Nucleophilic fluorination of alkynyliodonium salts by alkali metal fluorides: Access to fluorovinylic compounds

Article abstract of DOI:10.1016/j.tet.2011.03.043

Fluorovinylic compounds were synthesized by a one-pot procedure from the corresponding alkynyliodonium salts and alkali metal fluorides. Different reaction parameters, such as the temperature, the solvent and the reaction time were examined, and interesti

Full text of DOI:10.1016/j.tet.2011.03.043

Tetrahedron 67 (2011) 3434e3439
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Nucleophilic fluorination of alkynyliodonium salts by alkali metal fluorides:
access to fluorovinylic compounds
,
,
,
,
b
, ,
y
Thi-Huu Nguyen a b, Mohamed Abarbri c, Denis Guilloteau a b, Sylvie Mavel a b, Patrick Emond a
*
ˇ
a INSERM U930, CHRU, Hopital Bretonneau, 37000 Tours, France
Universite Franc¸ ois-Rabelais, Inserm U930, CNRS ERL3106, 37200 Tours, France
Universite Franc¸ ois-Rabelais, Laboratoire de Physicochimie des Materiaux et Biomolecules EA 4244, Faculte des Sciences, 37200 Tours, France
b
ꢀ
c
ꢀ
ꢀ
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Fluorovinylic compounds were synthesized by a one-pot procedure from the corresponding alkynylio-
donium salts and alkali metal fluorides. Different reaction parameters, such as the temperature, the
solvent and the reaction time were examined, and interestingly CsF was chosen for regio- and stereo-
selective reactions leading to different alkenyliodonium salts in good yields. Their reduction using NaBH4
provided the corresponding 2-fluorovinylic products quantitatively.
Received 21 January 2011
Received in revised form 15 March 2011
Accepted 16 March 2011
Available online 23 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Alkynyliodonium
Fluorination
Fluorovinyl compounds
Regioselectivity
1. Introduction
or to form carbonecarbon bonds, whereas iodonium salts provide
many by-products due to their very strong electron-withdrawing
Selective methods to introduce a fluorine atom in organic
compounds have found a large interest in organic synthesis, par-
ticularly for the preparation of pharmacologically active com-
pounds. These methods were also required to prepare fluorine-18
(F-18) labelled radiopharmaceuticals for molecular imaging tech-
niques, such as Positron Emission Tomography (PET). The use of
radiofluoride anion limits the preparation of aromatic1 or alkyl2
radiofluorinated tracers. Furthermore, many radiofluorinated
molecules, which contain a C(sp3)eF bond, could be unstable in
vivo leading to a defluorination, reducing the efficacy of the PET
analysis. The objective of this work is to achieve a facile preparation
of fluoroalkenyl moieties with a comparable stability to fluoroaryl
groups, and almost the same steric bulkiness as fluoroalkyl groups,
through nucleophilic substitution using a fluoride anion.
properties.3,4 Iodonium salts or iodine(III) compounds are repre-
sented by the ionic form R2IþXꢀ and classified according to the na-
ture of R, such as alkyliodonium, aryliodonium, alkenyliodonium, or
alkynyliodonium salts. Alkynyliodonium salts5e8 can react with
several nucleophiles as well as with Michael-type derivatives.9 They
can be used as electrophilic acetylene equivalents,6 in coupling
reaction8,10 or to form five-membered carbocycles or heterocycle
ringsviaa 1,5-carbene insertion.6 Recentstudiesshowed that HFand
its derivatives can be added to the triple bond of 1-alkynyl(aryl)
iodonium salts leading to (Z)-2-fluoro-1-alkenyl(aryl)iodonium
salts in good yields.11 However, the reaction between an excess of
alkali metal fluorides (LiF, CsF) and different alkynyliodonium tet-
rafluoroborate salts resulted in the recovery of the starting products
or very low yields of the fluorinated products.9,12
We focused on the fluorination of alkynyliodonium salts as po-
tential precursors to fluoroolefins. Iodo hypervalent compounds,
such as IBX, the DesseMartin periodinane (DMP), PhI(OAc)2, PhIO or
PhI(OH)OTf, are often used as mild and selective oxidizing reagents
In this paper, we report the fluorination of alkynyl(phenyl)
iodonium salts using different fluoride sources, especially alkali
metal fluorides. The optimized conditions were suitable for the
synthesis of different alkenyl(phenyl)iodonium salts in good yield,
which could afford fluoroolefin compounds by subsequent re-
duction. Furthermore, we propose a novel access to fluorovinylic
compounds from 1-alkynyl(phenyl)iodonium salts 1 in a one step
fashion, corresponding to a one-pot nucleophilic addition of a fluo-
ride anion to the triple bond followed by the reduction of the
iodonium function by NaBH4.
* Corresponding author. Tel.: þ33 0247367242; fax: þ33 0247367224; e-mail
address: patrick.emond@univ-tours.fr (P. Emond).
y
ꢀ
ꢀ
Faculte de Pharmacie, Laboratoire de Biophysique Medicale et Pharmaceutique,
31 avenue Monge, 37200 Tours, France.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.043

T.-H. Nguyen et al. / Tetrahedron 67 (2011) 3434e3439
3435
2. Results and discussion
R
F
R
F
H
Strep 1
Strep 2
+ H+
Protic solvent
R
F-
I+PhX-
I+PhX-
4
I+PhX-
nucleophilic
addition
1-Alkynyl(phenyl)iodonium salts used in this study were syn-
thesized using previously described methods with some modifi-
cations due to the instability of some of them.13
To optimize the fluorination of alkynyliodonium using fluoride
anion, and also with default reactant, which could be similar to
radiochemical processes, we decided to examine the influence of
different reaction parameters, such as the fluoride source, the
number of equivalents, the exposure time, the temperature and the
solvent, on the fluorine incorporation.
1
2
Byproducts
Scheme 1.
We concluded that the presence of a proton source was essential
to ensure the incorporation of fluorine, since the fluorination of 1a
using CsF gave similar yields in CH3CN/H2O, CH2Cl2/H2O, MeOH or
CH2Cl2/CH3COOH.
2.1. Choice of the fluoride source and the appropriate solvent
To determinate the influence of the fluoride anion source and the
nature of solvent used for the fluorination of alkynyliodoniums salts,
we examined avariety of fluoride sources (CsF, KF, LiF, nBu4NFand HF)
using the same number of equivalents [2.5 equiv, except for HF
(5 equiv)] in a variety of aprotic or protic solvents, at room tempera-
ture during 2 h (compatible with the F-18 half-life) (Table 1). 1-Hex-
ynyl(phenyl)iodonium tetrafluoroborate 1a was used as a iodonium
salt model for this reaction. The fluoride anion reacted with 1a in
a regio- and stereo-selective fashion, affording the (Z)-2-fluoro-
1-hexenyl(phenyl)iodonium tetrafluoroborate salt 2a as the unique
product.
2.2. Influence of the stoichiometry, the temperature, the
reaction time and concentration
Using CsF as the fluoride source, in conjunction with protic sol-
vents, we elected to optimize the fluorination of 1-hexynyl(phenyl)
iodonium tetrafluoroborate salt 1a by examining the effect of pa-
rameters such as the reaction stoichiometry, its temperature, length
of time and concentration. Salt 1awas reactedwith a limited amount
of CsF [0.5 (to use a default quantity of fluorine source as for radio-
labelling) to 1.2 equiv], in protic solvents, such as H2O, CH3CO2H in
acetonitrile or MeOH, with reaction temperatures ranging between
room temperature (rt) and reflux during a 2 h period (Table 2). The
reaction yield is calculated according to the default reactant (CsF, if
0.5 equiv, or 1a). The conversion of 1a was monitored every
15e30 min, and was reported in Table 2 and in Figs. 1e3.
Table 1
Yields of the fluorination of the 1-hexynyl(phenyl)iodonium tetrafluoroborate salt
1a by fluoride anion in different solvents
C4H9
MF
-
C4H9
I+PhBF4
I+PhBF4
2a
-
solvent, rt, 2h
F
Table 2
1a
Influence of the reaction stoichiometry and temperature over a 2 h period, in dif-
ferent solvent systemsa
Entrya,b Solvent
MF
C4H9
F
CsF (n equiv)
I+PhBF4
CsF I
30 (24)c 36
KF II LiF III nBu4NF IV HF V
-
C4H9
I+PhBF4
-
1
2
3
4
5
6
7
8
9
H2O
CH2Cl2
CH3CN
CH3CN/H2O
CH2Cl2/H2O
18
15
5
22
<5
<5
27
10
18
15
<5
d
9
0
0
0
9
0
9
0
d
Solvent, t°C, Time
11
10
20
13
1a
Entry Conditionsb
2a
31 (25)c 22
9
Time (h)
0.25 0.5
28 (25)c 26
24
< 5
9
1
1.5 2
CH2Cl2/H2O/CH3COCH3 24
17
27
<5
0
MeOH
CH2Cl2/AcOH
DMSO
25
31
0
1
2
3
4
5
6
7
8
CsF 1.2 equiv, H2O (50 equiv), CH3CN, rt
CsF 1.2 equiv, H2O (50 equiv), CH3CN, 40 ꢂ
CsF 1.2 equiv, H2O (50 equiv), CH3CN, 60 ꢂ
5
10 14 17 20
<5
0
C
C
12 24 46 49 43
25 59 56 43 39
31 45 27
CsF 1.2 equiv, H2O (50 equiv), CH3CN, reflux
9
0
The structure of 2a was confirmed by 1H-, 19F and 13C NMR spectroscopy.
The percentage of conversion was calculated by 1H NMR.
Isolated yield.
a
b
c
CsF 0.5 equiv, H2O (50 equiv), CH3CN, 60 ꢂ
C
C
d
d
d
d
84 100 98 94
60 100 74 66
24 28 26 10
58 100 94 86
CsF 0.5 equiv, H2O (2.2 equiv), CH3CN, 60 ꢂ
CsF 0.5 equiv, CH3CO2H (2.2 equiv), CH3CN, 60 ꢂ
CsF 0.5 equiv, MeOH
C
a
The conversion of 1a was calculated from 1H NMR. Yields are calculated from the
As shown in Table 1, CsF and KF showed a higher reactivity
compared to LiF, nBu4NF or HF. Except in aprotic solvents, all other
fluorinations using CsF afforded 2a in reasonable isolated yields
(25%, entries 1, 4 and 5, column I, Table 1). Likewise, KF afforded 2a
in reasonable yields, in protic solvents, such as H2O, MeOH, CH3CN/
H2O and CH2Cl2/H2O (entries 1, 4, 5 and 7, column II, Table 1). LiF
gave a correct conversion of 1a especially in H2O and in a mixture of
CH2Cl2/H2O (entries 1 and 5, column III, Table 1). Thus, the relative
reactivity of these alkali metal fluorides was strongly dependent on
the solvent used, however, their nucleophilic activity towards 1a
followed the following order: CsFꢁKF>LiF. When the nBu4NF was
used, the best results were obtained in water and in a mixture of
CH3CN/H2O (entries 1 and 4, column 4, Table 1). The low yields
obtained with nBu4NF in aprotic solvents could be explained by the
relative instability of the intermediate anion 4 under these condi-
tions (Scheme 1) as suggested in the literature.6 Furthermore, using
a large excess of HF (45e50% in water), none of the desired product
was observed (column V, Table 1).
limiting reagent (CsF or 1a).
b
The volume of CH3CN or MeOH was 4 mL/(mmol of 1a).
2.3. Effect of the temperature and reaction time on the
conversion of (1a)
When reacting 1a with CsF (1.2 equiv) in an CH3CN/H2O mix-
ture, at different temperatures (room temperature, 40 ꢂC, 60 ꢂC and
reflux) (entries 1e4, Table 2), we observed that the fluorination was
strongly dependent on the reaction temperature and length of
time. While the fluorination at room temperature gave only 20% of
2a after 2 h, at 40 ꢂC, the conversion to 2a was doubled after 1 h.
This conversion reached 59% when the reaction was carried out at
60 ꢂC in only 30 min. Refluxing the mixture did not increase the
yield of 2a and the undesired decompositions of iodonium salts
were observed.14e16 These results suggested that the formation of

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T.-H. Nguyen et al. / Tetrahedron 67 (2011) 3434e3439
from 1.2 to2.5 equivthe fluorination of 1a decreased (entry 4, Table 1
100
90
80
70
60
50
40
30
20
10
0
and entry 1, Table 2), maybe due to by-products as previously de-
scribed.7,17 Surprisingly, the use of 0.5 equiv of CsF resulted in
a higher conversion of 1a regardless of the reaction time (entries 4
and 5, Table 2). We found that this optimal condition concerning the
number of fluoride equivalents is different from those optimized for
general chemistry of F-19 (generally an excess of fluoride is sug-
gested). This could be rationalized bythe fact that the use of a limited
quantity of CsF will avoid the occurrence of side-reactions, making
the fluoride addition to the triple bond the predominant reaction,
which is a best for radiolabelling (where the fluoride anion is in
default).
rt
40°C
60°C
reflux
2.5. Solvent and reaction time influence on the reaction
0
0.5
1
Time (h)
1.5
2
As shown in Table 2, the use of a protic solvent increased the
formation of 2a. We subsequently attempted to minimize the
amount of solvent used in the reaction mixture (Fig. 3). The reaction
between 1a and 0.5 equiv of CsF in acetonitrile, in presence of only
2.2 equiv of water, gave the alkenyliodonium salt 2a quantitatively
after 1 h (entry 6, Table 2), while the use of 2.2 equiv of acetic acid
led to a poor fluorination yield (ꢃ28%, entry 7, Table 2). However,
excess of methanol (10 mL/mmol of substrate) gave an excellent
conversion yield of 1a. Thus, the optimal conditions for the fluori-
nation the 1-hexynyl(phenyl)iodonium tetrafluoroborate 1a were:
0.5 equiv of CsF, 60 ꢂC, in CH3CN/H2O for 1 h or 0.5 equiv of CsF, in
MeOH at reflux for 1 h. Finally, for a radiolabelling process to ensure
that the fluoride anion was provided by CsF and not the counter ion
Fig. 1. Influence of the temperature and the reaction time on the fluorination of 1a
using CsF.
100
90
0.5eq
1.2eq
80
70
60
50
40
30
20
10
0
BF4ꢀ, 1-dodecynyl(phenyl)iodonium tetrafluoroborate salt 1d was
refluxed in methanol during 1 h in absence of CsF, and derivative 2d
was not detected by 1H NMR in the crude reaction mixture. We thus
proposed that the BF4ꢀ ion was not involved as a fluorine source in
this fluorination process. Our choice of alkynyliodonium tetra-
fluoroborate salts compare to alkynyliodonium tosylate salts
seemed obvious as they gave higher yields.
0
0.5
1
Time (h)
1.5
2
2.6. Fluorination of different alkynyliodonium salts
Fig. 2. Influence of CsF stoichiometry and the reaction time on the fluorination of 1a.
To extend the scope of the method, we attempted to use the
optimized conditions [CsF 0.5 equiv, H2O (2.2 equiv), CH3CN, 60 ꢂC,
1 h] to fluorinate several salts 1aeg containing aliphatic, alicyclic
and aromatic groups (C4H9, C10H21, cyclohexyl-CH2, phenyl) with
tetrafluoroborate or tosylate counter ion (Table 3). The yields of the
resulting fluorinated substrates 2aeg were good to excellent
(31e87%, Table 3).
100
90
80
70
60
CH3CN/H2O 2.2equiv
Table 3
50
Fluorination of alkynyliodonium salts 1aeg using CsF
CH3CN/AcOH 2.2equiv
40
R
MeOH
CsF (0.5 equiv)
R
I+PhX-
30
20
10
0
F
I+PhX-
2a-g
CH3CN/H2O (2.2 equiv)
60 °C, 1h
1a-g
Entry
Compound
R
X
Yielda (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
C4H9
C4H9
BF4
OTs
BF4
BF4
BF4
BF4
OTs
2a (87)
2b (43)
2c (71)
2d (65)
2e (70)
2f (61)
2g (31)
0
0.5
1
1.5
2
Cyclohexyl-CH2
C10H21
Ph
PhCH2CH2
Ph
Time (h)
Fig. 3. Solvent and reaction time influences on the fluorination of 1a.
1g
2a was generally increased at higher temperatures over a longer
period of time as shown in Fig. 1.
aIsolated yield.
As shown in Table 3, the fluorination of compounds 1aeg
depended on the R group size and the counter ion nature. The
fluorine incorporation was rather successful with a small R group,
as shown with substrate 2a (87%) compared to 31e71% for
2.4. Influence of CsF stoichiometry and the reaction time
As shown in Fig. 2, a higher concentration of CsF did not increase
the reaction yield. Indeed, when the amount of CsF was increased

T.-H. Nguyen et al. / Tetrahedron 67 (2011) 3434e3439
3437
substrates 2cef (entries 1 and 3e7, Table 3). The nature of the
counter ion significantly influenced the fluorination yield of 1. The
tetrafluoroborate salts 2a,cef were obtained in better yields than
their analogue tosylate salts 2b and 2g (61e87% and 31e43%, re-
spectively). These results led us to believe that the optimal condi-
tions previously studied were suitable for several substrates
regardless of their structure.
CsF, KF, LiF and nBu4NF affording (Z)-2-fluoro-1-(phenyl)alkenyl
salts 2. CsF (0.5 equiv) proved to have the highest reactivity towards
alkynyliodonium salts 1.
Finally, the displacement of the alkenyliodonium group using
CsF as fluorine source, with NaBH4 yielded fluorovinyl derivatives
3def, either after isolation of intermediates 2def or directly from
alkynyliodonium salts 1def in a one-pot fashion.
4. Experimental section
2.7. Preparation of fluorovinyl compounds by reduction of
iodonium salts (2)
4.1. General
1H, 13C and 19F NMR spectra were recorded on a 200 or 500 MHz
Bruker spectrometer. Chemical shifts (d) are given in parts per million
To our knowledge several SN2 and coupling reactions allow for
the displacement of the iodonium function with different nucleo-
philes. However, the hydrolysis of the iodonium group has yet to be
described. In our hands, the reduction of the iodonium group using
NaBH4, yielded chemioselectively the fluorovinyl compounds 3cef
from the parent alkenyliodonium salts 2ceg (Table 4). This reaction
probably proceeds by a SN2 substitution. When the reaction be-
tween the salts 2ceg with an excess of NaBH4 (2 equiv) in refluxing
methanol was carried out for 1 h, the conversion to fluorovinyl
3cef was almost quantitative. Furthermore, the nature of the R
group and the counter ion did not seem to alter the formation of the
fluorovinyl compounds, which were obtained in good to excellent
yields (Table 4).
relative to the internal standard tetramethylsilane. IR spectra were
obtained on an Alpha-E FT-IR spectrometer (Bruker) with ATR crystal.
All fluoride reagents (CsF, LiF, KF, nBu4NF, HF) were commercially
available. Alkynyliodonium tosylates 1b and 1g were prepared from
the corresponding terminal alkynes and the PhI(OH)OTs at room
temperature, according to the Koser’s method.18,19 Alkynyliodonium
tetrafluoroborate salts 1a,cef were synthesized from terminal al-
kynes and PhIO at 0 ꢂC or at room temperature as the procedure of
Yoshida et al.20 The spectral data of 1a [n-hexynyl(phenyl)iodonium
tetrafluoroborate],21,22 1b [n-hexynyl(phenyl)iodonium tosylate],23
1c [phenyl(3-cyclohexylprop-1-ynyl)iodonium tetrafluoroborate],24
1d [1-dodecynyl(phenyl)iodonium tetrafluoroborate],20 1e [phenyl
(phenylethynyl)iodonium tetrafluoroborate]25 and 1g [phenyl(phe-
nylethynyl)iodonium tosylate]19 have been previously reported in
the literature. Products were characterized by comparisonwith these
data. All alkynyliodonium salts were stored at ꢀ20 ꢂC while the
phenyl(phenylethynyl)iodonium tetrafluoroborate salt 1e was used
immediately after its synthesis.
Table 4
Formation of fluorovinyl compounds 3cef by reduction of alkenyliodonium salts
2ceg
NaBH4 (2 equiv)
MeOH,reflux, 1h
R
F
R
F
I+PhX-
2c-g
3c-f
4.1.1. Phenyl(4-phenylbut-1-ynyl)iodonium tetrafluoroborate (1f).
Entry
Compound
R
X
Yielda (%)
Yield, 78%; 1H NMR (200 MHz, CDCl3):
d¼2.90e3.02 (m, 4H),
1
2
3
4
5
2c
2d
2e
2f
Cyclohexyl-CH2
C10H21
Ph
PhCH2CH2
Ph
BF4
BF4
BF4
BF4
OTs
3c (51)
3d (86)
3e (61)
3f (87)
3e (67)
7.11e7.33 (m, 7H), 7.51e7.56 (m, 1H), 7.63e7.67 (m, 1H), 7.95 ppm
(d, J¼7.8 Hz, 1H).
2g
4.2. General procedure for the fluorination of the n-hexynyl
(phenyl)iodonium tetrafluoroborate salt (1a) with different
fluoride sources
a Isolated yield.
2.8. Preparation of fluorovinyl compounds in a one-pot
reaction
4.2.1. Fluorination with alkaline fluorides. A mixture of the n-hex-
ynyl(phenyl)iodonium tetrafluoroborate salt 1a (372 mg, 1 mmol,
1 equiv) and an alkaline fluoride salt (CsF, KF or LiF, 2.5 equiv) was
dissolved in the appropriate solvent (H2O; CH2Cl2; CH3CN; CH3CN/
H2O: 3/1; CH2Cl2/H2O: 3/1; CH2Cl2/H2O/CH3COCH3: 2/1/1; MeOH;
CH2Cl2/AcOH: 3/1; DMSO; THF; or CHCl3; 4 mL) and stirred for 2 h,
at room temperature. A solution of NaBF4 (5% in water, 10 mL) was
then added and the mixture was stirred for an additional 15 min.
The resulting mixture was extracted with dichloromethane
(3ꢄ20 mL), and the combined organic layers were dried over
MgSO4 and concentrated under reduce pressure. The conversion of
the (Z)-2-fluorohex-1-enyl(phenyl)iodonium tetrafluoroborate salt
2a was established by 1H NMR of the crude product. The compound
2a was purified by column chromatography on silica gel (CH2Cl2/
MeOH: 90/10).
We succeed in one-pot preparation of fluorovinyl derivatives
3def from the corresponding alkynyliodonium salts: the reaction
of alkynyliodoniums salts 1def with CsF (0.5 equiv) in methanol
followed by the NaBH4 reduction (2 equiv) yielded 3def in 76%, 44%
and 77% yield, respectively (Scheme 2).
R
1. CsF (0.5 equiv), MeOH, reflux, 1h
R
I+PhX-
2. NaBH4 (2 equiv), 1h
F
1d:
1e
R = C10H21, X = BF4
3d
(76%)
: R = Ph, X = BF4
3e (44%)
3f (77%)
1f: R = PhCH2CH2, X = BF4
Scheme 2. Formation of fluorovinyl compounds 3def in one-pot reaction.
4.2.2. Fluorination with nBu4NF or HF solution. To a stirred solution
of the n-hexynyl(phenyl)iodonium tetrafluoroborate salt 1a
(372 mg, 1 mmol, 1 equiv) in the appropriate solvent (4 mL) was
added a solution of nBu4NF (1 M in THF, 2.5 mL, 2.5 equiv) or HF
(48e50% in water, 0.2 mL, 5 equiv). The reaction mixture was stirred
for 2 h at room temperature when a solution of NaBF4 (5% in water,
10 mL) was added. The mixture was further stirred for 15 min and
was extracted by CH2Cl2 (3ꢄ10 mL). The combined organic layers
3. Conclusion
Fluorinated derivatives with a stable C(sp2)eF bond can be
obtained by a nucleophilic fluorination of alkynyliodonium salts.
Optimization of the experimental conditions provided new insights
on this reaction, mainly on the regio- and stereo-selective reaction
between alkynyliodonium salts 1 and fluoride metal salts, such as

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T.-H. Nguyen et al. / Tetrahedron 67 (2011) 3434e3439
were dried over MgSO4 and concentrated under reduce pressure to
give the crude product, which was characterized by 1H NMR.
NMR (200 MHz, CDCl3):
d
¼2.91e2.99 (m, 4H), 6.47 (d, 1JHeF¼37.0 Hz,
1H), 7.13e7.30 (m, 6H), 7.41e7.48 (m, 2H), 7.59e7.66 (m, 1H),
7.88 ppm (d, J¼7.8 Hz, 1H); 13C NMR (50 MHz, CDCl3):
¼31.9, 34.3
d
4.3. General procedure for fluorination of the n-hexynyl
(phenyl)iodonium tetrafluoroborate salt 1a using CsF
(d, J¼23 Hz), 79.0 (d, J¼22 Hz), 111.8, 127.3, 129.1, 129.3, 132.8, 133.1,
135.6, 139.1, 173.2 ppm (d, J¼278 Hz); 19F NMR (470 MHz, CDCl3):
d
¼ꢀ64.8 ppm (dt, 3JFeH(olefin)¼32.9 Hz, 3JFeH¼18.8 Hz,1F); HRMS m/z
A mixture of the n-hexynyl(phenyl)iodonium tetrafluoroborate
salt 1a (372 mg, 1 mmol, 1 equiv) and CsF (0.5e1.2 equiv), in the
appropriate solvent (CH3CN/H2O: 3 mL/1 mL; CH3CN/H2O: 4 mL/
calcd for C16H15FI 353.0197, found 353.0195.
4.4.4. (Z)-(2-Fluoro-2-phenylvinyl)(phenyl)iodonium tosylate (2g).
The title compound was prepared according to the general pro-
cedure from phenyl(phenylethynyl)iodonium tosylate 1g (476 mg,
1 mmol). Purification by chromatography on silica gel led to com-
pound 2g as a white solid (77 mg, 31%). 1H NMR (200 MHz, CDCl3):
40 mL; CH3CN/CH3COOH: 96% 4 mL/135 mL or MeOH: 10 mL) was
stirred at desired temperature for 2 h. Small aliquots from the re-
action solution were collected using a syringe after 15 min, 30 min,
1 h, 1 h 30 min and 2 h, extracted with CH2Cl2 as described above,
and analyzed by 1H NMR.
d
¼2.30 (s, 3H), 7.13 (d, J¼8.0 Hz, 2H), 7.49 (d, J¼8.0 Hz, 2H),
1
7.55e7.80 (m, 7H), 7.96 (d, JHeF¼37.0 Hz, 1H), 8.18 ppm (d,
4.4. General procedure for the preparation of
alkenyliodonium salts (2aeg)
J¼7.4 Hz, 2H); 13C NMR (50 MHz, CDCl3):
¼21.8, 79.0 (d, J¼22 Hz),
d
115.6, 126.5, 126.8, 126.9, 128.6 (d, J¼27 Hz), 129.2, 129.4, 132.0,
132.6, 135.9, 140.2, 142.8, 165.4 ppm (d, J¼260.4 Hz); 19F NMR
Alkynyliodonium salt 1aeg (1 mmol, 1 equiv) and CsF (76 mg,
(470 MHz, CDCl3):
d
¼ꢀ82.4 ppm (d, 3JFeH(olefin)¼35.7 Hz,1F); HRMS
0.5 equiv)weredissolvedinamixtureofacetonitrile(4 mL)andwater
m/z calcd for C14H11FI 324.9884, found 324.9883.
(40 m
L). The reaction solution was stirred at 60 ꢂC for 1 h, cooled at
room temperature and was poured onto a solution of NaBF4 (for
1a,cef) or NaOTs (for 1b,g) (5% inwater,10 mL). The resulting mixture
was stirred for additional 10 min and extracted with CH2Cl2
(3ꢄ10 mL). The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure to give the corresponding flu-
oroalkenyliodonium salts 2aeg, which were purified by column
chromatography on silica gel (CH2Cl2/MeOH: 90/10).
4.5. General procedure for the preparation of fluorovinyl
products (3ceg)
4.5.1. Reduction of isolated alkenyliodonium salts (2aeg) using
NaBH4. To a stirred solution of the fluoroalkenyliodonium salt 2ceg
(1 mmol, 1 equiv) in MeOH (10 mL) at room temperature was added
NaBH4 (76 mg, 2 equiv) in small portions, and the mixture was reflux
for 1 h. After cooling to room temperature, water was added (5 mL),
and the mixture was further stirred 10 min, and extracted with
CH2Cl2 (3ꢄ30 mL). The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure to yield the cor-
responding fluorovinyl compound 3cef. Compounds 3c and 3d were
revealed on TLC using a KMnO4 solution and were purified by pre-
parative TLC (petroleum ether 100%). 1H and 13C NMR of 1-(1-fluo-
rovinyl)benzene 3e matched the literature spectral data.26
1H and 13C NMR spectral data of isolated compounds (Z)-(3-
cyclohexyl-2-fluoroprop-1-enyl)(phenyl)iodonium tetrafluoroborate
2c, (Z)-2-fluoro-dodec-1-enyl(phenyl)iodonium tetrafluoroborate 2d
and (Z)-(2-fluoro-2-phenylvinyl)(phenyl)iodonium tetrafluoroborate
2e were identical to the one described previously in the literature.11,24
4.4.1. (Z)-2-Fluorohex-1-enyl(phenyl)iodoniumtetrafluoroborate (2a).
The title compound was prepared according to the general procedure
from hexynyl(phenyl)iodonium tetrafluoroborate 1a (372 mg,
1 mmol). Compound 2a was obtained as an oil, which crystallized
upon treatment with Et2O as a yellow solid (170 mg, 87%). 1H NMR
4.5.2. (2-Fluoroallyl)cyclohexane (3c). Yield, 51%; 1H NMR (200 MHz,
CDCl3):
d
¼0.74e1.33 (m, 6H), 1.47e1.56 (m, 5H), 2.03e2.16 (dd,
(500 MHz, CDCl3):
d
¼0.89 (t, J¼7.2 Hz, 3H), 1.28e1.35 (m, 2H),
2JHeF¼20.0 Hz, J¼7.0 Hz, 2H), 4.22 (dd, 2JHeF¼50.0 Hz, J¼2.5 Hz, 1H),
2
1.53e1.38 (m, 2,), 2.55e2.61 (m, 2H), 6.54 (d, J¼33.5 Hz, 1H),
4.55 ppm (dd, JHeF¼18.0 Hz, J¼2.5 Hz, 1H); 13C NMR (50 MHz,
7.45e7.48 (m, 2H), 7.61e7.64 (m, 1H), 8.01 ppm (d, J¼8.0 Hz, 2H); 13C
CDCl3):
d¼26.7, 26.9, 30.3, 33.5, 35.4, 41.3 (d, J¼26 Hz), 91.0 (d,
NMR (50 MHz, CDCl3):
d¼14.0, 22.2, 28.0, 32.4 (d, J¼23 Hz), 75.0 (d,
J¼21 Hz), 167.9 ppm (d, J¼255 Hz); 19F NMR (470 MHz, CDCl3):
J¼22 Hz),112.2,132.8,133.2,135.8,174.6 ppm (d, J¼277 Hz); 19F NMR
d
¼ꢀ94.1 ppm (dtd, JFeHtrans(olefin)¼50.3 Hz, JFeH¼19.2 Hz, JFeHcis
3
3
3
3
3
(470 MHz, CDCl3):
d¼ꢀ63.7 ppm (dt, JFeH(olefin)¼31.5 Hz, JFeH
¼
¼18.8 Hz, 1F); IR:
n
¼2921, 2852, 1460, 1012, 795 cmꢀ1; HRMS
(olefin)
18.8 Hz, 1F); HRMS m/z calcd for C12H15FI 305.0197, found 305.0197.
m/z calcd for C9H15F 142.1158, found 142.1158.
4.4.2. (Z)-2-Fluorohex-1-enyl(phenyl)iodonium tosylate (2b). The
title compound was prepared according to the general procedure
from hexynyl(phenyl)iodonium tosylate 1b (456 mg, 1 mmol). Pu-
rification by chromatography on silica gel yielded compound 2b as
4.5.3. 2-Fluoro-dodec-1-ene (3d). Yield, 86%; 1H NMR (200 MHz,
CDCl3):
d
¼0.88 (t, J¼7.1 Hz, 3H), 1.19e1.63 (m, 16H), 2.13e2.28 (m,
2
2H), 4.24 (dd, JHeF¼51.0 Hz, J¼2.5 Hz, 1H), 4.52 ppm (dd,
2JHeF¼18.0 Hz, J¼2.5 Hz, 1H); 13C NMR (50 MHz, CDCl3):
¼14.5,
d
a white solid (102 mg, 43%). 1H NMR (500 MHz, CDCl3):
d
¼0.84 (t,
23.0, 26.3, 26.4, 29.3, 29.7, 29.9, 30.0, 32.2 (d, J¼27 Hz), 32.3, 89.6 (d,
J¼7.2 Hz, 3H), 1.21e1.43 (m, 4H), 2.33 (s, 3H), 2.34e2.48 (m, 2H),
6.50 (d, J¼35.0 Hz, 1H), 7.08 (d, J¼8.0 Hz, 2H), 7.30e7.38 (m, 2H),
7.48e7.58 (m, 3H), 8.00 ppm (d, J¼8.0 Hz, 2H); 13C NMR (50 MHz,
J¼21 Hz), 167.5 ppm (d, J¼256 Hz); 19F NMR (470 MHz, CDCl3):
d
¼ꢀ94.6 ppm (dq, 3JFeHtrans(olefin)¼50.6 Hz, 3JFeH¼3JFeHcis(ole-
¼16.6 Hz,1F); IR:
n
¼2961, 2852,1258,1014, 793 cmꢀ1; HRMS m/z
fin)
CDCl3):
d
¼14.0, 21.9, 22.4, 28.0, 32.4 (d, J¼23 Hz), 77.2 (d, J¼22 Hz),
calcd for C12H23F 186.0845, found 186.0847.
115.2, 126.5, 129.2, 131.9, 132.0, 135.8, 140.3, 142.9, 174.6 ppm (d,
J¼277 Hz); 19F NMR (470 MHz, CDCl3):
d
¼ꢀ67.8 ppm (dt, JFeH(ole-
4.5.4. 1-(1-Fluorovinyl)benzene (3e). The title compound was pre-
pared according to the general procedure described above. The
purification of the crude product by chromatography on silica gel
C-18 (gradient of CH3CN/H2O 1:1 to CH3CN/H2O 1:0) led to 3e in
67% yield.
3
3
¼32.9 Hz, JFeH¼16.9 Hz, 1F); HRMS m/z calcd for C12H15FI
fin)
305.0197, found 305.0198.
4.4.3. (Z)-(2-Fluoro-4-phenylbut-1-enyl)(phenyl)iodoniumtetrafluoro-
borate (2f). The title compound was prepared according to the
general procedure from phenyl(4-phenylbut-1-ynyl)iodonium tet-
rafluoroborate 1f (424 mg, 1 mmol). Purification by chromatography
on silica gel led to compound 2f as a brown solid (134 mg, 61%). 1H
4.5.5. 1-(3-Fluorobut-3-enyl)benzene (3f). Yield, 87%; 1H NMR
(200 MHz, CDCl3):
d
¼2.46e2.62 (m, 2H), 2.48e2.92 (m, 2H), 4.45
(dd, 2JHeF¼50.0 Hz, J¼2.5 Hz, 1H), 4.61 (dd, 2JHeF¼18.0 Hz, J¼2.5 Hz,

T.-H. Nguyen et al. / Tetrahedron 67 (2011) 3434e3439
3439
1H), 7.22e7.33 (m, 3H), 7.47e7.55 ppm (m, 2H); 13C NMR (50 MHz,
Tu, Z.; Efange, S. M.; Xu, J.; Li, S.; Jones, L. A.; Parsons, S. M.; Mach, R. H. J. Med.
Chem. 2009, 52, 1358; (g) LG¼tertiary amine: Haka, M. S.; Kilbourn, M. R.;
Watkins, L. G.; Toorongian, S. A. J. Labelled Compd. Radiopharm. 1989, 27, 823; (h)
LG¼ammonium triflate: Kuhnast, B.; Hinnen, F.; Hamzavi, R.; Boisgard, R.; Ta-
CDCl3):
d
¼32.9, 34.4 (d, J¼27 Hz), 90.4 (d, J¼20 Hz), 126.8, 128.9,
129.1, 141.2, 166.5 ppm (d, J¼255 Hz); 19F NMR (470 MHz, CDCl3):
¼ꢀ95.5 ppm (dq, 3JFeH(olefin)¼49.8 Hz, 3JFeH¼3JFeHcis(olefin)¼17.4 Hz,
ꢀ
vitian, B.; Nielsen, P. E.; Dolle, F. J. Labelled Compd. Radiopharm. 2005, 48, 51; (i)
d
ꢀ
¼2922, 2852,1460, 1258, 1017, 861, 795 cmꢀ1; HRMS m/z
Viel, T.; Kuhnast, B.; Hinnen, F.; Boisgard, R.; Tavitian, B.; Dolle, F. J. Labelled
1F,); IR:
n
Compd. Radiopharm. 2007, 50, 1159; (j) LG¼iodonium: Lee, B. C.; Dence, C. S.;
Zhou, H.; Parent, E. E.; Welch, M. J.; Katzenellenbogen, J. A. Nucl. Med. Biol. 2009,
36, 147.
calcd for C10H11F 150.0845, found 150.0844.
2. Substitution on the aliphatic chain, for reviews see for example: (a) Coenen, H. H.
Fluorine-18 Labeling Methods: Features and Possibilities of Basic Reactions;
Springer: Berlin Heidelberg, 2007, pp 15e50; (b) Kim, D. W.; Ahn, D.-S.; Oh, Y.-H.;
Lee, S.; Kil, H. S.; Oh, S. J.; Lee, S. J.; Kim, J. S.; Ryu, J. S.; Moon, D. H.; Chi, D. Y. J. Am.
4.6. One-pot preparation of fluorovinyl products (3def)
Alkynyliodonium salt (1d, 1e or 1f) (1 mmol, 1 equiv) and CsF
(0.5 equiv) were dissolved in MeOH (10 mL) and the mixture was
refluxed for 1 h. NaBH4 (2 equiv) was then added in small por-
tions, and the solution was further reflux for an additional hour.
The resulting solution was cooled at room temperature and hy-
drolyzed with water and was extracted with CH2Cl2 (3ꢄ30 mL).
The combined organic layers were dried over MgSO4, concen-
trated under reduced pressure to yield the corresponding com-
pound 3def, which were purified by preparative TLC (petroleum
ether 100%).
Chem. Soc. 2006, 128,
16394 others examples; (c) LG¼(COOꢀ)(NH3þ)
CHeCH2eCH2(Me)Sþ Martarello, L.; Schaffrath, C.; Deng, H.; Gee, A. ,D.; Lock-
hart, A.; O’Hagan, D. J. Labelled Compd. Radiopharm. 2003, 46,1181; (d) LG¼OMs or
OBs Zeng, F.; Jarkas, N.; Stehouwer, J. S.; Voll, R. J.; Owens, M. J.; Kilts, C. D.;
Nemeroff, C. B.; Goodman, M. M. Bioorg. Med. Chem. 2008, 16, 783; (e) LG¼sul-
fonate Zhang, M.-R.; Suzuki, K. Curr. Top. Med. Chem. 2007, 7, 1817.
3. (a) Okuyama, T.; Takino, T.; Sueda, T.; Ochiai, M. J. Am. Chem. Soc. 1995, 117,
3360; (b) Hinkle, R. J.; Thomas, D. B. J. Org. Chem. 1997, 62, 7534.
4. Adam, M. J.; Wilbur, D. S. Chem. Soc. Rev. 2005, 34, 153.
5. Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.
6. Zhdankin, V. V.; Stang, P. J. Tetrahedron 1998, 54, 10927.
7. Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523.
8. Sun, A.-M.; Huang, X. Tetrahedron 1999, 55, 13201.
9. Ochiai, M.; Kitagawa, Y.; Toyonari, M.; Uemura, K.; Oshima, K.; Shiro, M. J. Org.
Chem. 1997, 62, 8001.
Acknowledgements
10. Coupling by palladium catalysis: (a) Hinkle, R. J.; Poulter, G. T.; Stang, P. J. J. Am.
Chem. Soc. 1993, 115, 11626 coupling reaction with organocopper: (b) Moriarty,
R. M.; Epa, W. R.; Awasthi, A. K. J. Am. Chem. Soc. 1991, 113, 6315; (c) Kitamura,
T.; Lee, C. H.; Taniguchi, Y.; Fujiwara, Y.; Matsumoto, M.; Sano, Y. J. Am. Chem.
Soc. 1997, 119, 619 coupling reaction with organozirconium: (d) Huang, X.;
Zhong, P. J. Chem. Soc., Perkin Trans. 1 1999, 11, 1543.
This work was supported by INSERM for a post graduate grant.
ꢀ
We thank the “Departement d’analyses Chimiques et S.R.M. biol-
ꢀ
ogique et medicale” (Tours, France) for chemical analyses and
ꢀ
Nathalie Meheux for technical assistance.
11. Yoshida, M.; Hara, S. Org. Lett. 2003, 5, 573.
12. (a) Ochiai, M.; Oshima, K.; Masaki, Y. Chem. Lett. 1994, 23, 871; (b) Ochiai, M.;
Uemura, K.; Oshima, K.; Masaki, Y.; Kunishima, M.; Tani, S. Tetrahedron Lett.
1991, 32, 4753.
13. See Experimental section.
14. Fujita, M.; Sakanishi, Y.; Nishii, M.; Yamataka, H.; Okuyama, T. J. Org. Chem.
2002, 67, 8130.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.03.043. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article. These data include MOL files and InChIKeys
of the most important compounds described in this article.
15. Hinkle, R. J.; Mikowski, A. M. Arkivoc 2003, 6, 201.
16. Okuyama, T.; Fujita, M.; Gronheid, R.; Lodder, G. Tetrahedron Lett. 2000, 41, 5125.
17. Ochiai, M.; Uemura, K.; Masaki, Y. J. Am. Chem. Soc. 1993, 115, 2528.
18. (a) Koser, G. F.; Rebrovic, L.; Wettach, R. H. J. Org. Chem. 1981, 46, 4324; (b)
Margida, A. J.; Koser, G. F. J. Org. Chem. 1984, 49, 4703.
References and notes
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Soc. 1987, 109, 228.
ꢀ
1. Substitution on an aromatic ring, for review see for example: (a) Dolle, F. Curr.
Pharm. Des. 2005, 11, 3221 others examples: (b) Leaving Group (LG)¼Br: Briard,
E.; Zoghbi, S. S.; Simeon, F. G.; Imaizumi, M.; Gourley, J. P.; Shetty, H. U.; Lu, S.;
Fujita, M.; Innis, R. B.; Pike, V. W. J. Med. Chem. 2009, 52, 688; (c) LG¼F: Cacace,
F.; Speranza, M.; Wolf, A. P.; Fowler, J. S. J. Labelled Compd. Radiopharm. 1981, 18,
24. Yoshida, M.; Komata, A.; Hara, S. Tetrahedron 2006, 62, 8636.
€
25. Williamson, B. L.; Stang, P. J.; Arif, A. M. J. Am. Chem. Soc. 1993, 115, 2590.
1721; (d) Langer, O.; Mitterhauser, M.; Wadsak, W.; Brunner, M.; Muller, U.;
€
€
26. Schlosser, M.; Brugger, N.; Schmidt, W.; Amrhein, N. Tetrahedron 2004, 60,
Kletter, K.; Muller, M. J. Labelled Compd. Radiopharm. 2003, 46, 715; (e) LG¼NO2:
7731.
Dissoki, S.; Laky, D.; Mishani, E. J. Labelled Compd. Radiopharm. 2006, 49, 533; (f)