Fluorovinyl Thioethers as Putative Steric and Electronic Thioester Enolate Mimetics: Chemoselective HF Addition to Acetylene Thioethers

Article abstract of DOI:10.1071/CH14298

Fluorovinyl thioethers are presented as a putative biomimetic surrogate for the enol/ate of a thioester. A method is explored for the preparation of fluorovinyl thioethers by treatment of acetylene thioethers with pyridinium (poly)-hydrogen fluoride. Titr

Full text of DOI:10.1071/CH14298

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2015, 68, 72–79
Communication
http://dx.doi.org/10.1071/CH14298
Fluorovinyl Thioethers as Putative Steric and Electronic
Thioester Enolate Mimetics: Chemoselective HF
Addition to Acetylene Thioethers
A
A
A B
,
Davide Bello, Rodrigo A. Cormanich, and David O’Hagan
A
EaStChem School of Chemistry and Centre for Biomolecular Sciences,
University of St Andrews, KY16 9ST, UK.
B
Corresponding author. Email: do1@st-andrews.ac.uk
Fluorovinyl thioethers are presented as a putative biomimetic surrogate for the enol/ate of a thioester. A method is explored
for the preparation of fluorovinyl thioethers by treatment of acetylene thioethers with pyridinium (poly)-hydrogen
fluoride. Titration with pyridine is important for the selectivity of the reaction. Without titration the corresponding gem-
difluoroethyl thioethers are generated. With titration the hydrofluorination reaction can be stopped at an intermediate stage
to recover the fluorovinyl thioether, which is a relatively stable functionality to purification and manipulation. Preliminary
density functional theory calculations indicate that the fluorovinyl thioether motif shares a comparable steric and
electronic profile to a thioester enol. A fluorovinyl thioether representing the terminus of the pantothenoyl chain of acetyl-
CoA is prepared as a relevant biomimetic example.
Manuscript received: 14 May 2014.
Manuscript accepted: 28 May 2014.
Published online: 21 August 2014.
The incorporation of fluorine substituents has been widely
deployed in the development of pharmaceuticals, agrochem-
icals, and organic materials.[1,2] This is because the strong
electronic influence, but low steric impact of a fluorine sub-
stituent can confer improved properties on organic compounds,
such as modifications to lipophilicity, tuned pKa, and metabolic
stability which together can improve the pharmacokinetic pro-
file of drugs in development. Thus the syntheses of novel
structural motifs carrying fluorine is of general interest. In this
paper we report a synthesis of novel fluorovinyl thioethers by
HF addition to acetylene thioethers, and highlight their potential
as stereoelectronic mimetics of the enol/ate of thioesters.
Vinylfluorides are most commonly prepared via condensa-
tion (Horner–Wadsworth–Emmons (HWE) reaction, Fluoro–
Julia olefination)[3,4] and palladium-catalysed cross-coupling
reactions.[5,6] Also, hydrofluorination of alkynes allows access
to fluoroalkenes directly. However, this method is limited to
alkynes bearing electron-withdrawing groups,[7,8] as non-
activated alkynes only react with strongly acidic HF reagents,
such as pyridinium (poly)-hydrogen fluoride (30 % pyridine,
70 % HF), thus adding up to two equivalents of HF to the triple
bond, and yielding gem-difluorides as the sole reaction pro-
ducts.[9,10] An exception to the formation of gem-difluorides is
represented by the stereoselective HFꢀSbF5-mediated hydro-
fluorination of ynamides.[11] Gold- and palladium-catalysed
hydrofluorination reactions of alkynes have also been recently
described.[12–16]
benzenethiosufonate (Scheme 1).[18] Whereas the former meth-
od involves the use of a gaseous reagent under high pressure and
temperature, the latter requires the preparation of both the silyl
and thiosulfonate reagents for any variation of the S-aryl moiety,
thus making the synthetic process rather impractical.[19]
Aryl- and alkyl-thioacetylenes can be regarded as ‘activated’
alkynes in that the sulfur atom adjacent to the acetylene facil-
itates reaction towards weaker electrophiles. Thus we have
explored the reaction of benzylthioacetylene[20] 4a (readily
prepared from benzylthioethynyl trimethylsilane 3) with
HFꢀNEt3 in dry dichloromethane. Since no obvious conversion
was observed, the solvent was replaced with chloroform and the
mixture heated under reflux, but again without success.
Benzylthioacetylene 4a was then treated with 70 % pyridi-
nium (poly)-hydrogen fluoride in dry dichloromethane at
room temperature in a borosilicate glass flask (Scheme 2).
F
F
F
Base
ϩ
BnSH
BnS
BnS
Me
F
F
1a
2a
CsF
PhS
F
SiPh2Me
O
F
1b
PhS SPh
O
Fluorovinyl thioethers have been prepared by the reaction of
suitable mercaptans with vinylidene fluoride in the presence
of a base,[17] or via cesium fluoride-mediated cross-coupling
of (1-fluorovinyl)dimethylsilane with the corresponding S-aryl
Scheme 1. Literature methods for the synthesis of vinyl fluorides.[17,18]
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

Fluorovinyl Thioethers as Mimetics
73
BnS
TMS
F
F
HF-Py 70 %
3
BnS
BnS
Me
DCM
0ЊC to RT, 4h
BnS
F
glass flask
teflon flask
F
1a
1a
2a (53 % yield)
HF-Py 70 %
BnS
DCM
0ЊC to RT, 4h
Scheme 3. Hydrofluorination of benzyl fluorovinyl thioether 1a (HF-Py:
4a
F
F
HF-pyridine, DCM: dichloromethane, RT: room temperature).
BnS
Me
2a
Table 2. Selectivity of monofluorination with 50 % versus 70 % HF-
pyridine (Py)
Scheme 2. Preliminary hydrofluorination experiments (HF-Py: HF-
pyridine, DCM: dichloromethane, RT: room temperature, TMS:
trimethylsilyl).
F
RS
RS
Me
RS
ϩ
DCM
0ЊC to RT
F
F
4
1
2
Table 1. Screening reagent solutions for the transformation of 4a to
1a/2a, using different titrations of pyridine in the HF-pyridine reagent
Substrate
Conditions
1 : 2A, yieldB [%]
3a, Bn
3a, Bn
3b, Ph
3b, Ph
50 % HF-Py, 4 h
70 % HF-Py, 4 h
100 : 0, 1a 50
0 : 100, 2a 48
70 : 30, 1b 30
0 : 100, 2b 51
97 : 3, 1c 35
0 : 100, 2c 42
91 : 9, 1d 55
0 : 100, 2d 50
F
BnS
Me
BnS
BnS
ϩ
50 % HF-Py, 10 min
70 % HF-Py, 10 min
50 % HF-Py, 4 h
70 % HF-Py, 4 h
50 % HF-Py, 4 h
70 % HF-Py, 4 h
DCM
0ЊC to RT, 4h
F
F
4a
1a
2a
3c, Cyclohexyl
3c, Cyclohexyl
3d, 4-Phenylbutyl
3d, 4-Phenylbutyl
Dilution
1a : 2aA
60 %
50 %
40 %
85 : 15
100 : 0
A1 : 2 ratios determined by 1H and 19F NMR spectroscopy.
BIsolated yield (major product). All reactions were carried out in Teflon
flasks.
no reaction
ADetermined by 1H and 19F NMR spectroscopy. All reactions were carried
out in Teflon flasks.
Unexpectedly the mono-fluorinated product benzyl fluorovinyl
thioether 1a was obtained, without any trace of the expected
gem-difluoride 2a. The reaction was then repeated under the
same conditions in a teflon flask, and this time it furnished the
difluoride, benzyl 1,1-difluoroethyl thioether 2a as the sole
product. Thus a selectivity is achieved for the monofluoro 1a
or the difluoro 2a product, depending on the nature of the
reaction vessel that is utilised.
It would appear that the basic borosilicate glass, which is well
known to be susceptible to HF attack, can effectively reduce the
acidity of the HF-pyridine reagent to allow reaction with one
equivalent of HF, but not a second. Thus, it was envisaged that
titrating the 70 % pyridinium (poly)-hydrogen fluoride reagent
with a controlled amount of pyridine would increase basicity
and thus selectivity for the mono-fluorination reaction. Accord-
ingly different titrations of commercial 70 % HF-pyridine (see
Table 1) were prepared. It was most practical to add the 70 %
HF-pyridine reagent to a solution of 4a in dichloromethane at
08C and a measured amount of pyridine. Titrations to 60 % HF in
pyridine showed a significant improvement in the reaction
selectivity, with 84 % conversion into the monofluorinated
product 1a. Further titration to 50 % HF in pyridine resulted in
complete selectivity towards the monofluorination reaction.
Titration below 40 % HF in pyridine was ineffective, with no
reaction taking place.
The method was then applied to several aliphatic and
aromatic thioacetylene substrates and the results are sum-
marised in Table 2.
Benzylthioacetylene 4a was converted into the desired
fluorovinyl thioether 1a in 50 % yield. Also, the corresponding
difluoride 2a was prepared in 48 % yield using 70 % HF-
pyridine. Phenylthioacetylene[21] 4b (prepared from phe-
nylthioethynyl trimethylsilane 5) proved to be a particularly
reactive substrate under our reaction conditions; the reaction
was complete in 10 min, and furnished a 70 : 30 mixture of both
the mono- and di-fluorinated compounds 1b and 2b. Lowering
the temperature and increasing the amount of pyridine did not
change the outcome – in fact at less than 50 % HF in pyridine, the
reaction did not progress to completion, furnishing both 1b and
2b but in a lower conversion. As expected, treating 4b with neat
70 % HF-pyridine gave only the difluorinated derivative 2b in a
51 % yield.
Cyclohexylthioacetylene[22] 4c and 4-phenybutylthioacety-
lene 4d were chosen to investigate the reaction on aliphatic
substrates (these compounds were prepared from cyclohexyl-
thioethynyl trimethylsilane 6 and 4-phenylbutylthioethynyl
trimethylsilane 7, respectively). When treated with 50 % HF-
pyridine, both compounds furnished the expected fluorovinyl
thioethers 1c and 1d in 35 % and 55 % yield, respectively.
However, NMR analysis of the immediately formed reaction
mixtures indicated that small amounts of the difluorinated
derivatives 2c and 2d were also present (see Table 2). Shorter
reaction times did not prevent the formation of these species,
and a minimum of 4 h was required for reaction completion.
Treatment of 4c and 4d with 70 % HF-pyridine afforded the
difluorinated compounds 2c and 2d in 42 % and 50 % yields,
respectively.
The observed regioselectivity is consistent with Markovni-
kov hydrohalogenation of alkynes. An experiment was con-
ducted to demonstrate that monofluorinated 1a is an
intermediate in the production of difluorinated 2a. This was
shown to be the case after 1a was treated with 70 % HF-pyridine
in a teflon flask. The reaction resulted in a complete conversion
into 2a as illustrated in Scheme 3.

74
D. Bello, R. A. Cormanich, and D. O’Hagan
O
F
Given the close steric and electronic profiles we became
interested in preparing an acetyl CoA enol mimetic, and selected
compound 8a as an analogue of the enol moiety at the terminus
of a pantothenoyl chain of the acetyl CoA (Scheme 5).
We envisaged that compound 8a could be prepared by
hydrofluorination of the appropriate thioacetylene precursor
12 using our titrated HF-pyridine reagent methodology
(Scheme 6). Thus, compound 12 was prepared by the syn-
thetic sequence shown in Scheme 6. Cystamine hydrochlo-
ride 9 was treated with propionyl chloride in the presence of
pyridine to furnish the bis-amide disulfide 10, which was in
turn reacted with preformed lithium tetramethylsilyl (TMS)-
acetylide at ꢁ788C, giving rise to 11 upon warming to room
temperature. Finally tetrabutylammonium fluoride (TBAF)-
mediated TMS deprotection gave the required terminal
alkyne 12.
R
R
N
H
R
R
H
O
N
F
Me
Me
NH
O
HO
HO
F
O
O
OH
OH
Scheme 4. Already demonstrated stereoelectronic mimetics utilising
fluorine in partially enolised carbonyls in amides[23] and pyrimidines.[24]
With thioacetylene 12 in hand, hydrofluorination with 50 %
HF-pyridine was explored (Table 3). The reaction was carried
out accordingly to our conditions (room temperature, 4 h). This
gave a poor conversion (16 %) into 8a. Moreover, thioester
8b (16 %) and the difluorinated product 4c (3 %) were also
apparent in the product mixture, and the major component was
starting material 12 (65 %). However when the reaction time
was extended to 16 h, the consumption of 12 was complete,
and the reaction afforded 8a (54 % conversion), along with 8b
(36 % conversion) and 8c (10 %). Purification of 8a proved
difficult; after preliminary chromatography, 8b could be sepa-
rated by semi-preparative C18-HPLC, but both 8a and 8c have
very similar polarity, and co-eluted without resolution. For
comparison, 8c was separately prepared and isolated as a single
compound.
In this preliminary report we have demonstrated that the
addition of 1 or 2 equivalents of HF to thioacetylenes can be
controlled by pyridine dilution. For the more complex thioace-
tylene 12, a mixture of products is generated. Product 8a was
prepared as it shares steric and electronic properties with the
terminus of acetyl coenzyme-A in an enol form. This has
stimulated us to explore the chemistry and potential for applica-
tion of this fluorovinyl thioether motif in the design of enzyme
inhibitors.
F
OH
H3C
S
H3C
S
thioester
enol
fluorovinyl
thioether
1.79 Dy
1.47 Dy
Fig. 1. Calculated electrostatic profiles and dipole moments of a thioester
enol and that of a fluorovinyl thioether.[27] Red–green–blue colour scales
used, from ꢁ0.025 atomic units (au) to þ0.050 au.
It is well known that vinyl fluorides can act as an effective
amide bond mimetic in certain instances,[23] and Kool and
Sintim have demonstrated that difluorotoluene is a good
mimetic for thymine in DNA replication,[24] indicating that
the C–F bond can be a surrogate of a conjugated carbonyl
(Scheme 4). In this latter case it appears that the spatial/shape
correlation rather than the polarity of the C–O bond is sufficient
to explain its fidelity in DNA polymerase reactions. In this
general context we can envisage a role for fluorovinyl thioethers
as thioester enol/ate mimetics.
For example coenzyme A (CoA) plays a central role in
intermediary metabolism. Perhaps the most studied derivative
of CoA is acetyl-CoA, an essential intermediate in the tricar-
boxylic acid cycle (TCA cycle) and in key metabolic pathways
more generally.[25] The enzyme citrate synthase catalyses a
condensation between acetyl-CoA and oxaloacetate, to form
citrate, a reaction that proceeds via an enol/enolate intermediate
of acetyl-CoA.[26,27] For example in fatty acid biosynthesis
acetyl-CoA is activated by carboxylation by acetyl-CoA
carboxylase to generate malonyl-CoA when a thioester enol/
enolate reacts with carboxylated biotin in a C–C bond forming
reaction.[28] In that context we can envisage that the fluorovinyl
thioether (RSF¼CH2) offers a potential stereoelectronic mimet-
ic for a thioester enolate. In a preliminary theoretical calculation
at the B3LYP/6–31þG** level, performed on Gaussian-09[29]
we have compared the electrostatic profile of the mimetic with a
thioester enol as shown in Fig. 1. There is a similar geometric
and electrostatic match. Also the dipoles are of similar magni-
tude. Comparison with a full enolate compares a neutral with a
charged species and the negative electrostatic density of the
enolate is much greater (data not shown). However we envisage
that an enzyme bound enolate will be protonated and should
much more approximate an enol in geometry and electrostatic
character when bound into an enzyme active site.
Experimental
General Experimental Procedures
All commercially available reagents were purchased from
Acros, Alfa Aesar, Fisher Scientific, Fluorochem or Sigma-
Aldrich and used without further purification. Reactions were
performed under an atmosphere of argon using standard vacuum
line techniques, unless otherwise stated. All glassware was
flame-dried and allowed to cool down under high vacuum.
Reactions requiring the use of pyridinium (poly)-hydrogen
fluoride were carried out in oven-dried (1608C), Teflon round
bottom flasks. Dry solvents dichloromethane, diethyl ether, and
tetrahydrofuran were obtained from the MBraun SPS-800 Sol-
vent Purification System, by passing the solvent through two
drying columns under an argon atmosphere. Reaction tem-
peratures of ꢁ78 to ꢁ108C were obtained using an isopropyl
alcohol bath together with a LabPlant Refrigerated Immersion
Probe. A temperature of 08C was obtained using an ice/water
bath. Reactions requiring heating or reflux were carried out
using a heating block with a contact thermometer.
Thin-layer chromatography (TLC) was performed using
Merck TLC silica gel 60 F254 glass-backed plates. Compounds

Fluorovinyl Thioethers as Mimetics
75
NH2
N
N
N
Ϫ
HO
N
O
O
Ϫ
P
O
O
O
O
P
O
P
OH
O
H
N
H
N
O
O
Ϫ
O
Ϫ
S
O
O
O
O
NH2
N
Acetyl-CoA
N
N
HO
O
N
Ϫ
Ϫ
O
P
O
H
O
O
O
O
O
OH
O
H
N
H
N
P
P
O
O
Ϫ
O
Ϫ
S
O
O
O
O
Acetyl-CoA enol/ate
F
H
N
S
O
8a
Scheme 5. Acetyl-CoA, a common intermediate in metabolism is often activated through enzyme condensations
by enol/ate formation and then carbonyl condensation. Fluorovinyl thioether 8a presents as a potential coenzyme-A
enol/ate mimetic.
Et
O
Table 3. Synthesis of acetyl-CoA enol mimic 8a
propionyl chloride
pyridine
H2N
H2N
O
O
S
S
HN
2HCl
50 % HF-Py
S
O
S
S
DCM, 0ЊC to RT, 4h
S
N
H
N
H
DCM
R
Et
Et
Et
N
H
0ЊC to RT, 4h
9
10 (25 %)
12
8
Time [h]
4
Compound
Conversion,A yield [%]
16
TMS
Li
F
THF
Ϫ78ЊC to RT, 3h
16
54, 28B
8a
O
O
TBAF
S
S
TMS
Me
Et
N
4
16
36
MeOH/THF
16h
Et
N
H
H
12 (97 %)
11 (60 %)
O
16
8b
8c
Scheme 6. Synthesis of thioacetylene 12 (DCM: dichloromethane,
RT: room temperature, TBAF: tetrabutylammonium flouride, TMS:
trimethylsilyl).
F
4
3
Me
F
16
10
ADetermined by 1H and 19F NMR spectroscopy.
BIsolated yield, 8a contains 10 % of 8c. For comparison, compound 8c has
were visualised by either UV light (254 nm) or by the use of
potassium permanganate stain or molybdenum-based stain.
Reverse-phase semi-preparative HPLC column chromatogra-
phy was performed using a Waters 600E multisolvent HPLC
system coupled to a Waters 2487 dual wavelength absorbance
detector and a Phenomenex Kingsorb C18 250 ꢂ 21.20 mm 5m
column. Retention time values are quoted as Rf.
been also prepared and isolated in pure form.
NMR spectra were acquired on Bruker Avance 300 (1H at
300 MHz, 13C at 75 MHz, 19F at 282 MHz) or Bruker Avance II
400 spectrometer (1H at 400 MHz, 13C at 100 MHz, and 19F at
376 MHz), or Bruker Avance 500 spectrometer (1H at 500 MHz,

76
D. Bello, R. A. Cormanich, and D. O’Hagan
13C at 126 MHz, 19F at 470 MHz). Chemical shifts (d) are
reported in parts per milion (ppm) and are quoted relative to
the residual peak of CDCl3. Coupling constants (J) are given in
Hertz. 13C NMR and 19F NMR spectra were recorded with 1H
decoupling. Signal splitting patterns are described as: s – singlet,
br s – broad singlet, d – doublet, t – triplet, tt – triplet of
triplets, m – multiplet.
Mass spectrometric data were acquired by electron impact
ionisation (EI), electrospray ionisation (ESI), and nano-
electrospray ionisation (NSI) or chemical ionisation (CI), using
Waters Micromass LCT (ESI) or GCT (CI) spectrometers
(University of St Andrews), or a Thermofisher LTQ Orbitrap
XL spectrometer (APCI) (National Mass Spectrometry Service
Centre, Swansea). Values are reported as a ratio of mass to
charge (m/z).
Benzyl 1-Fluorovinyl Sulfane (1a)
Benzyl ethynyl sulfane (4a) (201.0 mg, 1.36 mmol,
1.0 equiv.) was dissolved in dry dichloromethane (10 mL) under
an atmosphere of argon. Pyridine (48 mL, 0.596 mmol, amount
required to attain 50 % dilution of HF-pyridine reagent) and the
mixture was cooled to 08C. Hydrogen fluoride pyridine 70 %
(106 mL, 4.10 mmol, 3.0 equiv.) was added, the cooling bath
removed, and the resulting mixture allowed to warm to room
temperature and stirred for 4 h. The hydrogen fluoride was then
quenched by slowly adding a saturated aqueous solution of
sodium hydrogen carbonate (5 mL). The layers were separated
and the organic layer was washed with brine (5 mL), dried on
magnesium sulfate, and concentrated under reduced pressure to
furnish a yellow oil. Purification by silica gel column chroma-
tography, eluting with hexane, gave the title compound as a
colourless oil (115 mg, 50 % yield). dH (500 MHz, CDCl3) 7.34–
7.24 (m, 5H), 4.91 (dd, JHF 11.8, J 3.1, 1H), 4.65 JHF 44.1, J 3.1,
1H), 3.94 (s, 2H). dF (470 MHz, CDCl3) ꢁ80.86. dC (126 MHz,
CDCl3) 159.4 (d, JCF 298.0), 136.9, 128.8, 128.6, 127.4, 98.8 (d,
JCF 23.5), 36.2; m/z (HRMS APCIþ) 169.0477; C9H10FS
requires [M þ H]þ 169.0482.
Selected Chemical Transformations
4-Phenylbutyl-thioethynyl Trimethylsilane (7)
Trimethylsilyl acetylene (3.5 mL, 24.9 mmol, 1.1 equiv.)
was dissolved in diethyl ether (30 mL) and the resulting mixture
cooled to ꢁ788C. Buthyllithium (1.6 M in hexanes, 15.6 mL,
24.9 mmol, 1.1 equiv.) was slowly added dropwise with stirring,
and the mixture stirred at ꢁ788C for a further 15 min. Molecular
sulfur (797 mg, 24.9 mmol, 1.1 equiv.) was then added portion-
wise at ꢁ788C, and the resulting mixture allowed to warm to
room temperature and stirred for a further hour, upon which
time the sulfur completely dissolved to yield an orange colour.
The mixture was then re-cooled to 08C and a solution of
4-phenylbutyl bromide (4.83 g, 22.7 mmol, 1.0 equiv.) in dry
diethyl ether (10 mL) was added dropwise, the resulting mixture
allowed to warm to room temperature, and then stirred for 16 h.
The mixture was then washed with a saturated aqueous
solution of sodium hydrogen carbonate (2 ꢂ 10 mL), brine
(10 mL), dried over magnesium sulfate, filtered, and concen-
trated under reduced pressure. The material obtained was puri-
fied by silica gel flash column chromatography, eluting with
hexane, to furnish the title compound as a colourless oil (5.3 g,
90 % yield). dH (500 MHz, CDCl3) 7.30–7.27 (m, 2H), 7.20–
7.18 (m, 3H), 2.74 (t, J 6.7, 2H), 2.65 (t, J 7.1, 2H), 1.79–1.75
(m, 4H), 0.16 (s, 9H). dC (126 MHz, CDCl3) 142.0, 128.4, 125.9,
100.5, 94.8, 68.0, 35.4, 30.0, 28.9, 25.7, 0.1; m/z (HRMS NSIþ)
263.1286; C15H23SSi requires [M þ H]þ 263.1284.
Benzyl (1,1-Difluoroethyl) Sulfane (2a)
Benzyl ethynyl sulfane (4a) (800.0 mg, 5.4 mmol, 1.0 equiv.)
was dissolved in dry dichloromethane (25 mL) under an atmo-
sphere of argon, and the mixture was cooled to 08C. Hydrogen
fluoride pyridine 70 % (560 mL, 21.6 mmol, 4.0 equiv.) was
added, the cooling bath removed and the resulting mixture
allowed to warm up to room temperature and stirred for 4 h.
The hydrogen fluoride was then quenched by slowly adding a
saturated aqueous solution of sodium hydrogen carbonate
(20 mL). The layers were separated and the organic layer was
washed with brine (20 mL), dried on magnesium sulfate and
concentrated under reduced pressure to furnish a yellow oil.
Purification by silica gel column chromatography, eluting with
hexane, gave the title compound as a colourless oil (488 mg,
48 % yield). Compound 2a was also synthesised from benzyl
1-fluorovinyl sulfane 1a in the following manner: compound 1a
(62.5 mg, 0.37 mmol, 1.0 equiv.) was dissolved in dry dichloro-
methane (3 mL) under an atmosphere of argon. The mixture
was cooled to 08C and hydrogen fluoride pyridine 70 % (30 mL,
1.1 mmol, 3.0 equiv.) was added, the cooling bath removed and
the resulting mixture stirred at room temperature for 4 h. The
mixture was diluted with dichloromethane (5 mL) and the
hydrogen fluoride was quenched by slowly adding a saturated
aqueous solution of sodium hydrogen carbonate (5 mL). The
layers were separated and the organic layer was washed with
brine (10 mL), dried on magnesium sulfate and concentrated
under reduced pressure to furnish a clear oil. Purification by
silica gel column chromatography, eluting with hexane,
afforded compound 2a as a clear oil (37 mg, 53 % yield). dH
(500 MHz, CDCl3) 7.38–7.28 (m, 5H), 4.11 (s, 2H), 1.94 (t, JHF
16.7, 3H). dF (470 MHz, CDCl3) ꢁ67.26. dC (126 MHz, CDCl3)
136.8, 129.1, 129.0 (7, JCF 290.3) 128.8, 127.5, 32.7 (t, JCF 3.6),
26.4 (t, JCF 25.8) m/z (HRMS APCIþ) 187.0385; C9H9F2S
[M ꢁ H]þ requires 187.0388.
4-Phenylbutyl Ethynyl Sulfane (4d)
4-Phenylbutyl-thioethynyl trimethylsilane
7
(500 mg,
1.9 mmol, 1.0 equiv.) was dissolved in a 3 : 1 mixture of tetra-
hydrofuran and methanol (5 mL), and tetrabutylammonium
fluoride trihydrate (48.0 mg, 0.152 mmol, 0.08 equiv.) was
added in one portion. The resulting mixture was stirred at room
temperature for 16 h. The mixture was then concentrated under
reduced pressure, the residue taken up in dichloromethane
(10 mL) and the resulting solution washed with brine
(3 ꢂ 5 mL), dried over magnesium sulfate, filtered and concen-
trated under reduced pressure, to furnish a yellow oil. Purifica-
tion by silica gel column chromatography, eluting with hexane,
afforded the title compound as a colourless oil (298 mg, 82 %
yield). dH (500 MHz, CDCl3) 7.31–7.28 (m, 2H), 7.22–7.19 (m,
3H), 2.76 (t, J 6.9, 2H), 2.757 (s, 1H), 2.66 (t, J 7.2, 2H), 1.85–
1.73 (m, 4H). dC (126 MHz, CDCl3) 142.0, 128.5, 128.4, 125.9,
82.0, 74.6, 35.4, 34.9, 29.9, 28.8. m/z (HRMS APCIþ) 191.0888;
C12H15S [M þ H]þ requires 191.0889.
Phenyl 1-Fluorovinyl Sulfane (1b) and Phenyl
(1,1-Difluoroethyl) Sulfane (2b)
Phenyl ethynyl sulfane (4b) (130.0 mg, 0.97 mmol,
1.0 equiv.) was dissolved in dry dichloromethane (5 mL) under
an atmosphere of argon. Pyridine (44 mL, 0.546 mmol, amount

Fluorovinyl Thioethers as Mimetics
77
required to attain 50 % dilution of HF-pyridine reagent) and the
mixture was cooled to 08C. Hydrogen fluoride pyridine 70 %
(100 mL, 3.9 mmol, 4.0 equiv.) was added, the cooling bath
removed, and the resulting mixture stirred at room temperature
for 10 min. The hydrogen fluoride was then quenched by slowly
adding a saturated aqueous solution of sodium hydrogen car-
bonate (5 mL). The layers were separated and the organic layer
was washed with brine (5 mL), dried on magnesium sulfate, and
carefully concentrated under reduced pressure (both products 1b
and 2b are very volatile) to furnish a yellow oil. Purification by
silica gel column chromatography, eluting with hexane, furn-
ished monofluorinated compound 1b as a colourless oil (45 mg,
30 % yield), and the difluorinated product 2b as a colourless oil
(23 mg, 14 % yield). Compound 1b was also synthesised by the
following method: phenyl ethynyl sulfane (4b) (120.0 mg,
0.89 mmol, 1.0 equiv.) was dissolved in dry dichloromethane
(4 mL) under an atmosphere of argon, and the mixture was
cooled to 08C. Hydrogen fluoride pyridine 70 % (93 mL,
3.6 mmol, 4.0 equiv.) was added, the cooling bath removed
and the resulting mixture stirred at room temperature for
20 min. The hydrogen fluoride was then quenched by slowly
adding a saturated aqueous solution of sodium hydrogen car-
bonate (5 mL). The layers were separated and the organic layer
was washed with brine (5 mL), dried on magnesium sulfate, and
carefully concentrated under reduced pressure (2b is highly
volatile) to furnish a yellow oil. Purification by silica gel column
chromatography, eluting with hexane, gave the title compound
as a colourless oil (79 mg, 52 % yield).
Cyclohexyl (1,1-Difluoroethyl) Sulfane (2c)
Cyclohexyl ethynyl sulfane (4c) (420.0 mg, 3.0 mmol,
1.0 equiv.) was dissolved in dry dichloromethane (15 mL) under
an atmosphere of argon, and the resulting mixture was cooled
to 08C. Hydrogen fluoride pyridine 70 % (234 mL, 9.0 mmol,
3.0 equiv.) was added, the cooling bath removed, and the
resulting mixture stirred at room temperature for 4 h. The
hydrogen fluoride was then quenched by slowly adding a
saturated aqueous solution of sodium hydrogen carbonate
(5 mL). The layers were separated and the organic layer was
washed with brine (10 mL), dried on magnesium sulfate, and
concentrated under reduced pressure to furnish a yellow oil.
Purification by silica gel column chromatography, eluting with
hexane, gave the title compound as a colourless oil (227 mg,
42 % yield). dH (500 MHz, CDCl3) 3.33–3.21 (m, 1H), 2.08–
1.98 (m, 2H), 1.90 (t, JHF 16.7, 3H), 1.78–1.67 (m, 2H), 1.63–
1.55 (m, 1H), 1.49–1.33 (m, 4H), 1.31–1.20 (m, 1H). dF
(470 MHz, CDCl3) ꢁ65.55. dC (126 MHz, CDCl3) 129.9 (t,
JCF 273.1), 42.1, 34.7, 27.0 (t, JCF 26.3), 26.1, 25.6. m/z (HRMS
CIþ) 181.0858; C8H15F2S [M þ H]þ requires 181.0863.
4-Phenylbutyl 1-Fluorovinyl Sulfane (1d)
4-Phenylbutyl ethynyl sulfane (4d) (460.0 mg, 2.4 mmol,
1.0 equiv.) was dissolved in dry dichloromethane (15 mL) under
an atmosphere of argon. Pyridine was added (85 mL, 1.05 mmol,
amount required to attain 50 % dilution of HF-pyridine reagent)
and the mixture was cooled to 08C. Hydrogen fluoride pyridine
70 % (188.3 mL, 7.2 mmol, 3.0 equiv.) was added, the cooling
bath removed and the resulting mixture stirred at room temper-
ature for 3 h. The hydrogen fluoride was then quenched by
slowly adding a saturated aqueous solution of sodium hydrogen
carbonate (5 mL). The layers were separated and the organic
layer was washed with brine (10 mL), dried on magnesium
sulfate, and concentrated under reduced pressure to furnish a
clear oil. Purification by silica gel column chromatography,
eluting with hexane, furnished the title compound 1d as a
colourless oil (280 mg, 55 % yield). dH (500 MHz, CDCl3)
7.31–7.26 (m, 2H), 7.22–7.15 (m, 3H), 4.93 (dd, JHF 11.9, 3.0,
1H), 4.72 (dd, JHF 44.4, 3.0, 1H), 2.76 (t, J 6.8, 2H), 2.64 (t, J 7.2,
2H), 1.79–1.64 (m, 4H). dF (470 MHz, CDCl3) ꢁ81.61. dC
(126 MHz, CDCl3) 160.23 (d, JCF 297.2), 142.1, 128.5, 128.4,
125.9, 97.61 (d, JCF 23.9), 35.4, 31.6, 30.3, 29.0. m/z (HRMS
CIþ) 211.0946; C12H16FS [M þ H]þ requires 211.0957.
Compound 1b: dH (500 MHz, CDCl3) 7.48–7.43 (m, 2H),
7.37–7.32 (m, 2H), 7.32–7.28 (m, 1H), 5.12 (dd, JHF 10.4, J 2.9,
1H), 4.97 (dd, JHF 42.4, J 2.9, 1H). dF (470 MHz, CDCl3)
ꢁ79.78. dC (126 MHz, CDCl3) 158.9 (d, JCF 301.1), 131.2,
130.8, 129.5, 128.0, 100.9 (d, JCF 23.3). m/z (HRMS APCIþ)
155.0325; C8H8FS [M þ H]þ requires 155.0322.
Compound 2b: dH (500 MHz, CDCl3) 7.62–7.60 (m, 2H),
7.44–7.46 (m, 3H), 1.92 (t, JHF 16.6, 3H). dF (470 MHz, CDCl3)
ꢁ66.55. dC (126 MHz, CDCl3) 136.2, 129.9, 129.2, 128.4 (t, JCF
275.4), 127.6, 26.3 (t, JCF 26.4). m/z (HRMS EIþ) 174.0311;
C8H8F2S [M]þ requires 174.0309.
Cyclohexyl 1-Fluorovinyl Sulfane (1c)
Cyclohexyl ethynyl sulfane (4c) (420.0 mg, 3.0 mmol,
1.0 equiv.) was dissolved in dry dichloromethane (15 mL) under
an atmosphere of argon. Pyridine was added (105 mL, 1.3 mmol,
amount required to attain 50 % dilution of HF-pyridine reagent)
and the mixture was cooled to 08C. Hydrogen fluoride pyridine
70 % (234 mL, 9.0 mmol, 3.0 equiv.) was added, the cooling bath
removed and the resulting mixture stirred at room temperature
for 3 h. The hydrogen fluoride was then quenched by slowly
adding a saturated aqueous solution of sodium hydrogen car-
bonate (5 mL). The layers were separated and the organic layer
was washed with brine (10 mL), dried on magnesium sulfate,
and concentrated under reduced pressure to furnish a yellow oil.
Purification by silica gel column chromatography, eluting with
hexane, furnished the title compound 1c as a colourless oil
(168 mg, 35 % yield). dH (500 MHz, CDCl3) 5.00 (dd, JHF 10.9,
J 2.6, 1H), 4.79 (dd, JHF 43.5, J 2.6, 1H), 3.11–3.02 (m, 1H),
2.04–1.96 (m, 2H), 1.82–1.73 (m, 2H), 1.65–1.58 (m, 1H), 1.45–
1.20 (m, 5H). dF (470 MHz, CDCl3) ꢁ76.25. dC (126 MHz,
CDCl3) 159.9 (d, JCF 298.8), 100.1 (d, JCF 25.4), 44.6, 33.2,
26.0, 25.7. m/z (HRMS APCIþ) 161.0794; C8H14FS [M þ H]þ
requires 161.0795.
4-Phenylbutyl (1,1-Difluoroethyl) Sulfane (2d)
4-Phenylbutyl ethynyl sulfane (4d) (74.0 mg, 0.4 mmol,
1.0 equiv.) was dissolved in dry dichloromethane (3 mL) under
an atmosphere of argon, and the resulting mixture was cooled
to 08C. Hydrogen fluoride pyridine 70 % (40 mL, 1.6 mmol,
4.0 equiv.) was added, the cooling bath removed, and
the resulting mixture stirred at room temperature for 3 h. The
mixture was diluted with dichloromethane (3 mL) and the
hydrogen fluoride quenched by slowly adding a saturated
aqueous solution of sodium hydrogen carbonate (1 mL). The
layers were separated and the organic layer was washed with
brine (5 mL), dried on magnesium sulfate, and concentrated
under reduced pressure to furnish a yellow oil. Purification by
silica gel column chromatography, eluting with hexane, gave the
title compound as a colourless oil (45 mg, 50 % yield). dH
(500 MHz, CDCl3) 7.31–7.26 (m, 2H), 7.22–7.16 (m, 3H),
2.86 (t, J 7.0, 2H), 2.64 (t, J 7.1, 2H), 1.91 (t, JHF 16.7, 3H),
1.78–1.64 (m, 4H). dF (470 MHz, CDCl3) ꢁ67.42. dC

78
D. Bello, R. A. Cormanich, and D. O’Hagan
(126 MHz, CDCl3) 142.1, 129.4 (t, JCF 273.2 Hz), 128.4, 128.3,
125.8, 35.4, 30.5, 29.5, 28.0 (t, JCF 3.1), 26.5 (t, JCF 26.1 Hz). m/z
(HRMS APCIþ) 247.0959; C12H17F2SO [M þ OH]þ requires
247.0963.
furnish a yellow oil. Purification by silica gel column chromato-
graphy, eluting with 1/99 methanol/dichloromethane allowed
to remove most of the impurities. A further purification by
semi-preparative HPLC (isocratic elution with 50/50 water/
acetonitrile, 10 mL minꢁ1 flow) furnished the title compound
8a, along with 10 % of compound 8c which co-eluted as a single
peak with Rf 9.53 min (obtained 30 mg, 28 % yield). dH
(500 MHz, CDCl3) 5.83 (s, 1H), 4.99 (dd, JHF 11.8, 3.1, 1H),
4.83 (dd, JHF 44.2, 3.2, 1H), 3.52 (q, J 6.2, 1H), 2.99 (t, J 6.4,
0.2H, compound 8c), 2.90 (t, J 6.3, 2H), 2.22 (q, J 7.6, 2H), 1.93
(t, JHF 16.8, 0.3H), 1.16 (t, J 7.6 Hz, 3H). dF (470 MHz, CDCl3)
ꢁ66.66 (compound 8c), ꢁ80.88. dC (126 MHz, CDCl3) 174.1,
159.2 (d, JCF 297.5), 98.7 (d, JCF 23.4), 39.5 (compound 8c),
39.0, 37.1, 29.7, 28.5 (compound 8c), 26.5 (t, JCF 26.3, com-
pound 8c), 9.8. m/z (HRMS NSIþ) 178.0694. C7H13FNOS
[M þ H]þ requires 178.0696.
N-(2-Trimethylsilylethynyl)thioethyl Propionamide (11)
Trimethylsilyl acetylene (828 mL, 5.86 mmol, 3.1 equiv.)
was dissolved in dry diethyl ether (20 mL) under an atmosphere
of argon. The mixture was cooled to ꢁ788C and butyllithium
(1.6 M in hexanes, 3.66 mL, 5.86 mmol, 3.1 equiv.) was added
dropwise. The resulting mixture was stirred at ꢁ788C for
30 min, and then it was cannulated onto a vigorously stirred
mixture of N,N0-(disulfanediylbis(ethane-2,1-diyl))dipropiona-
mide (10) (500 mg, 1.89 mmol, 1.0 equiv.) in dry tetrahydrofu-
ran (30 mL) maintained at ꢁ788C and under an atmosphere of
argon. The resulting mixture was then allowed to warm to room
temperature and stirred for 3 h. A saturated aqueous solution of
sodium hydrogen carbonate was added, the layers separated, and
the aqueous layer extracted with ethyl acetate (2 ꢂ 10 mL). The
combined organic layers were washed with brine (15 mL), dried
onto magnesium sulfate, and concentrated under reduced pres-
sure. The resulting material was purified by silica gel column
chromatography, eluting with 1/99 methanol/dichloromethane,
to afford the title compound as a clear oil (260 mg, 60 % yield).
dH (500 MHz, CDCl3) 5.94 (s, 1H), 3.63 (q, J 5.9, 2H), 2.85 (t, J
5.8 2H), 2.23 (q, J 7.6, 2H), 1.17 (t, J 7.6, 3H), 0.18 (s, 9H). dC
(126 MHz, CDCl3) 174.1, 101.2, 93.3, 38.4, 35.2, 29.6, 9.8,
0.02. m/z (HRMS ESIþ) 252.0847; C10H19ONNaSSi [M þ Na]þ
requires 252.0852.
N-(2-((1,1-Difluoroethyl)thio)ethyl)propionamide (8c)
N-(2-(Ethynylthio)ethyl)propionamide
(12)
(280 mg,
1.78 mmol, 1.0 equiv.) was dissolved in dry dichloromethane
(12 mL) under an atmosphere of argon and the mixture was
cooled to 08C. Hydrogen fluoride pyridine 70 % (185 mL,
7.12 mmol, 4.0 equiv.) was added, the cooling bath removed,
and the resulting mixture stirred at room temperature for 4 h. The
hydrogen fluoride was then quenched by slowly adding a
saturated aqueous solution of sodium hydrogen carbonate
(10 mL). The layers were separated and the organic layer was
washed with brine (10 mL), dried on magnesium sulfate, and
concentrated under reduced pressure to furnish a colourless
oil. Purification by silica gel column chromatography, eluting
with 1/99 methanol/dichloromethane, removed most of the
impurities, and the obtained material was further purified by
semi-preparative HPLC (isocratic elution with 50/50 water/
acetonitrile, 10 mL minꢁ1 flow) to furnish the title compound
as a colourless oil (Rt 10.1 min, 105 mg, 30 % yield). dH
(500 MHz, CDCl3) 5.87 (s, 1H), 3.52 (q, J 6.3, 2H), 2.98 (t,
J 6.4, 2H), 2.22 (q, J 7.6, 2H), 1.92 (t, J 16.8, 3H), 1.15 (t, J 7.6,
3H). dF (470 MHz, CDCl3) ꢁ66.18. dC (126 MHz, CDCl3)
174.0, 129.4 (t, JCF 276.9), 39.5, 29.9, 28.6, 26.6 (t, JCF 26.4),
9.9. m/z (HRMS APCIþ) 198.0769. C7H14F2NOS [M þ H]þ
requires 198.0764.
N-(2-(Ethynylthio)ethyl)propionamide (12)
N-(2-Trimethylsilylethynyl)thioethyl propionamide 11
(1.5 g, 6.5 mmol, 1.0 equiv.) was dissolved in a 3 : 1 mixture of
tetrahydrofuran and methanol (15 mL), and tetrabutylammo-
nium fluoride trihydrate (50 mg, 0.158 mmol, 0.025 equiv.) was
added in one portion. The resulting mixture was stirred at room
temperature for 16 h. The mixture was then concentrated under
reduced pressure, the residue taken up in dichloromethane
(10 mL), and the resulting solution washed with brine
(3 ꢂ 5 mL), dried over magnesium sulfate, filtered, and concen-
trated under reduced pressure, to furnish the desired pure
compound as a colourless oil (1.0 g, 97 % yield). dH
(500 MHz, CDCl3) 6.16 (s, 1H), 3.63 (q, J 6.0, 2H), 2.87 (t, J
6.1, 2H), 2.78 (s, 1H), 2.24 (q, J 7.6, 2H), 1.16 (t, J 7.6, 3H). dC
(126 MHz, CDCl3) 174.34, 82.46, 73.40, 38.42, 29.40, 9.74. m/z
(HRMS APCIþ) 180.0452. C7H11ONNaSS [M þ Na]þ requires
180.0459.
Supplementary Material
The detailed procedures for the synthesis of compounds 4a, 4b,
4c, 3, 5, 6, 10, 11, and 12, as well as the 1H, 19F, and 13C NMR
spectra for all compounds, are available on the Journal’s
website.
Acknowledgements
N-(2-((1-Fluorovinyl)thio)ethyl)propionamide (8a)
The authors thank the EPSRC National Mass Spectrometry Service Centre
(Swansea) and EPSRC for a grant (EP/L017911/1).
N-(2-(Ethynylthio)ethyl)propionamide
(12)
(247 mg,
0.6 mmol, 1.0 equiv.) was dissolved in dry dichloromethane
(4 mL) under an atmosphere of argon. Pyridine was added
(21 mL, 0.43 mmol, amount required to attain 50 % dilution of
HF-pyridine reagent) and the mixture was cooled to 08C.
Hydrogen fluoride pyridine 70 % (47 mL, 1.8 mmol, 3.0 equiv.)
was added, the cooling bath removed, and the resulting mixture
stirred at room temperature for 16 h. The mixture was diluted
with dichloromethane (10 mL) and the hydrogen fluoride was
then quenched by slowly adding a saturated aqueous solution of
sodium hydrogen carbonate (5 mL). The layers were separated
and the organic layer was washed with brine (10 mL), dried on
magnesium sulfate, and concentrated under reduced pressure to
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