 mg). Mp 78–80 °C.
1H NMR (CDCl3, 300 MHz) δ 3.86 (s, 3H; OCH3), 6.45 (d, J = 33.0 Hz,
1H; CH), 6.93 (d, J = 9.0 Hz, 2H; 2CH), 7.51–7.65 (m, 5H; 5CH), 8.07
(d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 55.5
(OCH3), 107.1 (d, J = 13.6 Hz, CH), 114.5 (2CH), 120.8 (d,
J = 25.6 Hz, C), 127.5 (2CH), 127.9 (J = 8.3 Hz, 2CH), 129.1 (2CH),
133.3 (CH), 142.4 (C), 163.0 (C), 164.5 (d, 1J = 273.0 Hz, C) ppm. 19F
NMR (CDCl3, 282.4 MHz) δ −92.7 (d, J = 33.0 Hz, 1F; CF) ppm. HRMS
(EI) calcd. for C15H13FO3S [M + H+]: 293.0642, found 293.0642.
4.3.10. (Z)-1-((2-Fluoro-2-(4-(trifluoromethyl)phenyl)vinyl)sulfonyl)-4-
methylbenzene (2k)
Flash chromatography of the crude reaction product [n-hexane-
EtOAc (5:1)] afforded 2k as
a white solid (28%, 20 mg). Mp
129–131 °C. 1H NMR (CDCl3, 300 MHz) δ 2.45 (s, 3H; CH3), 6.64 (d,
J = 32.0 Hz, 1H; CH), 7.37 (dd, J = 8.6, 0.7 Hz, 1H; CH), 7.68 (s, 2H;
2CH), 7.94 (d, J = 8.0 Hz, 1H; CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ
21.6 (CH3), 111.9 (d, J = 13.1 Hz, C), 111.9 (d, J = 13.1 Hz, C), 125.9
(q, J = 2.4 Hz, CH), 126.2 (d, J = 7.6 Hz, CH), 127.8 (CH), 129.9 (CH),
132.2 (d, J = 27.4 Hz, C), 133.8 (d, J = 33.1 Hz, C), 138.6 (C), 144.9
(C), 162.1 (d, J = 274.0 Hz, C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ
−94.84 (d, J = 31.9 Hz, CF), −63.71 (s, CF3) ppm. HRMS (EI) calcd.
for C16H12F4O2S [M+NH4+]: 362.0832, found 362.0825.
4.3.6. (Z)-1-[(2-Fluoro-2-(4-methoxyphenyl)vinyl)sulfonyl]-4-
methylbenzene (2g)
Flash chromatography of the crude reaction product [n-hexane-
EtOAc (5:1)] afforded 2g as a white solid (71%, 45 mg). Mp 74–75 °C.
1H NMR (CDCl3, 300 MHz) δ 2.45 (s, 3H; CH3), 3.84 (s, 3H; OCH3), 6.43
(d, J = 32.8 Hz, 1H; CH), 6.92 (d, J = 9.1 Hz, 1H; CH), 7.36 (d,
J = 9.0 Hz, 1H; CH), 7.51 (d, J = 9.0 Hz, 1H; CH), 7.94 (d, J = 9.0 Hz,
1H; CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 55.2 (OCH3),
107.4 (d, 2J = 13.4 Hz, CH), 114.5 (2CH), 120.9 (d, 2J = 25.6 Hz, C),
127.5 (2CH), 127.8 (d, 3J = 8.2 Hz, 2CH), 129.7 (2CH), 139.5 (C),
144.3 (C), 162.9 (C), 164.2 (d, 1J = 272.2 Hz, CF) ppm. 19F NMR
(CDCl3, 282.4 MHz) δ −93.3 (d, J = 33.9 Hz, 1F; CF) ppm. HRMS (EI)
calcd. for C16H15O3S [M+H+]: 307.0799, found 307.0800.
4.3.11. (Z)-1,3-Difluoro-5-(1-fluoro-2-tosylvinyl)benzene (2l)
Flash chromatography of the crude reaction product [n-hexane-
EtOAc (10:1)] afforded 2l as
a white solid (30%, 21 mg). Mp
158–160 °C. 1H NMR (CDCl3, 300 MHz) δ 2.48 (s, 3H; CH3), 6.57 (d,
J = 30.0 Hz, 1H; CH), 6.92-7.00 (m, 1H; CH), 7.08-7.11 (m, 2H; 2CH),
7.40 (d, J = 9.0 Hz, 2H; 2CH), 7.95 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C
NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 107.7 (dd, 2J = 24.8, 24.9 Hz,
CH), 109.0 (dd, 2J = 27.1, 27.2 Hz, CH), 112.1 (d, J = 12.8 Hz, CH),
127.8 (2CH), 129.9 (2CH), 131.9 (d, 2J = 28.7 Hz, C), 138.5 (C), 145.1
(C), 161.1 (d, 1J = 274.0 Hz, CF), 163.0 (d, 1J = 251.4 Hz, CF), 163.2
(d, 1J = 251.5 Hz, CF) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −106.7 (s,
2F; 2CF), −94.2 (d, J = 31.0 Hz, 1F; CF) ppm. HRMS (EI) calcd. for
4.3.7. (Z)-1-(1-Fluoro-2-tosylvinyl)-3,5-dimethoxybenzene (2h)
C
15H11F3O2S [M+H+]: 313.0505, found 313.0506.
Flash chromatography of the crude reaction product [n-hexane-
EtOAc (10:1)] afforded 2h as
a
white solid (70%, 30 mg). Mp
4.3.12. (Z)-3-(1-Fluoro-2-tosylvinyl)thiophene (2m)
158–160 °C. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 3.80 (s, 6H;
2OCH3), 6.53 (d, J = 33.0 Hz, 1H; CH), 6.57-6.59 (m, 1H; CH), 6.67 (d,
J = 3.0 Hz, 2H; 2CH), 7.38 (d, J = 9.0 Hz, 2H; 2CH), 7.94 (d,
J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3),
55.6 (OCH3), 103.9 (CH), 104.3 (d, 2J = 52.1 Hz, CH), 110.2 (d,
Flash chromatography of the crude reaction product [n-hexane-
EtOAc (5:1)] afforded 2m as
a white solid (70%, 65 mg). Mp
121–123 °C. 1H NMR (CDCl3, 300 MHz) δ 2.46 (s, 3H; CH3), 6.39 (d,
J = 33.2 Hz, 1H; CH), 7.15 (d, J = 6.0 Hz, 1H; CH), 7.35-7.38 (m, 3H;
3CH), 7.74 (d, J = 3.0 Hz, 1H; CH), 7.94 (d, J = 9.0 Hz, 1H; CH) ppm.
114

D.M. Sedgwick et al.
JournalofFluorineChemistry206(2018)108–116
13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 109.0 (d, J = 12.5 Hz, CH),
124.4 (d, J = 7.5 Hz, CH), 127.6 (2CH), 128.0 (CH), 128.2 (d,
J = 6.0 Hz, CH), 129.8 (2CH), 131.0 (d, 2J = 27.9 Hz, C), 139.3 (C),
144.5 (C), 160.0 (d, 1J = 270.9 Hz, CF) ppm. 19F NMR (CDCl3,
282.4 MHz) δ −92.7 (d, J = 32.1 Hz, 1F; CF) ppm. HRMS (EI) calcd. for
3.43 (ddd, J = 33.0, 15.0, 3.0 Hz, 1H; CHH), 3.77-3.90 (m, 1H; CHH),
5.99 (ddd, J = 45.0, 9.0, 3.0 Hz, 1H; CHF), 7.22 (d, J = 9.0 Hz, 2H;
2CH), 7.35-7.40 (m, 4H; 4CH), 7.85 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C
NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 31.2 (3CH3), 34.7 (C), 62.7 (d,
2J = 26.4 Hz, CH2), 88.5 (d, 1J = 176.7, CHF), 125.4 (d, 3J = 6.0 Hz,
2CH), 125.8 (2CH), 128.3 (2CH), 129.8 (2CH), 133.8 (d,
2J = 13.6 Hz, C), 136.7 (C), 144.9 (C), 152.6 (C) ppm. 19F NMR (CDCl3,
282.4 MHz) δ −171.9 (ddd, J = 48.0, 31.1, 14.0 Hz, 1F; CHF) ppm.
HRMS (EI) calcd. for C19H23FO2S [M + NH4+]: 352.1741, found
352.1742.
C
13H11FO2S2 [M+H+]: 283.0257, found 283.0254.
4.3.13. Ethyl (Z)-3-fluoro-3-phenylacrylate (8)
Described in reference [35].
4.4. Hydrogenation of β-fluorovinylsulfones
4.4.6. 1-(1-Fluoro-2-(phenylsulfonyl)ethyl)-4-methoxybenzene (5f)
Crude reaction product 5f (95%, 19 mg) was obtained as viscous oil.
1H NMR (CDCl3, 300 MHz) δ 3.47 (ddd, J = 33.0, 15.0, 3.0 Hz, 1H;
CHH), 3.81 (s, 3H; OCH3), 3.78-3.93 (m, 1H; CHH), 5.97 (ddd,
J = 48.0, 9.0, 3.0 Hz, 1H; CHF), 6.88 (d, J = 9.0 Hz, 2H; 2CH), 7.22 (d,
J = 9.0 Hz, 2H; 2CH), 7.55-7.60 (m, 2H; 2CH), 7.65–7.70 (m, 1H; CH),
7.97 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 55.3
(OCH3), 62.5 (d, 2J = 27.2 Hz, CH2), 88.3 (d, 1J = 175.2 Hz, CHF),
114.3 (2CH), 127.3 (d, 3J = 5.3 Hz, 2CH), 128.3 (2CH), 128.7 (d,
2J = 20.4 Hz, C), 129.2 (2CH), 133.9 (CH), 139.7 (C), 160.4 (C) ppm.
19F NMR (CDCl3, 282.4 MHz) δ −167.8 (ddd, J = 48.0, 31.1, 14.1, 1F;
CHF) ppm. HRMS (EI) calcd. for C15H15FO3S [M+NH4+]: 312.1064,
found 312.1056.
4.4.1. General procedure for the synthesis of β-fluoro sulfones 5
Pd(C) catalyst (15 mol%) was added to a solution of the corre-
sponding β-fluorovinyl sulfone 2 (0.05 mmol) in toluene (0.033 M), and
hydrogen gas was charged by purging the reaction flask several times,
without stirring. The reaction was then stirred under H2 (atmospheric
pressure) at room temperature for 1–3 h. The mixture was filtered to
remove the catalyst, and the solvent was evaporated in vacuo. In most
cases, compounds 5 contain small amounts of inseparable defluorinated
sulfones 6. Compound 5a has been described in reference [31]. For
compounds 10 and 11, see reference [14].
4.4.2. -(1-Fluoro-2-tosylethyl)naphthalene (5b)
Crude reaction product 5b (96%, 20 mg) was obtained as viscous
oil. 1H NMR (CDCl3, 300 MHz) δ 2.45 (s, 3H; CH3), 3.57 (ddd, J = 30.0,
15.0, 3.0 Hz, 1H; CHH), 3.86-3.98 (m, 1H; CHH), 6.18 (ddd, J = 45.0,
9.0, 3.0 Hz, 1H; CHF), 7.33-7.38 (m, 3H; 3CH), 7.52-7.55 (m, 2H; 2CH),
7.76–7.87 (m, 6H; 6CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6
(CH3), 62.6 (d, 2J = 26.4 Hz, CH2), 88.8 (d, 1J = 177.4 Hz, CHF), 122.5
(d, 3J = 5.3 Hz, CH), 125.3 (d, 3J = 7.5 Hz, CH), 126.8 (CH), 126.9
(CH), 127.7 (CH), 128.1 (CH), 128.3 (2CH), 128.9 (CH), 129.8 (2CH),
132.9 (C), 133.5 (C), 134.1 (d, 2J = 20.4 Hz, C), 136.6 (C), 145.0 (C)
ppm. 19F NMR (CDCl3, 282.4 MHz) δ −173.1 (ddd, J = 45.1, 28.2,
11.3 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C19H17FO2S [M+NH4+]:
346.1272, found 346.1268.
4.4.7. 1-((2-Fluoro-2-(4-methoxyphenyl)ethyl)sulfonyl)-4-methylbenzene
(5g)
Crude reaction product 5g (96%, 21 mg) was obtained as viscous
oil. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 3.45 (ddd, J = 30.0,
15.0 3.0 Hz, 1H; CHH), 3.81 (s, 3H; OCH3), 3.78–3.90 (m, 1H; CHH),
5.95 (ddd, J = 48.0, 9.0, 3.0 Hz, 1H; CHF), 6.89 (d, J = 9.0 Hz, 2H;
2CH), 7.22 (d, J = 9.0 Hz, 2H; 2CH), 7.37 (d, J = 9.0 Hz, 2H; 2CH),
7.84 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7
(CH3), 55.3 (OCH3), 62.5 (d, 2J = 27.2 Hz, CH2), 88.4 (d,
1J = 175.9 Hz, CHF), 114.2 (2CH), 127.3 (d, 3J = 6.0 Hz, 2CH), 128.3
(2CH), 128.9 (d, 2J = 20.4 Hz, C), 129.8 (2CH), 136.7 (C), 144.9 (C),
160.4 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −168.0 (ddd, J = 45.2,
28.2, 11.3 1F; CHF) ppm. HRMS (EI) calcd. for C16H17FO3S [M
+NH4+]: 326.1221, found 326.1215.
4.4.3. 4-(1-Fluoro-2-tosylethyl)-1,1′-biphenyl (5c)
Crude reaction product 5c (94%, 16 mg) was obtained as viscous oil.
1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 3.52 (ddd, J = 30.0,
15.0, 3.0 Hz, 1H; CHH), 3.81-3.93 (m, 1H; CHH), 6.08 (ddd, J = 45.0,
9.0, 3.0 Hz, 1H; CHF), 7.36-7.61 (m, 11H; 11CH), 7.87 (d, J = 9.0 Hz,
2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7 (CH3), 62.7 (d,
2J = 25.7 Hz, CH2), 88.5 (d, 1J = 177.4 Hz, CHF), 126.0 (d,
3J = 6.8 Hz, 2CH), 127.1 (2CH), 127.6 (2CH), 127.7 (CH), 128.3 (2CH),
128.8 (2CH), 129.9 (2CH), 135.7 (d, 2J = 19.6 Hz, C), 136.7 (C), 140.2
(C), 142.4 (C), 145.0 (C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −173.1
(ddd, J = 45.1, 31.1, 11.3 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for
4.4.8. 1-(1-Fluoro-2-tosylethyl)-3,5-dimethoxybenzene (5h)
Crude reaction product 5h (95%, 12 mg) was obtained as viscous
oil. 1H NMR (CDCl3, 300 MHz) δ 2.48 (s, 3H; CH3), 3.45 (ddd, J = 33.5,
15.0, 3.1 Hz, 1H; CHH), 3.72-3.84 (m, 1H; CHH), 3.78 (s, 6H; 2OCH3),
5.90 (ddd, J = 48.1, 9.0, 3.1 Hz, 1H; CHF), 6.41 (s, 3H; 3CH), 7.39 (d,
J = 9.0 Hz, 2H; 2CH), 7.86 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR
(CDCl3, 75.5 MHz) δ 21.7 (CH3), 55.4 (2OCH3), 62.4 (d, 2J = 25.7 Hz,
CH2), 88.5 (d, 1J = 180.0 Hz, CHF), 101.0 (CH), 103.2 (d, 3J = 6.8 Hz,
2CH), 128.3 (2CH), 129.9 (2CH), 136.7 (C), 139.3 (d, 2J = 20.4 Hz, C),
145.0 (C), 161.2 (2C) ppm. 19F NMR (CDCl3, 282.4 MHz) δ −175.2
(ddd, J = 48.0, 33.5, 14.0 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for
C
21H19FO2S [M+NH4+]: 372.1428, found 372.1426.
4.4.4. 1-((2-Fluoro-2-(p-tolyl)ethyl)sulfonyl)-4-methylbenzene (5d)
Crude reaction product 5d (92%, 23 mg) was obtained as viscous
oil. 1H NMR (CDCl3, 300 MHz) δ 2.36 (s, 3H; CH3), 2.48 (s, 3H; CH3),
3.45 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.76–3.89 (m, 1H; CHH),
7.18 (s, 4H; 4CH), 7.38 (d, J = 9.0 Hz, 2H; 2CH), 7.86 (d, J = 9.0 Hz,
2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.2 (CH3), 21.7 (CH3),
62.7 (d, 2J = 26.4 Hz, CH2), 88.5 (d, 1J = 176.0 Hz, CHF), 125.6 (d,
3J = 6.0 Hz, 2CH), 128.3 (2CH), 129.5 (2CH), 129.8 (2CH), 133.9 (d,
2J = 20.4 Hz, C), 136.7 (C), 139.4 (C), 144.9 (C) ppm. 19F NMR (CDCl3,
282.4 MHz) δ −171.7 (ddd, J = 48.0, 31.0, 14.0 Hz, 1F; CHF) ppm.
C
17H19FO4S [M+H+]: 339.1061, found 339.1050.
4.4.9. 4-(1-Fluoro-2-tosylethyl)-1-trifluoromethylbenzene (5k)
Crude reaction product 5k (90%, 9 mg) was obtained as viscous oil.
Data taken from the crude mixture. Only the most characteristic signals
for 5k are described in the following data, due to the difficulties in
isolating this compound (see spectrum 5k). 1H NMR (CDCl3, 300 MHz)
δ 2.48 (s, 3H; CH3), 3.48 (ddd, J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.80
(ddd, J = 24.0, 15.0, 9.0 Hz, 1H; CHH), 6.09 (ddd, J = 48.0, 9.0,
3.0 Hz, 1H; CHF) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.6 (CH3), 62.5
(d, 2J = 24.9 Hz, CH2), 87.9 (d, 1J = 179.7 Hz, CHF) ppm. 19F NMR
(CDCl3, 282.4 MHz) δ −177.0 (ddd, J = 46.0, 30.0, 14.2 Hz, 1F; CHF),
−63.1 (s, 3F; CF3) ppm. HRMS (EI) calcd. for C16H14F4O2S [M
+NH4+]: 364.0989, found 364.0993.
HRMS (EI) calcd. for
310.1269.
C
16H17FO2S [M+NH4+]: 310.1272, found
4.4.5. 1-(tert-Butyl)-4-(1-fluoro-2-tosylethyl)benzene (5e)
Crude reaction product 5e (96%, 16 mg) was obtained as viscous
oil. 1H NMR (CDCl3, 300 MHz) δ 1.32 (s, 9H; 3CH3), 2.47 (s, 3H; CH3),
115

D.M. Sedgwick et al.
JournalofFluorineChemistry206(2018)108–116
4.4.10. 1,3-Difluoro-5-(1-fluoro-2-tosylethyl)benzene (5l)
[2] D.E. Yerien, S. Bonesi, A. Postigo, Org. Biomol. Chem. 14 (2016) 8398–8427.
[3] (a) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J.L. Aceña, V.A. Soloshonok,
K. Izawa, H. Liu, Chem. Rev. 116 (2016) 422–518.
[4] J.F. Nadon, K. Rochon, S. Grastilleur, G. Langlois, T.T.H. Dao, V. Blais, B. Guérin,
L. Gendron, Y.L. Dory, ACS Chem. Neurosci. 8 (2017) 40–49.
[5] B.E. McKinney, J.J. Urban, J. Phys. Chem. A 114 (2010) 1123–1133.
[6] M. Drouin, J.F. Paquin, Beilstein J. Org. Chem. 13 (2017) 2637–2658 For a very
recent review, see:.
Crude reaction product 5l (94%, 18 mg) was obtained as viscous oil.
1H NMR (CDCl3, 300 MHz) δ 2.48 (s, CH3), 3.44 (ddd, J = 30.0, 15.0,
3.0 Hz, 1H; CHH), 3.75 (ddd, J = 21.0, 15.0, 9.0 Hz, 1H; CHH), 6.00
(ddd, J = 45.0, 9.0, 3.0 Hz, 1H; CHF), 6.77-6.85 (m, 3H; 3CH), 7.40 (d,
J = 9.0 Hz, 2H; 2CH), 7.85 (d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR
(CDCl3, 75.5 MHz) δ 21.7 (CH3), 62.4 (d, 2J = 25.7 Hz, CH2), 87.4 (d,
1J = 180.4 Hz, CHF), 104.6 (dd, 2J = 25.7 Hz, CH), 108.5 (ddd,
J = 25.6, 7.5 Hz, 2CH), 128.2 (2CH), 129.9 (2CH), 136.4 (C), 140.7 (C),
145.3 (C), 163.1 (d, 1J = 252.4 Hz, CF), 163.1 (d, 1J = 252.4 Hz, CF)
ppm. 19F NMR (CDCl3, 282.4 MHz) δ −176.6 (ddd, J = 45.1, 28.2,
14.0 Hz, 1H; CHF), −107.5 to (−107.4) (m, 2F; 2CF) ppm. HRMS (EI)
calcd. for C15H13F3O2S [M+NH4+]: 332.0927, found 332.0926.
[7] O.E. Okoromoba, J. Han, G.B. Hammond, B. Xu, J. Am. Chem. Soc. 136 (2014)
14381–14384.
[8] A.-N.R. Alba, X. Companyó, R. Rios, Chem. Soc. Rev. 39 (2010) 2018.
[9] D.C. Meadows, J. Gervay-Hague, Med. Res. Rev. 26 (2006) 793–814.
[10] N.S. Simpkins, Tetrahedron 46 (1990) 6951–6984.
[11] D.C. Meadows, J. Gervay-Hague, Med. Res. Rev. 26 (2006) 793–814 For a review on
vinyl sulfones and their used in medicinal chemistry see:.
[12] A.K. Ghosh, B. Zajc, Synlett (2008) 999–1004.
[13] G.K.S. Prakash, S. Chacko, H. Vaghoo, N. Shao, L. Gurung, T. Mathew, G.A. Olah,
Org. Lett. 11 (2009) 1127–1130.
[14] C.D. McCune, M.L. Beio, J.M. Sturdivant, R. de la Salud-Bea, B.M. Darnell,
D.B. Berkowitz, J. Am. Chem. Soc. 139 (2017) 14077–14089.
[15] X. Zeng, S. Liu, G.B. Hammond, B. Xu, J. Chem. Eur. 23 (2017) 11977–11981.
[16] T.B. Patrick, J. Neumann, A. Tatro, J. Fluor. Chem. 132 (2011) 779–782.
[17] M. Hudlicky, J. Fluor. Chem. 14 (1979) 189–199.
[18] R. Sauvetre, J.-F. Normant, P. Martinet, J. Fluor. Chem. 52 (1991) 419–432.
[19] M. Saburi, H. Takeuchi, M. Ogasawara, T. Tsukahara, Y. Ishii, T. Ikariya,
T. Takahishi, T. Uchida, J. Organomet. Chem. 428 (1992) 155–167.
[20] S.W. Krska, J.V. Mitten, P.G. Dormer, D. Mowrey, F. Machrouhi, Y. Sun,
T.D. Nelson, Tetrahedron 65 (2009) 8987–8994.
[21] M. Engman, J.S. Diesen, A. Paptchikhine, P.G. Andersson, J. Am. Chem. Soc. 129
(2007) 4536–4537.
[22] P. Kaukoranta, M. Engman, C. Hedberg, J. Bergquist, P.G. Andersson, Adv. Synth.
Catal. 350 (2008) 1168–1176.
[23] (a) For the synthesis of other β-halovinyl sulfones, see: Y. Liang, S.H. Suzol,
Z. Wen, A.G. Artiles, L. Mathivathanan, R.G. Raptis, S.F. Wnuk, Org. Lett. 18 (2016)
1418–1421;
4.4.11. 3-(1-Fluoro-2-tosylethyl)thiophene (5m)
Crude reaction product 5m (85%, 10 mg) was obtained as viscous
oil. 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H; CH3), 3.52 (ddd, J = 30.0,
15.0, 3.0 Hz, 1H; CHH), 3.79-3.92 (m, 1H; CHH), 6.10 (ddd, J = 6.0 Hz,
1H; CH), 7.30-7.34 (m, 2H; 2CH), 7.38 (d, J = 9.0 Hz, 2H; 2CH), 7.84
(d, J = 9.0 Hz, 2H; 2CH) ppm. 13C NMR (CDCl3, 75.5 MHz) δ 21.7
(CH3), 62.0 (d, 2J = 25.7 Hz, CH2), 84.8 (d, 1J = 174.4 Hz, CHF), 123.6
(d, 3J = 7.5 Hz, CH), 124.8 (d, 3J = 3.0 Hz, CH), 127.3 (CH), 128.3
(2CH), 129.9 (2CH), 136.6 (C), 137.8 (d, 2J = 21.9 Hz, C), 145.1 (C)
ppm. 19F NMR (CDCl3, 282.4 MHz) δ −167.5 (ddd, J = 45.2, 28.2,
11.3 Hz, 1F; CHF) ppm. HRMS (EI) calcd. for C13H13FO2S2 [M+NH4+]:
302.0679, found 302.0682.
(b) X. Zeng, L. Ilies, E. Nakamura, Org. Lett. 14 (2012) 954–956.
[24] T. Kitazume, T. Ohnogi, H. Miyauchi, T. Yamazaki, J. Org. Chem. 54 (1989)
5630–5632.
[25] V. Nair, A. Augustine, T.D. Suja, Synthesis 15 (2002) 2259–2265.
[26] Y. Li, X. Liu, D. Ma, B. Liu, H. Jiang, Adv. Synth. Catal. 354 (2012) 2683–2688.
[27] J. Che, Y. Li, F. Zhang, R. Zheng, Y. Bai, G. Zhu, Tetrahedron Lett. 55 (2014)
6240–6242.
[28] (a) Fluorovinyl sulfones 2 and β-keto sulfones 3 were easily separated by flash
chromatography. For recent examples of the synthesis of β-keto sulfones, see:
S. Handa, J.C. Fennewaald, B.H. Lipshutz, Angew. Chem. Int. Ed. 53 (2014)
3432–3435;
4.4.12. ((2-Fluorooctyl)sulfonyl)benzene (5n)
Crude reaction product 5n (94%, 14 mg) was obtained as viscous
oil. 1H NMR (CDCl3, 300 MHz) δ 0.89–1.72 (m, 13H; C6H13), 3.28 (ddd,
J = 30.0, 15.0, 3.0 Hz, 1H; CHH), 3.54-3.60 (m, 1H; CHH), 4.92-5.15
(m, 1H; CHF), 7.57-7.71 (m, 3H; 3CH), 7.95-7.97 (m, 2H; 2CH) ppm.
13C NMR (CDCl3, 75.5 MHz) δ 13.9 (CH3), 22.4 (CH2), 24.4 (d,
3J = 4.5 Hz, CH2), 28.7 (CH2), 31.5 (CH2), 34.8 (d, 2J = 20.4 Hz, CH2),
61.0 (d, 2J = 23.4 Hz, CH2), 88.1 (d, 1J = 174.4 Hz, CHF), 128.2 (2CH),
129.2 (2CH), 133.9 (CH), 139.7 (C) ppm. 19F NMR (CDCl3, 282.4 MHz)
δ −180.0 to (−179.5) (m, 1F; CHF) ppm. HRMS (EI) calcd. for
(b) Q. Lu, J. Zhang, P. Peng, G. Zhang, Z. Huang, H. Yi, J.T. Miller, A. Lei, Chem.
Sci. 6 (2015) 4851–4854;
(c) D. Yang, B. Huang, W. Wei, J. Li, G. Lin, Y. Liu, J. Ding, P. Sun, H. Wang, Green
Chem. 18 (2016) 5630–5634;
C
14H21FO2S [M+NH4+]: 290.1585, found 290.1578.
(d) L. Xie, X. Zhen, S. Huang, X. Su, M. Lin, Y. Li, Green Chem. 19 (2017)
3530–3534;
Acknowledgments
(e) J. Yu, R. Mao, Q. Wang, J. Wu, Org. Chem. Front. 4 (2017) 617–621.
[29] More than ten years ago Sun and DiMagno described a methodology for the pre-
paration of anhydrous TBAF. However, their procedure is somewhat laborious and
tedious and therefore its use would not be desirable in this study, which aims to
provide a practical and inexpensive alternative for the synthesis of the title com-
pounds: H. Sun, S.G. DiMagno, J. Am. Chem. Soc., 127 (2005) 2050–2051.
[30] S.E. Denmark, M.A. Harmata, K.S. White, J. Org. Chem. 52 (1987) 4031–4042.
[31] Z. Yuan, H.-Y. Wang, X. Mu, P. Chen, Y.-L. Guo, G. Liu, J. Am. Chem. Soc. 137
(2015) 2468–2471.
We would like to thank the Spanish Ministerio de Economía y
Competitividad (CTQ-2013-43310-P) and the Generalitat Valenciana
(GV/PrometeoII/2014/073). D. M. S. thanks the Spanish Ministerio de
Educación, Cultura y Deporte for a predoctoral fellowship (FPU15/
01485). The authors are also grateful to Alberto Llobat and Daniel
Dávila for assistance in the synthesis of the starting materials.
[32] S. Bloom, S.A. Sharber, M.G. Holl, J.L. Knippel, T. Lectka, J. Org. Chem. 78 (2013)
11082–11086.
References
[33] S. Bloom, M. McCann, T. Lectka, Org. Lett. 16 (2014) 6338–6341.
[34] (a) P. Chen, Ch. Zhu, R. Zhu, W. Wu, H. Jiang, Chem. Asian. J. 12 (2017)
1875–1878.
[1] E.P. Gillis, K.J. Eastman, M.D. Hill, D.J. Donnelly, N.A. Meanwell, J. Med. Chem. 58
[35] S. Peng, F.-L. Qing, Y.-Q. Li, Ch-M. Hu, J. Org. Chem. 65 (2000) 694–700.
(2015) 8315–8359.
116