Stereoselective formation of (Z)-2-fluoroalkenoates via Julia-Kocienski reaction of aldehydes with pyrimidinyl-fluorosulfones

Article abstract of DOI:10.1016/j.tet.2014.06.081

The selective synthesis of fluoroalkenoates is reported from a pyrimidinyl fluorosulfone. This sulfone allowed the preparation of Z-fluoroalkenoates with very high stereoselectivity from both aromatic and aliphatic aldehydes. The nature of the heterocycle

Full text of DOI:10.1016/j.tet.2014.06.081

Tetrahedron 70 (2014) 5632e5639
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Stereoselective formation of (Z)-2-fluoroalkenoates via
JuliaeKocienski reaction of aldehydes with pyrimidinyl-
fluorosulfones
a
a
b
a,
*
Florent Larnaud , Emmanuel Pfund , Bruno Linclau , Thierry Lequeux
a
Laboratoire de Chimie Mol ꢀe culaire et Thioorganique, UMR CNRS 6507 & FR3038, ENSICAEN, Universit ꢀe de Caen Basse-Normandie, 6 Boulevard du
Marechal Juin, 14050 Caen, France
b
Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 April 2014
Received in revised form 13 June 2014
Accepted 18 June 2014
Available online 24 June 2014
The selective synthesis of fluoroalkenoates is reported from a pyrimidinyl fluorosulfone. This sulfone
allowed the preparation of Z-fluoroalkenoates with very high stereoselectivity from both aromatic and
aliphatic aldehydes. The nature of the heterocycle on the course of the JuliaeKocienski reaction is
discussed.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Fluoroalkenes
JuliaeKocienski reaction
Fluoroalkenoates
Selective synthesis
1. Introduction
reaction presents some advantages, such as the preparation of both
alkenoate isomers from the same reagent. However, as observed
The introduction of fluorine atoms onto bioactive compounds
from the previous methods, this reaction also has limitations. In-
has been largely applied in the design of analogues of pheromones,
herbicides, or drugs. In this field, fluoroalkenoates are important
deed, the selective preparation of Z or E-fluoroalkenoates is con-
fined to aromatic aldehydes. Despite great efforts in this field,
1
8
building-blocks for the multi-steps synthesis of a large variety of
while the synthesis of alkenoates from aromatic aldehydes and
a large variety of heterocyclic fluorosulfones is selective, the control
of the reaction is problematic with aliphatic aldehydes. Previous
reports involving the synthesis of fluoroalkenoates through the
JuliaeKocienski reaction (Table 1), showed that from benzothia-
zolylsulfonyl acetates and aromatic aldehydes, the E-alkene was
biomolecules.2 Fluoroalkenoates are prepared from aldehydes or
3
ketones through the Wittig and related reactions, Peterson re-
4
5
action, or Durst reaction. For this one-step synthesis performed
from aldehydes the HornereWadswortheEmmons (HWE) reaction
afforded mainly the E-alkenoates, while the Z-alkenoates were
obtained as major products with the Peterson, Durst, and Wittig
reactions. Alternatively, Z-alkenoates can be prepared in two steps
from aldehydes, by isomerization of intermediate E-alkenoates in
the presence of catalytic amount of iodine or bromine, or by ad-
dition of the dianionic form of diethyl 2-fluoro-phosphonoacetic
acid followed by an esterification step. The acylation of an HWE
reagent followed by the reduction of the intermediate phospho-
noketoesters represents another possibility.6
9
mainly obtained when the reaction was mediated by DBU, and the
8
a,b
Z-alkene was produced as major isomer with DBU and MgBr
In contrast, from bis-(CF )phenylsulfonyl acetates, Z-alkenes
were obtained when the reaction was performed under phase-
2
.
3
8
c
transfer condition. However, it is clear that the main limit of
these reagents, as for the phosphorus containing reagents, is the
control of the selectivity from aliphatic aldehydes. From nonanal,
heptanal, and citronellal and the same fluorosulfones, a mixture of
alkenoates is obtained (Table 1). In order to achieve selective for-
mation of Z-alkenoates from both aliphatic and aromatic aldehydes,
we initiated an investigation involving alternative fluorosulfonyl
acetate derivatives in this reaction, with a focus on the role of the
aromatic sulfone on the course of the reaction.
Recently the modified Julia reaction has been introduced as
7
a complementary method for the synthesis of fluoroalkenes. This
*
Corresponding author. Tel.: þ33 (0)231452854; fax: þ33 (0)231452865; e-mail
address: Thierry.Lequeux@ensicaen.fr (T. Lequeux).
http://dx.doi.org/10.1016/j.tet.2014.06.081
0
040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

F. Larnaud et al. / Tetrahedron 70 (2014) 5632e5639
5633
Table 1
Synthesis of fluoroalkenoates from arylsulfones
EtO C
tBuO C
N
F
N
F
Base
SO
SO
S
S
DBU
DBU/MgBr
2
DBU
2 3
K CO TBAB
8
b
92/88b PhCHO (71%)
88/12 Nonanal (87%)
8a
93/78c PhCHO (95%)
43/57 Citronellal (61%)
Z/E RCHO (yield)
24/76 PhCHO (70%)
2
25/75 PhCHO (78%)
8
b
8b
8a
8c
4/76 Nonanal (66%)
17/83 Heptanal (75%)
2
. Results and discussion
The olefination reaction of both aromatic and aliphatic alde-
hydes was realized from these sulfones and the results were
compared to those observed from the corresponding benzothia-
zolylsulfone. For a practical convenience, the study was realized
The modified Julia reaction, originally developed with benzo-
thiazolylsulfones, has been largely applied in total synthesis with
10
8b
other heterocyclic sulfones. It has been already shown by
with NaHMDS as base. The synthesis of fluorinated sulfones
Kocienski,11 Charette, N aꢀ jera, and Zhu, for example, that the
nature of the heteroaryl sulfone modified the course of the reaction.
In an early work, S. Julia suggested that the Smiles rearrangement is
the limiting step, with the formation of the cis-olefin going through
a fast Smiles rearrangement, and the formation of the trans-olefin
12
13
14
3aed, was realized in two steps by alkylation of sulfanyl derivatives
1aed with ethyl bromofluoroacetate in the presence of triethyl-
amine, followed by oxidation of the intermediate sulfide with hy-
drogen peroxide in the presence of catalytic amount of molybdate
8
b
complex (Scheme 2, Method A). Although good yields were ob-
served from benzothiazolyl-, pyridinyl,- and pyrimidinyl-sulfides
2a, 2c, 2d, the oxidation step did not succeed from 5-nitro-benzo-
thiazolyl-sulfides 2b. For these substrates, corresponding sulfone
15
going through a slow Smiles rearrangement (Scheme 1). The
p-
deficient character of the heterocycle appears essential, and the
Smiles rearrangement is possible and faster when the heterocycle
15c
presents a high
p-deficient character.
4
3b was obtained after oxidation of 2b in the presence of NaIO and
17
3
RuCl (Scheme 2, Method B).
Scheme 2. Synthesis of fluorinated heteroaromatic sulfones.
In
a preliminary experiment, the reactivity of the pyr-
idinylsulfone reagents was investigated using our standard exper-
imental conditions previously developed with sulfone 3a
Scheme 1. Mechanism of the JuliaeKocienski reaction.
ꢁ
ꢁ
8b
(
NaHMDS, THF, ꢀ78 C to 20 C).
While the reaction with the benzothiazolyl group (3a) afforded
exclusively alkenes 4, with 3c the reaction did not reach completion
In order to increase the rate of the Smiles rearrangement, we
explored the reaction with sulfones containing more
heterocycles compared to benzothiazole. We should expect that
with a pronounced -deficient character of the heterocycle, the
p-deficient
ꢁ
ꢁ
after 4hstirringfromꢀ78 C to 20 C (Scheme 3): a mixture of starting
sulfone 3c, corresponding fluoroalkenes 4, and diastereoisomeric
hydroxysulfones 5 was obtained in a 3:4:3 ratio. NMR analysis did not
allow unambiguous assignment of the diastereomers 5. Clearly, the
formation of hydroxysulfones 5 indicated that the pyridinyl hetero-
cycle is not electron deficient enough to ensure completion of the
p
slow Smiles rearrangement will accelerate, possibly to the extent
that the relative rate of the formation of the alcoholates (I) and (II)
will reflect the stereoselectivity of the reaction. Given the reaction
15c
to the anti-alcoholate is thought to be favorable, this could then
lead to an increase in Z-fluoroalkenoate selectivity.
15c
Smiles rearrangement, which confirms a report by S. Julia.
Hence, more
were selected (based on the carbon NMR chemical shift of the C
carbon atom of the heterocycle), such as 5-(NO )-benzothiazolyl
and pyrimidinyl heterocycles, and a less -deficient, such as pyr-
p-deficient heterocycles than benzothiazolyl ring
Then, the stereoselectivity of the olefination reaction was in-
vestigated using the more reactive benzothiazolylsulfone 3b and
pyrimidinylsulfone 3d, and compared to sulfone 3a, with aromatic
aldehydes (Table 2). In all cases, alkenes 4e8 were exclusively ob-
tained, and isolated in good yields (Table 2). From 4-
bromobenzaldehyde and sulfone 3a, the corresponding fluo-
roalkenes 4 were obtained in 72% yield in a Z/E ratio of 85:15.
Gratifyingly, it was indeed observed that the selectivity depends on
the nature of the heterocycle, with an increase up to 98:2 from
sulfone 3b, and the virtually exclusive formation of Z-alkene 4 from
pyrimidinylsulfone 3d. This observation was general, and from 2,5-
dibromobenzaldehyde, thiophenecarboxaldehyde, and furfural, the
corresponding fluoroalkenoates 6, 7, 8 were obtained in good yields
2
2
p
16
idinyl heterocycle (Fig. 1).
Fig. 1. Carbon NMR chemical shift.

5634
F. Larnaud et al. / Tetrahedron 70 (2014) 5632e5639
Table 3
Modified Julia reaction with aliphatic aldehydes
Sulfone
Ar¼BT 3a
Yielda (%) Z/Eb
Ar¼NO
2
-BT 3b
Ar¼Pym 3d
Yielda (%) Z/Eb
Fluoroalkene
Yielda (%) Z/Eb
CO
2
Et
Et
C
6
H
13
17
F
F
50
81
66
49
53:47 60
74:26 84
100:0
99:1
96:4
97:3
CO
2
C
8
H
46:54 92
43:57 82
84:16 73
85:15 79
2
CO Et
8
F
Scheme 3. Synthesis of fluoroalkenoates from pyridinylsulfone.
Table 2
Modified Julia reaction with aromatic aldehydes
CO Et
F
55:45
69:31
d
d
d
d
81
52
Sulfone
Ar¼BT 3a
Yielda (%) Z/Eb
Ar¼NO
2
-BT 3b
Ar¼Pym 3d
Yielda (%) Z/Eb
Fluoroalkene
Yielda (%) Z/Eb
2
CO Et
F
F
40
97:3
99:1
2
CO R
7
2
85:15 74
92:8
96:4
72
83
100:0
Br
Br
2
CO Et
F
F
62
57
71:29 60
88:12 60
2
CO R
Br
52
80
75
98:2
78
99:1
100:0
99:1
MeO
2
C
2
CO Et
F
S
F
33:67
d
d
72
95:5
CO
2
R
83:17 82
83:17 69
a
Isolated yield.
b
Determined by 19F NMR of the crude.
O
F
CO
2
R
88:12
d
d
87
biocartol methyl ester, Z-alkene 15 was also obtained selectively,
and in good yield.
As mentioned in Table 1, the use of DBU as base led to an in-
crease in E-selectivity of the reaction, with a benzothiazolylsulfone
a
Isolated yield.
Determined by 19F NMR of the crude.
b
2
reagent, and that the selectivity was reversed when MgBr was
8
b
added. An additional experiment was carried out by reacting
pyrimidinyl- and benzothiazolylsulfone 3d and 3a with 10-
undecenal in the presence of DBU instead of NaHMDS (Scheme
and excellent selectivities (Table 2). Again, this selectivity increased
from benzothiazolyl- to pyrimidinyl-sulfones 3a, 3b, 3d.
Following the excellent stereoselectivity obtained from aro-
matic aldehydes this study was then extended to the more prob-
lematic aliphatic aldehydes (Table 3). As mentioned in the
4
). However, while with benzothiazolylsulfone 3a alkenes were
ꢁ
isolated in 92% yield after 3 h at 20 C, from pyrimidinylsulfone 3d
the reaction did not reach completion, even after an overnight re-
action. A different selectivity was obtained and from 3a, the E-al-
kene 11 was the major product (Z/E¼1:4), but from 3d the Z-alkene
was still obtained as the major isomer (Z/E¼7:3). As expected, this
ratio was increased when the reaction was carried out with DBU
3
introduction, when benzothiazolyl-, tetrazolyl-, and bis(CF )-phe-
nyl-sulfones were involved in the reaction, a mixture of fluo-
roalkenoates was obtained from aliphatic aldehydes (see Table 1).
This was confirmed by the olefination reaction carried out with the
standard benzothiazolysulfone 3a and heptanal (Table 3), with
a 1:1 mixture of isomeric alkenes 9 obtained. However, the in-
fluence of the nature of the heterocycle was again observed, and
when the nitro-benzothiazolylsulfone 3b was used, a significant
increase in selectivity was observed, with Z-alkene 9 formed as
major product (Z/E¼74:26). This effect was even more pronounced
using pyrimidinylsulfone 3d, affording alkene 9 exclusively. This
remarkably high selectivity with sulfone 3d appeared general, and
from nonanal, 10-undecenal, and citronellal, the corresponding
alkenes 10, 11, 12 were obtained in good yields and in 99:1, 96:4,
and 97:3 Z/E ratios, respectively. This selectivity was maintained
with 3-phenylpropanal, while the yield dropped down up to 52%.
From cyclohexycarbaldehyde, Z-isomer 14 was obtained as major
product regardless the sulfone, with an excellent selectivity with
sulfone 3d. In addition, with a more complex aldehyde, such as
and MgBr
2
: the reaction with 3d reached completion after 2 h at
ꢁ
20 C to afford 11, but only in a 9:1 Z/E ratio. Hence, it is interesting
to observe that the NaHMDS conditions lead to a higher ratio (96:4,
Table 3) compared to the DBU and MgBr
2
conditions.
10-undecenal
(1.05 equiv), DBU
(1.5 equiv), THF, 20 °C
EtO C
2
2
CO Et
F
92% (Ar = BT)
8
Ar SO2
F
1
1
3
3
d, Ar = Pym
a, Ar = BT
Z/E = 1:4 (Ar = BT)
Z/E = 7:3 (Ar z Pym)
Scheme 4. Influence of the base.

F. Larnaud et al. / Tetrahedron 70 (2014) 5632e5639
5635
These results obtained with pyrimidinylsulfone 3d confirm the
influence of the -deficient character of the heterocyclic sulfone on
benzothiazole (1.00 g, 4.7 mmol) in EtOH (12.6 mL), followed by
the addition of triethylamine (0.67 mL, 4.7 mmol) and ethyl bro-
mofluoroacetate (0.53 mL, 4.7 mmol). The crude product was pu-
rified by flash silica gel chromatography (pentane/AcOEt, 80:20) to
p
the course of the reaction. In the present case, we presume that this
electronic effect considerably enhances the rate of the Smiles rear-
rangement, and that the relative rate of formation of the in-
termediate alcoholates is reflected in the stereoselectivity of the
reaction. To rule out fluoroalkene product isomerization, possibly
catalyzed by the corresponding nucleophilic 2-hydroxypyrimidine
byproduct, a control experiment was carried out in which a 1:1
mixture of Z/E alkene 9 was treated with 2-hydroxypyrimidine
ꢁ
1
afford 2b (1.49 g, 100%) as a yellow solid (mp 76e78 C). H NMR
4
5
(400 MHz, CDCl
3
)
d
8.79 (dd,
J
HH¼2.2 Hz,
J
HH¼0.4 Hz, 1H), 8.26
3
4
3
(dd,
J
HH¼8.8 Hz,
J
HH¼2.2 Hz, 1H), 7.94 (dd,
J
HH¼8.8 Hz,
5
2
HF¼50.4 Hz, 1H), 4.36 (q, 3JHH¼7.4 Hz,
JHH¼0.4 Hz, 1H), 7.02 (d,
J
3
13
2H), 1.35 (t, JHH¼7.4 Hz, 3H). C NMR (100 MHz, CDCl
3
) d 164.6 (d,
2
J
J
J
CF¼26.6 Hz), 164.5, 152.4, 147.1, 142.4, 121.7, 119.7, 117.8, 91.4 (d,
ꢁ
ꢁ
1
2
19
(
1 equiv) in the presence of NaHMDS at ꢀ78 C, and then at 20 C.
CF¼239.7 Hz), 63.4, 14.0. F NMR (376 MHz, CDCl
3
)
d
ꢀ161.9 (d,
þ
In this case, the ratio was maintained and no isomerization was
observed, even after 18 h at 20 C. Considering that the retro-addi-
HF¼50.4 Hz, 1F). HRMS (MSþ) for C11
H
10
N
2
O
4
FS
2
(MþH) calcd
ꢁ
317.0066, found 317.0061.
tion reaction is thus negligible for aliphatic aldehydes, the high Z-
stereoselectivity implies that the reaction proceeds via the anti-
alcoholate (II), assuming an anti elimination is occurring. However, it
was not possible to trap this intermediate alcoholate. Indeed, when
4.1.2. Ethyl 2-fluoro-2-(pyridin-2-ylthio)acetate (2c).19 General
procedure was followed with 2-pyridinethiol (3.00 g, 27.0 mmol) in
EtOH (72 mL), followed by the addition of triethylamine (3.77 mL,
27.0 mmol) and ethyl bromofluoroacetate (3.2 mL, 27.0 mmol). The
crude product was purified by flash silica gel chromatography
ꢁ
adding AcOH to the reaction mixture at ꢀ78 C after 10 min of
stirring the corresponding alkenes were already obtained. Recently,
another mechanism going through a syn-periplanar elimination was
proposed, which cannot be excluded in the present case.1
1
(pentane/AcOEt, 80:20) to afford 2c (5.7 g, 98%) as a yellow oil. H
8
NMR (400 MHz, CDCl
3
) d 8.52e8.53 (m, 1H), 7.60e7.64 (m, 1H),
2
7
.07e7.31 (m, 2H), 7.11 (d,
J
HF¼51.6 Hz, 1H), 4.32e4.38 (m, 2H),
1
3
3
. Conclusion
1.28e1.26 (m, 3H). C NMR (100 MHz, CDCl 166.4 (d,
3
) d
2
J
J
J
CF¼27.9 Hz), 153.4, 149.0, 137.0, 123.3, 121.5, 90.8 (d,
1
2
19
In conclusion, the use of a pyrimidinylsulfone for the modified
CF¼230.6 Hz), 62.6, 14.0. F NMR (376 MHz, CDCl
3
)
d
ꢀ162.9 (d,
Julia reaction to 2-fluoroacrylates is shown to yield the Z-isomer in
very high diastereomeric ratio, even when aliphatic aldehydes are
employed as starting materials. The electron deficient nature of the
pyrimidine ring appeared important to promote the formation of
the Z-alkenes. Further research toward the use of pyrimidinyl flu-
orosulfone-based reagents for the selective synthesis of fluo-
roalkenes from aliphatic and aromatic aldehydes is underway.
HF¼51.6 Hz, 1F).
4.1.3. Ethyl 2-fluoro-2-(pyrimidin-2-ylthio)acetate (2d).20 General
procedure was followed with 2-pyrimidinethiol (4.00 g,
35.7 mmol) in EtOH (95 mL), followed by the addition of triethyl-
amine (5 mL, 35.7 mmol) and ethyl bromofluoroacetate (4.2 mL,
35.7 mmol). The sulfide 2d was obtained without any further pu-
1
rification as a yellow oil. H NMR (400 MHz, CDCl
3
J
)
d
8.60 (d,
3
HH¼4.9 Hz, 2H), 7.12 (t, 3JHH¼4.9 Hz, 1H), 7.09 (d,
2
4
. Experimental section
J
HF¼50.6 Hz,
3
3
13
1H), 4.33 (q,
J
HH¼7.2 Hz, 2H), 1.33 (t,
J
HH¼7.2 Hz, 3H). C NMR
2
All commercially available reagents were bought and used as
(100 MHz, CDCl
3
)
d
177.6, 167.6, 165.9 (d, JCF¼27.0 Hz), 157.8, 118.2,
19
1
received. For anhydrous conditions, the glassware was dried in the
91.0 (d,
J
CF¼229.5 Hz), 62.7, 13.9. F NMR (376 MHz, CDCl
3
)
ꢁ
2
oven at 120 C and cooled to room temperature under a continuous
d
ꢀ165.6 (d, JHF¼50.6 Hz, 1F).
nitrogen flow. THF, CH
2 2 2 3
Cl , Et O, and CH CN were dried at a solvent
generator, which uses an activated alumina column to remove
4.2. Ethyl 2-fluoro-2-(5-nitrobenzothiazol-2-ylsulfonyl)ace-
tate (3b)
ꢁ
water. DMF and NEt
sieves. Flash column chromatography was realized on silica gel 60
40e63 m) with air pressure and were detected by thin layer
chromatography, on which the spots were visualized by UV-
3
were distilled under CaH
2
or 4 A molecular
(
m
To a solution of sulfide 2b (200 mg, 0.63 mmol, 1 equiv) in MeCN/
2
H O (0.8 mL/2 mL), were added sodium periodate (22 mg, 2.91 mmol,
irradiation and/or KMnO
4
solution. NMR spectra were recorded
4.6 equiv) and ruthenium (III) chloride hydrate (1.3 mg, 0.06 mmol,
0.01 equiv). The resulting mixture was stirred at 20 C and a white
precipitate was formed. After 16 h of stirring, the precipitate was
ꢁ
ꢁ
on a 250 MHz or 400 MHz apparatus in deuterated solvent at 25 C.
19
F NMR spectral line is with respect to the internal reference CFCl
3
.
All chemical shifts are reported in parts per million (ppm) and
d
filtered and washed with CH
and washed successively with a saturated aqueous solution of
NaHCO and brine, dried over MgSO , and the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography (pentane/AcOEt, 80:20) to afford the sulfone 3b
2 2 2 2
Cl . The filtrate was diluted with CH Cl
coupling constants are in Hertz (Hz). High-resolution mass data
were recorded on a high-resolution mass spectrometer in the EI or
ESI mode. High-resolution mass data were recorded on a Micro-
mass Q-TOF (Quadrupole Time-of-Flight) instrument with an
electrospray source in the EI or ESI mode.
3
4
ꢁ
1
(179.0 mg, 81%) as a white solid (mp 113e115 C). H NMR (400 MHz,
4
5
3
CDCl
3
)
d
9.12 (dd, JHH¼2.2 Hz, JHH¼0.4 Hz,1H), 8.52(dd, JHH¼9.0 Hz,
4
2
3 5
4
.1. General procedure for the alkylation of thiol
J
J
HH¼2.2 Hz, 1H), 7.94 (dd,
J
HH¼9.0 Hz,
J
HH¼0.4 Hz, 1H), 6.07 (d,
3 13
HF¼47.3 Hz, 1H), 4.45e4.38 (m, 2H), 1.39 (t, JHH¼7.1 Hz, 3H).
C
2
Triethylamine (1 equiv) was added dropwise to a solution of
NMR (100 MHz, CDCl
3
)
d
165.3, 159.7 (d, JCF¼23.3 Hz), 152.4, 147.9,
ꢁ
1 19
sulfide (1 equiv) in EtOH (0.4 M) at 0 C under N
2
. After 10 min of
143.0, 123.4, 122.9, 121.5, 96.4 (d, JCF¼235.6 Hz), 64.3, 13.9. F NMR
2
stirring, ethyl bromofluoroacetate (1 equiv) was added to the
(376 MHz, CDCl
3
)
d
ꢀ180.8 (d, JHF¼47.3 Hz, 1F). MS (ESIþ) m/z (%)
ꢁ
þ
resulting mixture and was stirred 3 h at 20 C. The reaction mixture
349.0 ((MþH) , 62), 321.0 (100), 303.0 (24). HRMS (MSþ) for
was quenched with HCl (1 N), then extracted with CH
2
Cl
2
. The or-
C H N O FS
11 10 2 6 2
(MþH)þ calcd 348.9964, found 348.9980.
ganic layer was washed with brine, dried over MgSO
evaporated under reduced pressure.
4
, filtered, and
4.3. Ethyl 2-fluoro-2-(pyridin-2-ylsulfonyl)acetate (3c)
4
.1.1. Ethyl
2-fluoro-2-(5-nitrobenzothiazol-2-ylthio)acetate
In
(NH
a
Mo
round bottom flask, under
N
2
,
were placed
(85 mL,
(2b). General procedure was followed with 5-nitro-2-mercapto
4
)
6
7
O
24$4H O (6.67 g, 5.4 mmol, 0.2 equiv) and H O
2
2 2

5636
F. Larnaud et al. / Tetrahedron 70 (2014) 5632e5639
ꢁ
10 mmol, 30 equiv). After cooling to 0 C, a solution of sulfide 2c
130.0 (d, 3JCF¼5.0 Hz), 124.0 (d, JCF¼4.8 Hz), 116.3 (d, JCF¼24.7 Hz),
3
2
8
(
19
3
5.8 g, 27 mmol, 1 equiv) in EtOH (43 mL) was added dropwise. The
62.1, 14.2. F NMR (376 MHz, CDCl
1F). (E)-Isomer: H NMR (400 MHz, CDCl ) d 7.47e7.54 (m, 4H), 6.82
3
3
)
d
ꢀ123.9 (d, JHFtrans¼34 Hz,
ꢁ
1
mixture was stirred at 20 C and quenched with H
2
SO
4
(10%). EtOH
3
3
was removed by evaporation and NaCl was added. The resulting
mixture was extracted with CH Cl . Combined organic layers were
washed with brine, with saturated aqueous Na SO , dried over
MgSO , filtered, and evaporated under reduced pressure to afford
the sulfone 3c (4.21 g, 63%) without any further purification as
a colorless oil. 1H NMR (400 MHz, CDCl
8.74e8.72 (m, 1H),
.10e8.07 (m, 1H), 7.98e7.94 (m, 1H), 7.59e7.55 (m, 1H), 6.02 (d,
(d,
J
HFcis¼21.4 Hz, 1H), 4.26 (q,
J
HH¼7.2 Hz, 2H), 1.27 (t,
3
13
2
2
J
J
HH¼7.2 Hz, 3H).
C NMR (100 MHz, CDCl ) d 160.3 (d,
3
2
1
4
2
3
CF¼37.0 Hz), 147.3 (d, JCF¼258.2 Hz), 132.5, 131.3 (d, JCF¼3.0 Hz),
4 2
4
131.3, 131.0, 129.9 (d,
J
CF¼9.3 Hz) 123.0, 120.5 (d,
J
CF¼26.9 Hz),
19
ꢀ115.8 (d, 3JHFcis¼21.4 Hz,
61.8, 13.9. F NMR (376 MHz, CDCl
1F).
3
) d
3
) d
8
2
13
J
HF¼47.6 Hz, 1H), 4.37e4.29 (m, 2H), 1.31e1.21 (m, 3H). C NMR
4.5.2. Ethyl 3-(2,5-dibromophenyl)-2-fluoroacrylate (6). General
procedure was followed with sulfone 3d (100 mg, 0.40 mmol), 2,5-
dibromobenzaldehyde (111 mg, 0.42 mmol), and NaHMDS (600 mL,
0.60 mmol) in THF (8.8 mL). The crude product (Z/E: 99:1) afforded
a mixture of fluoroalkene 6 (116.8 mg, 83%) as a colorless oil.
From sulfone 3b (91 mg, 0.26 mmol), 2,5-dibromobenzaldehyde
2
(
1
d
100 MHz, CDCl
3
)
d
160.8 (d, JCF¼25.1 Hz),154.0,150.6,138.4,128.4,
19
1
24.6, 94.7 (d, JCF¼231.3 Hz), 63.7, 13.9. F NMR (376 MHz, CDCl
3
)
2
þ
ꢀ184.5 (d,
J
HF¼47.6 Hz, 1F). MS (ESIþ) m/z (%) 248.1 ((MþH) ,
1
00), 220.1 (60), 202.0 (59). HRMS (MSþ) for C
9
H11NO
4
FS (MþH)þ
calcd 248.0393; found 248.0403.
(
72.4 mg, 0.27 mmol), NaHMDS (290 mL, 0.29 mmol), and THF
4
.4. Ethyl 2-fluoro-2-(pyrimidin-2-ylsulfonyl)acetate (3d)20
(6 mL). The crude product (Z/E: 96:4) afforded a mixture of fluo-
roalkene 6 (71.5 mg, 78%) as a white solid.
In
NH
a
Mo
round bottom flask, under
N
2
,
were placed
(112 mL,
From sulfone 3a (79 mg, 0.26 mmol), 2,5-dibromobenzaldehyde
(72.4 mg, 0.27 mmol), NaHMDS (390 mL, 0.39 mmol), and THF
(6 mL). The crude product (Z/E: 98:2) afforded a mixture of fluo-
roalkene 6 (47.9 mg, 52%) as a white solid.
(
4
)
6
7
O
24$4H O (8.82 g, 7.14 mmol) and H
2
2
O
2
ꢁ
1.07 mol, 30 equiv). After cooling to 0 C, a solution of sulfide 2d
(
7.07 g, 35.7 mmol) in EtOH (57 mL) was added dropwise. The
ꢁ
1
4
mixture was stirred 48 h at 20 C and quenched with H
EtOH was removed by evaporation and NaCl was added. The
resulting mixture was extracted with CH Cl . Combined organic
layers were washed with brine, with saturated aqueous Na SO
dried over MgSO , filtered, and evaporated under reduced pressure
to afford the sulfone 3d (4.43 g, 50%) without any further purifi-
2
SO
4
(10%).
(Z)-Isomer: H NMR (400 MHz, CDCl
3
)
d
7.98 (d, JHH¼2.3 Hz,1H),
3
3
4
7.48 (d, JHH¼9.0 Hz, 1H), 7.33 (dd, JHH¼9.0 Hz, JHH¼2.3 Hz, 1H),
3
3
2
2
7.23 (d,
J
HFtrans¼33.3 Hz, 1H), 4.37 (q,
J
HH¼7.4 Hz, 2H), 1.39 (t,
3
13
2
3
,
J
J
J
J
J
HH¼7.4 Hz, 3H).
C NMR (100 MHz, CDCl ) d 160.6 (d,
3
2
2
4
3
1
4
CF¼34.6 Hz), 136.6 (d,
J
CF¼272.3 Hz), 134.3, 133.9 (d,
3
CF¼13.9 Hz), 133.5, 132.7 (d,
J
CF¼4.2 Hz), 123.3, 121.5, 11.4 (d,
CF¼3.4 Hz), 62.2, 14.1. F NMR (376 MHz, CDCl ꢀ122.6 (d,
HFtrans¼33.3 Hz, 1F). (E)-Isomer: H NMR (400 MHz, CDCl 8.01
1
19
cation as a colorless oil. H NMR (400 MHz, CDCl
3
)
d
8.94 (d,
3
) d
3
HH¼4.8 Hz, 2H), 7.64 (t, 3JHH¼4.8 Hz, 1H), 6.28 (d,
2
1
J
J
HF¼47.1 Hz,
3
) d
H), 4.31 (q, 3
J
HH¼7.1 Hz, 2H), 1.24 (t,
3
J
HH¼7.1 Hz, 3H). C NMR
13
(d, JHH¼2.4 Hz, 1H), 7.44 (d,
4
3
J
HH¼8.5 Hz, 1H), 7.33e7.30 (m, 1H),
1
2
3
3
(
100 MHz, CDCl
3
)
d
207.5, 163.8, 161.5 (d, JCF¼39.6 Hz), 159.4, 125.2,
6.83 (d,
J
HFcis¼18.5 Hz, 1H), 4.19 (q,
J
HH¼7.4 Hz, 2H), 1.18 (t,
4.8 (d, 1
J
CF¼232.7 Hz), 64.1, 14.2. F NMR (376 MHz, CDCl
19
)
3
J
J
J
J
J
HH¼7.4 Hz, 3H).
13
C NMR (100 MHz, CDCl ) d 160.6 (d,
9
3
3
2
2
2
4
3
1
d
ꢀ185.1 (d, JHF¼47.1 Hz, 1F).
CF¼34.6 Hz), 148.3 (d,
J
CF¼276.2 Hz), 134.3, 133.9 (d,
3
CF¼13.9 Hz), 133.5, 132.7 (d,
J
CF¼4.2 Hz), 123.3, 121.5, 11.4 (d,
19
4
.5. General procedure for the formation of fluoroacrylates
CF¼3.4 Hz), 61.9, 13.7. F NMR (376 MHz, CDCl
3
)
d
ꢀ115.1 (d,
79
þ
HFcis¼18.5 Hz, 1F). HRMS (MSþ) for C11
H
10
O
2
F
Br
2
Na (MþNa)
NaHMDS 1 M in THF (1.5 equiv) was added dropwise to a solu-
calcd 350.9032, found 350.9035.
tion of sulfone 3aeb, 3d (1 equiv) and aldehyde (1.05 equiv) in THF
ꢁ
4.5.3. Ethyl 2-fluoro-3-(thiophen-2-yl)acrylate (7).8b General pro-
cedure was followed with sulfone 3d (100 mg, 0.40 mmol), 2-
(
0.04 M) at ꢀ78 C under N
2
. After 30 min of stirring, the resulting
ꢁ
ꢁ
mixture was stirred for 2 h from ꢀ78 C to 20 C and then was
quenched with a saturated solution of NH Cl and brine, then
extracted with CH Cl . The organic layer was washed with brine,
dried over MgSO , filtered, and evaporated under reduced pressure.
4
thiophenecarboxaldehyde (40
mL, 0.42 mmol), and NaHMDS
2
2
(600 L, 0.60 mmol) in THF (8.8 mL). The crude product (Z/E: 99:1)
m
4
afforded a mixture of fluoroalkene 7 (69.7 mg, 87%) as a colorless
The crude product was purified by flash chromatography (pentane/
oil.
AcOEt, 95:5).
From sulfone 3b (100 mg, 0.29 mmol), 2-thiophene
carboxaldehyde (28.2
mL, 0.30 mmol), NaHMDS (440 mL,
4
.5.1. Ethyl 3-(4-bromophenyl)-2-fluoroacrylate (4).8b General pro-
cedure was followed with sulfone 3d (100 mg, 0.40 mmol), 4-
bromobenzaldehyde (78 mg, 0.42 mmol), and NaHMDS (600 L,
.60 mmol) in THF (8.8 mL). The crude product (Z/E: 100:0) was
0.44 mmol), and THF (6.6 mL). The crude product (Z/E: 83:17)
afforded a mixture of fluoroalkene 7 (47.4 mg, 82%) as a colorless oil.
From sulfone 3a (87.1 mg, 0.29 mmol), 2-thiophene
m
0
carboxaldehyde (28.2
mL, 0.30 mmol), NaHMDS (320
mL,
purified and afforded Z-fluoroalkene 4 (78.56 mg, 72%) as a color-
less oil.
0.32 mmol), and THF (6.6 mL). The crude product (Z/E: 83:17)
afforded a mixture of fluoroalkene 7 (46.7 mg, 80%) as a colorless oil.
1
3
From sulfone 3b (100 mg, 0.29 mmol), 4-bromobenzaldehyde
(Z)-Isomer: H NMR (400 MHz, CDCl
3
)
d
7.50 (d, JHH¼5.0 Hz,1H),
3
3
(
55.8 mg, 0.30 mmol), NaHMDS (320
mL, 0.32 mmol), and THF
7.35 (d, JHH¼3.7 Hz, 1H), 7.20 (d, JHFtrans¼34.2 Hz, 1H), 7.11e7.05
3 3 13
(
6.6 mL). The crude product (Z/E: 92:8) afforded a mixture of flu-
(m, 1H), 4.13 (q, JHH¼7.1 Hz, 2H), 1.19 (t, JHH¼7.1 Hz, 3H). C NMR
2
1
oroalkene 4 (58.4 mg, 74%).
(100 MHz, CDCl
3
)
d
161.3 (d, JCF¼32.9 Hz), 145.7 (d, JCF¼265.2 Hz),
3 3
3
From sulfone 3a (87.1 mg, 0.29 mmol), 4-bromobenzaldehyde
134.6 (d, JCF¼5.8 Hz), 133.8 (d, JCF¼5.5 Hz), 131.5 (d, JCF¼4.8 Hz),
2
19
(
55.8 mg), NaHMDS (320
m
L, 0.32 mmol), and THF (6.6 mL). The
112.2 (d,
J
CF¼8.8 Hz), 62.1, 17.8, 14.5. F NMR (376 MHz, CDCl
3
)
3
1
crude product (Z/E: 85:15) afforded a mixture of fluoroalkene 4
d
ꢀ124.2 (d, JHFtrans¼34.2 Hz, 1F). (E)-Isomer: H NMR (400 MHz,
3
(
56.8 mg, 72%).
CDCl
3
)
d
7.48 (d,
J
HH¼5.1 Hz, 1H), 7.38e7.36 (m, 1H), 7.10 (d,
1
3
3
(
Z)-Isomer: H NMR (400 MHz, CDCl
3
)
d
7.47e7.54 (m, 4H), 6.85
J
HFcis¼24.3 Hz, 1H), 7.11e7.05 (m, 1H), 4.18 (q, JHH¼7.1 Hz, 2H), 1.16
3
3
3
13
(
d,
J
HFtrans¼33.9 Hz, 1H), 4.34 (q,
JHH¼7.2 Hz, 2H), 1.37 (t,
(t,
J
HH¼7.1 Hz, 3H). C NMR (100 MHz, CDCl
3
) d 161.2 (d,
3
13
2
1
3
J
HH¼7.2 Hz, 3H).
C
NMR (100 MHz, CDCl
3
)
d
161.2 (d,
J
CF¼33.8 Hz), 144.4 (d, JCF¼253.6 Hz), 133.2 (d, JCF¼8.8 Hz), 131.2
2JCF¼34.1 Hz), 147.4 (d, JCF¼269.0 Hz), 132.4, 131.7 (d, 4JCF¼8 Hz),
1
(d, JCF¼4.7 Hz), 130.4 (d, JCF¼9.8 Hz), 127.1, 117.4 (d, JCF¼33.0 Hz),
3 3 2

F. Larnaud et al. / Tetrahedron 70 (2014) 5632e5639
5637
2.0, 14.4. 19F NMR (376 MHz, CDCl
F).
d
ꢀ123.9 (d, JHFcis¼24.3 Hz,
3
From sulfone 3a (87.1 mg, 0.29 mmol), nonanal (52
mL,
6
1
3
)
0.30 mmol), NaHMDS (320 L, 0.32 mmol), and THF (6.6 mL). The
m
crude product (Z/E: 46:54) afforded a mixture of fluoroalkene 10
(53.6 mg, 81%) as a colorless oil.
4
.5.4. Ethyl 2-fluoro-3-(furan-2-yl)acrylate (8).8b General pro-
1
cedure was followed with sulfone 3d (100 mg, 0.40 mmol), 2-
furaldehyde (35
0
a mixture of fluoroalkene 8 (49.5 mg, 87%) as a colorless oil.
From sulfone 3a (121 mg, 0.40 mmol), 2-furaldehyde (35
0
(Z)-Isomer:
H
NMR (400 MHz, CDCl
3
)
d
6.00 (dt,
3
mL, 0.42 mmol), and NaHMDS (600
mL,
3JHFtrans¼33.5 Hz, JHH¼8.2 Hz, 1H) 4.20 (m, 2H), 2.18e2.48 (m, 2H)
3
13
.60 mmol) in THF (8.8 mL). The crude product (Z/E: 99:1) afforded
1.14e1.39 (m, 15H), 0.80 (t, JHH¼10.0 Hz, 3H). C NMR (100 MHz,
2 1
CDCl
3
)
d
161.3 (d, JCF¼35.4 Hz), 147.3 (d, JCF¼248.6 Hz), 121.2 (d,
3
2
mL,
J
CF¼36.1 Hz), 61.8, 37.4, 32.2, 30.0, 29.6, 29.5, 28.7 (d, JCF¼1.7 Hz),
4 19
.42 mmol), NaHMDS (600
mL, 0.60 mmol) in THF (8.8 mL). The
24.5 (d, JCF¼2.6 Hz), 22.9, 14.4. F NMR (376 MHz, CDCl
3
)
d
ꢀ131.1
3
1
crude product (Z/E: 88:12) afforded a mixture of fluoroalkene 8
(d,
d
J
HFtrans¼33.3 Hz, 1F). (E)-Isomer: H NMR (400 MHz, CDCl
3
)
3
3
(
55.2 mg, 75%) as a colorless oil.
5.80 (dt, JHFcis¼21.2 Hz, JHH¼7.9 Hz, 1H), 4.20 (m, 2H), 2.18e2.48
1
3
13
(
Z)-Isomer: H NMR (400 MHz, CDCl
3
)
d
7.52e7.51 (m, 1H), 6.94
(m, 2H) 1.14e1.39 (m, 15H), 0.80 (t,
J
HH¼10.0 Hz, 3H). C NMR
3
2
1
(
4
(
d,
.32 (q, 3
100 MHz, CDCl
J
HFtrans¼33.4 Hz, 1H), 6.86e6.84 (m, 1H), 6.52e6.51 (m, 1H),
(100 MHz, CDCl
3
)
d
161.4 (d, JCF¼35.8 Hz), 142.1 (d, JCF¼235.2 Hz),
3
13
2
J
HH¼7.1 Hz, 2H), 1.36 (t,
J
HH¼7.1 Hz, 3H). C NMR
124.2 (d,
J
CF¼36.1 Hz), 61.8, 37.4, 32.2, 30.0, 29.6, 29.5, 28.7 (d,
2
3
3
4
19
3
)
d
161.2 (d,
J
CF¼28.0 Hz), 147.1 (d,
J
CF¼4.3 Hz),
J
CF¼1.7 Hz), 24.5 (d,
J
CF¼2.6 Hz), 22.9, 14.4. F NMR (376 MHz,
1
2
3
1
J
45.4 (d,
J
CF¼266.4 Hz), 144.5 (d,
J
CF¼3.9 Hz), 115.5 (d,
CDCl
3
)
d
ꢀ122.8 (d, JHFcis¼21.5 Hz, 1F).
3
3
19
CF¼11.3 Hz), 112.8, 107.5 (d,
J
CF¼8.5 Hz), 62.0, 14.4. F NMR
3
1
(
376 MHz, CDCl
3
)
d
ꢀ123.6 (d, JHFtrans¼33.4 Hz, 1F). (E)-Isomer: H
7.52e7.51 (m, 1H), 6.86e6.84 (m, 1H), 6.65
4.5.7. Ethyl 2-fluorotrideca-2,4-dienoate (11). General procedure
was followed with sulfone 3d (100 mg, 0.40 mmol), 10-undecenal
(84 mL, 0.42 mmol), and NaHMDS (600 mL, 0.60 mmol) in THF
(8.8 mL). The crude product (Z/E: 96:4) afforded a mixture of flu-
oroalkene 11 (74.9 mg, 79%) as a colorless oil.
NMR (400 MHz, CDCl
3
) d
3
3
(
d, JHFcis¼21.3 Hz, 1H), 6.52e6.51 (m, 1H), 4.32 (q, JHH¼7.1 Hz, 2H),
.23 (t, 3
J
HH¼7.2 Hz, 3H). C NMR (100 MHz, CDCl
13
)
d
160.8 (d,
1
3
2
2
1
J
CF¼33.4 Hz),146.3 (d, JCF¼10.4 Hz),144.9 (d, JCF¼256.8 Hz),144.3
3
3
2
(
6
d, JCF¼4.7 Hz), 116.2 (d, JCF¼6.4 Hz), 112.8, 111.7 (d, JCF¼33.2 Hz),
From sulfone 3b (100 mg, 0.29 mmol), 10-undecenal (60
0.30 mmol), NaHMDS (320 L, 0.32 mmol), and THF (6.6 mL). The
crude product (Z/E: 85:15) afforded a mixture of fluoroalkene 11
mL,
19
3
1.8, 14.3. F NMR (376 MHz, CDCl
3
)
d
ꢀ122.8 (d, JHFcis¼21.3 Hz,
m
1
F).
(60.4 mg, 82%) as a colorless oil.
4
.5.5. Ethyl 2-fluoronon-2-enoate (9). General procedure was fol-
L,
L, 0.60 mmol) in THF (8.8 mL). The
From sulfone 3a (87.1 mg, 0.29 mmol), 10-undecenal (60 mL,
0.30 mmol), NaHMDS (320 mL, 0.32 mmol), and THF (6.6 mL). The
crude product (Z/E: 43:57) afforded a mixture of fluoroalkene 11
lowed with sulfone 3d (100 mg, 0.40 mmol), heptanal (84
.42 mmol), and NaHMDS (600
m
0
m
crude product (Z/E: 100:0) afforded Z-fluoroalkene 9 (67.7 mg, 84%)
as a colorless oil.
(48.8 mg, 66%) as a colorless oil.
1
(Z)-Isomer:
H
NMR (400 MHz, CDCl
3
)
d
6.10 (dt,
3
3
3
4
HFtrans¼33.5 Hz, 3JHH¼7.7 Hz, 1H), 5.79 (ddt,
3
From sulfone 3b (100 mg, 0.29 mmol), heptanal (42.3
.30 mmol), NaHMDS (440 L, 0.44 mmol) in THF (6.6 mL). The
crude product (Z/E: 74:26) afforded a mixture of fluoroalkene 9
mL,
J
J
J
J
J
HH¼17.0 Hz,
3
HH¼6.7 Hz, 1H), 4.98 (ddt, 3JHH¼17.0 Hz,
0
m
HH¼13.4 Hz,
J
4
3
3
HH¼3.8 Hz, JHH¼1.5 Hz, 1H), 4.92 (ddt, JHH¼13.4 Hz, JHH¼3.8 Hz,
3
(
34.7 mg, 60%) as a colorless oil.
HH¼1.2 Hz, 1H), 4.26 (q,
JHH¼7.2 Hz, 2H), 2.25e2.19 (m, 2H),
13
From sulfone 3a (87.1 mg, 0.29 mmol), heptanal (42.3
mL,
3
2.05e2.00 (m, 2H), 1.42e1.27 (m, 15H). C NMR (100 MHz, CDCl )
2
1
0
.30 mmol), NaHMDS (440
mL, 0.44 mmol) in THF (6.6 mL). The
d
2
160.9 (d,
J
CF¼32.2 Hz), 147.9 (d, JCF¼257.6 Hz), 139.1, 120.7 (d,
crude product (Z/E: 53:47) afforded a mixture of fluoroalkene 9
J
J
CF¼12.0 Hz), 114.1, 61.4, 33.7, 29.3, 29.2, 29.1, 29.0, 28.8, 28.2 (d,
4
3
19
(
34.7 mg, 50%) as a colorless oil.
CF¼1.8 Hz), 24.2 (d, JCF¼2.6 Hz), 14.1. F NMR (376 MHz, CDCl
3
)
1
3
5
1
(
Z)-Isomer:
H
NMR (400 MHz, CDCl
3
)
d
6.10 (dt,
d
ꢀ131.1 (dt, JHFtrans¼33.5 Hz, JHF¼2.0 Hz, 1F). (E)-Isomer: H NMR
3
HFtrans¼33.3 Hz, 3JHH¼7.0 Hz, 1H), 4.31e4.24 (m, 2H), 2.23 (dq,
3 3
J
(400 MHz, CDCl
3
)
d
5.90 (dt, JHFcis¼21.8 Hz, JHH¼8.2 Hz, 1H), 5.79
3 3
3JHH¼7.4 Hz, JHF¼2.2 Hz, 2H), 1.45e1.41 (m, 2H), 1.39e1.23 (m, 9H),
4
(ddt,
3
J
HH¼17.0 Hz,
J
HH¼13.4 Hz,
J
HH¼6.7 Hz, 1H), 4.92 (ddt,
3
.89 (t, 3
J
J
HH¼6.2 Hz, 3H). C NMR (100 MHz, CDCl
13
)
d
160.9 (d,
3
J
HH¼13.4 Hz, JHH¼3.8 Hz, JHH¼1.2 Hz, 1H), 4.29 (q, JHH¼7.2 Hz,
3
4
0
3
2
1
2
13
CF¼35.5 Hz), 147.9 (d, JCF¼255.0 Hz), 146.9 (d, JCF¼11.9 Hz), 61.4,
2H), 2.52e2.46 (m, 2H), 2.05e2.00 (m, 2H), 1.42e1.27 (m, 15H).
C
4
3
2
3
1.5, 28.8, 28.3 (d, JCF¼1.8 Hz), 24.2 (d, JCF¼2.5 Hz), 22.5, 14.1, 14.0.
NMR (100 MHz, CDCl
3
)
d
160.5 (d,
J
CF¼36.2 Hz), 146.9 (d,
1
9
3
1
2
F NMR (376 MHz, CDCl
3
)
d
ꢀ131.1 (dt,
J
HFtrans¼33.3 Hz,
J
CF¼248.7 Hz), 139.1, 123.8 (d, JCF¼17.9 Hz), 114.1, 61.2, 33.7, 29.3,
4
3
1
4
3
J
HF¼2.2 Hz, 1F). (E)-Isomer. H NMR (400 MHz, CDCl
3
)
d
5.91 (dt,
29.2, 29.1, 29.0, 28.8, 28.2 (d, JCF¼1.8 Hz), 25.4 (d, JCF¼5.4 Hz), 14.1.
3
19
3
5
JHFcis¼21.8 Hz,
J
HH¼8.2 Hz, 1H), 4.31e4.24 (m, 2H), 2.50 (dq,
F NMR (376 MHz, CDCl
3
)
d
ꢀ122.7 (dt, JHFcis¼21.8 Hz, JHF¼1.4 Hz,
3JHH¼8.1 Hz, JHF¼1.6 Hz, 2H), 1.45e1.41 (m, 2H), 1.39e1.23 (m, 9H),
4
1F). HRMS (MSþ) for C15
H
FNa (MþNa)þ calcd 279.1736, found
25 2
O
13
0
.89 (t, 3
J
J
HH¼6.2 Hz, 3H). C NMR (100 MHz, CDCl
3
)
d
161.1 (d,
279.1747.
2
1
2
CF¼36.0 Hz), 146.9 (d, JCF¼250.0 Hz), 123.8 (d, JCF¼17.4 Hz), 61.2,
4
3
3
1.5, 29.2 (d, JCF¼2.0 Hz), 28.8, 25.4 (d, JCF¼5.0 Hz), 22.5, 14.1, 14.0.
4.5.8. (S)-Ethyl 2-fluoro-5,9-dimethyldeca-2,8-dienoate
1
9
3
4
21
F NMR (376 MHz, CDCl
3
)
d
ꢀ122.8 (dt, JHFcis¼21.8 Hz, JHF¼1.6 Hz,
(12). General procedure was followed with sulfone 3d (100 mg,
1
2
F). HRMS (MSþ) for C11
H
19
O
2
FNa (MþNa)þ calcd 225.1267, found
0.40 mmol), (S)-citronellal (76
mL, 0.42 mmol), and NaHMDS
25.1264.
(600 L, 0.60 mmol) in THF (8.8 mL). The crude product (Z/E: 97:3)
m
afforded a mixture of fluoroalkene 12 (78.4 mg, 81%) as a colorless
oil.
4
.5.6. Ethyl 2-fluoroundec-2-enoate (10).8b General procedure was
L,
L, 0.60 mmol) in THF (8.8 mL). The
crude product (Z/E: 99:1) afforded a mixture of fluoroalkene 10
followed with sulfone 3d (100 mg, 0.40 mmol), nonanal (69
.42 mmol), and NaHMDS (600
m
From sulfone 3a (121 mg, 0.40 mmol), (S)-citronellal (76
mL,
0
m
0.42 mmol), NaHMDS (600 L, 0.60 mmol), and THF (8.8 mL). The
m
crude product (Z/E: 55:45) afforded a mixture of fluoroalkene 12
(
67.3 mg, 73%) as a colorless oil.
From sulfone 3b (100 mg, 0.29 mmol), nonanal (52
(47.5 mg, 49%) as a colorless oil.
1
mL,
(Z)-Isomer:
H
NMR (400 MHz, CDCl
3
)
d
6.11 (dt,
3
3
3
3
0
.30 mmol), NaHMDS (320
crude product (Z/E: 84:16) afforded a mixture of fluoroalkene 10
61 mg, 92%) as a colorless oil.
mL, 0.32 mmol), and THF (6.6 mL). The
J
J
HFtrans¼33.2 Hz, JHH¼7.6 Hz, 1H), 5.07 (t, JHH¼7.6 Hz, 1H), 4.26 (q,
HH¼7.0 Hz, 2H), 2.26e2.18 (m, 1H), 2.14e2.06 (m, 1H), 2.04e1.92
(
(m, 2H), 1.67 (s, 3H), 1.63e1.57 (m, 1H), 1.58 (s, 3H), 1.38e1.30 (m,

5638
F. Larnaud et al. / Tetrahedron 70 (2014) 5632e5639
1
H), 1.32 (t, 3JHH¼7.0 Hz, 3H), 1.24e1.15 (m, 1H), 0.91 (d,
4.5.11. (1S,3S)-Methyl 3-(3-ethoxy-2-fluoro-3-oxoprop-1-enyl)-2,2-
dimethylcyclopropane-carboxylate (15). General procedure was
followed with sulfone 3d (100 mg, 0.40 mmol), bio-
3
13
8b
J
J
HH¼6.7 Hz, 3H).
C
NMR (100 MHz, CDCl
3
)
d
160.8 (d,
2
1
CF¼35.3 Hz), 148.4 (d,
J
CF¼253.8 Hz), 131.4, 124.3, 119.3 (d,
3JCF¼11.7 Hz), 61.4, 36.5, 32.2 (d, JCF¼1.7 Hz), 31.2 (d, JCF¼1.7 Hz),
4
5
cartolmethylester (66 mg, 0.42 mmol), and NaHMDS (600
mL,
1
9
2
J
5.6, 25.4, 19.4, 17.5, 14.1. F NMR (376 MHz, CDCl
3
)
d
ꢀ130.5 (d,
0.60 mmol) in THF (8.8 mL). The crude product (Z/E: 95:5) afforded
a mixture of fluoroalkene 15 (69.9 mg, 72%) as a colorless oil.
From sulfone 3a (121 mg, 0.40 mmol), biocartolmethylester
(66 mg, 0.42 mmol), and NaHMDS (600 mL, 0.60 mmol) in THF
(8.8 mL). The crude product (Z/E: 33:67) afforded a mixture of
3
1
HFtrans¼33.2 Hz, 1F). (E)-Isomer: H NMR (400 MHz, CDCl
3
) d
6.11
3
3
3
(
(
dt, JHFcis¼22.1 Hz, JHH¼8.1 Hz, 1H), 5.07 (t, JHH¼7.6 Hz, 1H), 4.28
3
q, JHH¼7.0 Hz, 2H), 2.55e2.36 (m, 2H), 2.06e1.91 (m, 2H), 1.67 (s,
3
H), 1.63e1.57 (m, 1H), 1.58 (s, 3H), 1.38e1.30 (m, 1H), 1.33 (t,
3
3
13
J
HH¼7.0 Hz, 3H), 1.24e1.15 (m, 1H), 0.91 (d, JHH¼6.7 Hz, 3H).
C
fluoroalkene 15 (55.3 mg, 57%) as a colorless oil.
2
1
NMR (100 MHz, CDCl
3
)
d
161.0 (d,
J
CF¼35.9 Hz), 147.3 (d,
(Z)-Isomer:
H
NMR (400 MHz, CDCl
3
)
d
6.56 (dt,
1
3
3JHFtrans¼32.3 Hz, JHH¼10.5 Hz, 1H), 4.30e4.19 (m, 2H), 3.65 (s, 3H),
3
J
CF¼248.9 Hz), 131.4, 124.4, 122.5 (d, JCF¼17.9 Hz), 61.2, 36.6, 32.9
4 5 19
2
3
3
(
d, JCF¼1.7 Hz), 32.4 (d, JCF¼4.5 Hz), 25.6, 25.4, 19.4, 17.6, 14.1.
F
2.16 (dd, JHH¼10.5 Hz, JHH¼8.5 Hz, 1H), 1.88 (d, JHH¼8.5 Hz, 1H),
13
3
NMR (376 MHz, CDCl
3
)
d
ꢀ121.4 (d, JHFcis¼22.1 Hz, 1F).
1.31e1.28 (m, 3H), 1.19 (s, 6H). C NMR (100 MHz, CDCl
3
)
d
171.0,
2
1
1
J
60.7 (d,
J
CF¼35.2 Hz), 149.7 (d,
J
CF¼255.2 Hz), 119.7 (d,
.5.9. Ethyl 2-fluoro-5-phenylpent-2-enoate (13).22 General pro-
2
CF¼24.8 Hz), 61.7, 51.7, 33.0, 28.7, 29.0 (d, JCF¼7.4 Hz), 15.1 (2C),
3
4
19
3
cedure was followed with sulfone 3d (100 mg, 0.40 mmol), 3-
phenylpropanal (55
14.4. F NMR (376 MHz, CDCl
3
)
d
ꢀ132.5 (d, JHFtrans¼31.4 Hz, 1F).
1
3
mL, 0.42 mmol), and NaHMDS (600
mL,
(E)-Isomer: H NMR (400 MHz, CDCl
3
)
d
6.39 (dt,
J
HFcis¼20.9 Hz,
3
0
.60 mmol) in THF (8.8 mL). The crude product (Z/E: 97:3) afforded
J
J
HH¼10.3 Hz, 1H), 4.30e4.19 (m, 2H), 3.58 (s, 3H), 2.77 (ddd,
2
3
3
3
a mixture of fluoroalkene 13 (46 mg, 52%) as a colorless oil.
From sulfone 3a (121 mg, 0.40 mmol), 3-phenylpropanal (55
HH¼10.0 Hz, JHH¼8.5 Hz, JHH¼1.3 Hz, 1H), 1.84 (d, JHH¼8.5 Hz,
13
mL,
3
1H), 1.31e1.28 (m, 3H), 1.19 (s, 6H). C NMR (100 MHz, CDCl )
2
1
0
.42 mmol), NaHMDS (600
mL, 0.60 mmol), and THF (8.8 mL). The
d
171.2, 161.6 (d,
J
CF¼34.6 Hz), 148.3 (d, JCF¼252.1 Hz), 116.3 (d,
2
3
crude product (Z/E: 69:31) afforded a mixture of fluoroalkene 13
J
CF¼7.5 Hz), 61.5, 51.7, 32.5, 28.6, 28.2 (d,
J
CF¼5.1 Hz), 14.9 (2C),
3
19
(
35.8 mg, 40%) as a colorless oil.
14.3. F NMR (376 MHz, CDCl
3
)
d
ꢀ120.9 (d, JHFcis¼21.2 Hz, 1F).
1
7.32 (d, 3JHH¼7.5 Hz, 2H),
(
3
Z)-Isomer: H NMR (400 MHz, CDCl ) d
3
3
7
J
.25 (d,
J
HH¼7.5 Hz, 1H), 7.22 (d,
J
HH¼7.5 Hz, 2H), 6.17 (dt,
3
3
3
Acknowledgements
HFtrans¼33.3 Hz, JHH¼7.8 Hz, 1H), 4.29 (q, JHH¼7.1 Hz, 2H), 2.79 (t,
3JHH¼7.9 Hz, 2H), 2.59 (dtd, JHH¼7.9 Hz, JHH¼7.8 Hz, JHF¼1.9 Hz,
3 3 4
3
13
The authors acknowledge the European Regional Development
Fund (ERDF) for co-financing the ISCE-Chem project (No. 1907/
4061) through the INTERREG IV A France (Channel)dEngland
cross-border cooperation Programme.
2
H), 1.34 (t, JHH¼7.1 Hz, 3H). C NMR (100 MHz, CDCl
3
) d 160.7 (d,
2
1
J
1
J
CF¼35.2 Hz), 148.1 (d, JCF¼254.9 Hz), 140.5, 128.4 (2C), 128.2 (2C),
26.2, 119.4 (d, 2
4
J
CF¼11.5 Hz), 61.4, 34.3 (d,
J
CF¼1.9 Hz), 25.8 (d,
ꢀ129.6 (dt,
HF¼1.9 Hz, 1F). (E)-Isomer: H NMR (400 MHz,
3
19
CF¼2.4 Hz), 14.0. F NMR (376 MHz, CDCl
3
) d
3JHFtrans¼33.3 Hz,
4
J
1
3
3
CDCl
3
)
d
7.34e7.21 (m, 5H), 5.95 (dt,
J
HFcis¼21.5 Hz,
JHH¼8.2 Hz,
3
References and notes
1
J
H), 4.31 (q,
J
HH¼7.1 Hz, 2H), 2.90e2.77 (m, 4H), 1.36 (t,
3
13
HH¼7.1 Hz, 3H).
C NMR (100 MHz, CDCl ) d 160.8 (d,
3
1. Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology; Wiley-Blackwell:
2JCF¼35.5 Hz), 147.3 (d, JCF¼250.7 Hz), 140.6, 128.4 (2C), 128.2 (2C),
1
Chichester, UK, 2009.
26.1, 122.3 (d, 2
J
CF¼18.4 Hz), 61.3, 35.2 (d,
4
J
CF¼2.3 Hz), 27.1 (d,
2. (a) Landelle, G.; Bergeron, M.; Turcotte-Savard, M. O.; Paquin, J. F. Chem. Soc.
1
J
3
19
Rev. 2011, 40, 2867e2908; (b) Yanai, H.; Taguchi, T. Eur. J. Org. Chem. 2011,
CF¼5.0 Hz), 14.0. F NMR (376 MHz, CDCl
3
)
d
ꢀ121.7 (d,
5939e5954.
3JHFcis¼21.5 Hz, 1F).
3. (a) Suzuki, Y.; Sato, M. Tetrahedron Lett. 2004, 45, 1679e1681; (b) Lemonnier, G.;
Zoute, L.; Quirion, J.-C.; Jubault, P. J. Org. Chem. 2009, 74, 4124e4131; (c) Ma-
chleidt, H.; Wessendorf, R. Justus Liebigs Ann. Chem. 1964, 674, 1e10; (d) Ete-
mad-Moghadam, G.; Seyden-Penne, J. Bull. Soc. Chim. Fr. 1985, 448e454; (e)
Daubresse, N.; Chupeau, Y.; Francesch, C.; Lapierre, C.; Pollet, B.; Rolando, C.
Chem. Commun. 1997, 1489e1490.
.5.10. Ethyl 3-cyclohexyl-2-fluoroacrylate (14).8b General pro-
cedure was followed with sulfone 3d (100 mg, 0.40 mmol), cyclo-
hexylcarboxaldehyde (84 L, 0.42 mmol), and NaHMDS (600 L,
.60 mmol) in THF (8.8 mL). The crude product (Z/E: 96:4) afforded
a mixture of fluoroalkene 14 (74.9 mg, 79%) as a colorless oil.
From sulfone 3b (100 mg, 0.29 mmol), cyclo-
hexylcarboxaldehyde (36.5 L), NaHMDS (320 L, 0.32 mmol), and
4
m
m
4. (a) Welch, J. T.; Herbert, R. W. J. Org. Chem. 1990, 55, 4782e4784; (b) Lin, J.;
Welch, J. T. Tetrahedron Lett. 1998, 39, 9613e9616.
0
5. Chevrie, D.; Lequeux, T.; Pommelet, J.-C. Org. Lett. 1999, 1, 1539e1541.
6. (a) Daubresse, N.; Chupeau, Y.; Francesh, C.; Lapierre, C.; Pollet, B.; Rolando, C. J.
Chem. Soc., Chem. Commun. 1997, 1489e1490; (b) Sano, S.; Teranishi, R.; Nagao,
Y. Tetrahedron Lett. 2002, 43, 9183e9186; (c) Sano, S.; Katsuyuki, S.; Nagao, Y.
Tetrahedron Lett. 2003, 44, 3987e3990; (d) Sano, S.; Kuroda, Y.; Katsuyuki, S.;
Ose, Y.; Nagao, Y. Tetrahedron 2006, 62, 11881e11890.
m
m
THF (6.6 mL). The crude product (Z/E: 88:12) afforded a mixture of
fluoroalkene 14 (34.4 mg, 60%) as a colorless oil.
7. Chevrie, D.; Lequeux, T.; Demoute, J. P.; Pazenok, S. Tetrahedron Lett. 2003, 44,
From sulfone 3a (87.1 mg, 0.29 mmol), cyclo-
8127e8130.
hexylcarboxaldehyde (36.5 mL), NaHMDS (320 mL, 0.32 mmol), and
THF (6.6 mL). The crude product (Z/E: 71:29) afforded a mixture of
fluoroalkene 14 (35.8 mg, 62%) as a colorless oil.
8
. (a) Zajc, B.; Kake, S. Org. Lett. 2006, 8, 4457e4460; (b) Pfund, E.; Lebargy, C.;
Rouden, J.; Lequeux, T. J. Org. Chem. 2007, 72, 7871e7877; (c) Alonso, D. A.;
Fuensanta, M.; G oꢀ mez-Bengoa, E.; N ꢀa jera, C. Adv. Synth. Catal. 2008, 350,
1
1823e1829.
(
Z)-Isomer:
H
NMR (400 MHz, CDCl
3
)
d
5.90 (dd,
9. Zajc, B.; Kumar, R. Synthesis 2010, 1822e1836.
3JHFtrans¼33.6 Hz,
3
J
HH¼9.6 Hz, 1H), 4.16e4.27 (m, 2H), 2.47e2.50
10. (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563e2585; (b) Aissa, C.
Eur. J. Org. Chem. 2009, 1831e1844.
11. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998,
13
(
m, 1H), 1.57e1.65 (m, 4H), 1.01e1.29 (m, 9H). C NMR (100 MHz,
2
1
CDCl
3
)
d
161.4 (d, JCF¼36.1 Hz), 147.1 (d, JCF¼255.2 Hz), 129.0 (d,
2
6e28.
2
19
J
CF¼15.3 Hz), 61.6, 34.1, 32.2, 26.0, 25.9, 25.7, 25.6, 14.3. F NMR
12. Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron Lett. 2001, 42,
5149e5153.
3
1
(
376 MHz, CDCl
3
)
d
ꢀ131.8 (d, JHFtrans¼33.9 Hz, 1F). (E)-Isomer: H
3 3
13. (a) Alonso, D. A.; N ꢀa jera, C.; Varea, M. Tetrahedron Lett. 2004, 45, 573e577; (b)
NMR (400 MHz, CDCl
3
)
d
5.73 (dd, JHFcis¼22.00 Hz, JHH¼10.4 Hz,
Alonso, D. A.; Fuensanta, M.; N aꢀ jera, C.; Varea, M. J. Org. Chem. 2005, 70,
1
H), 4.16e4.27 (m, 2H), 2.99e3.01 (m, 1H), 1.57e1.65 (m, 4H),
6404e6416.
1
3
1
J
.01e1.29 (m, 9H).
C NMR (100 MHz, CDCl 161.1 (d,
3
)
d
14. Mirk, D.; Grassot, J.-M.; Zhu, J. Synlett 2006, 1255e1259.
15. (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc. Chim. Fr.
2
1
2
CF¼36.2 Hz), 146.3 (d, JCF¼251.7 Hz), 125.8 (d, JCF¼11.2 Hz), 61.4,
1993, 130, 856e878; (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron
4.8 (d, 3
376 MHz, CDCl
J
CF¼4.6 Hz), 33.0, 26.0, 25.9, 25.7, 25.6, 14.2. F NMR
19
3
(
Lett. 1991, 32, 1175e1178; (c) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull.
Soc. Chim. Fr. 1993, 130, 336e357.
3
3
)
d
ꢀ125.1 (d, JHFcis¼22.4 Hz, 1F).

F. Larnaud et al. / Tetrahedron 70 (2014) 5632e5639
5639
1
6. (a) Faure, R.; Elguero, J.; Vincent, E. J.; Lazaro, R. Org. Magn. Reson. 1978, 11,
17e627; (b) Breitmaier, E. Structure Elucidation by NMR in Organic Chemistry: A
Practical Guide; John Wiley & Sons: Chichester, UK, 2002.
7. Xu, L.; Cheng, J.; Trudell, M. L. J. Org. Chem. 2003, 68, 5388e5391.
8. Robiette, R.; Pospisil, J. Eur. J. Org. Chem. 2013, 836e840.
19. Erian, A. W.; Konno, A.; Fuchigami, T. J. Org. Chem. 1995, 60, 7654e7659.
6
20. Calata, C.; Catel, J. M.; Pfund, E.; Lequeux, T. Tetrahedron 2009, 65, 3967e3973.
21. Jin, Y. Z.; Yasuda, N.; Inanaga, J. Green Chem. 2002, 4, 498e500.
22. Zoute, L.; Dutheuil, G.; Quirion, J. C.; Jubault, P.; Pannecoucke, X. Synthesis 2006,
20, 3409e3418.
1
1