Some synthetic applications of the reactivity of methyl 2-fluoro-3-(phenylthio)acrylate

Article abstract of DOI:10.1016/S0022-1139(98)00249-8

The synthetic usefulness of the title compound is demonstrated through its reactivity towards thio and amino nucleophiles as well as tin-centred radicals. The synthesis of a 2-fluoro analogue of a natural fungicide (Sinharine) is reported. We also show th

Full text of DOI:10.1016/S0022-1139(98)00249-8

Journal of Fluorine Chemistry 92 (1998) 63±67
Some synthetic applications of the reactivity
of methyl 2-¯uoro-3-(phenylthio)acrylate
1
Didier F. Andr eÁ s , Eliane G. Laurent, Bernard S. Marquet
Universit e Claude Bernard, Laboratoire de Chimie Organique 3, (UMR CNRS 5622) 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
*
Received 24 April 1998; accepted 10 July 1998
Abstract
The synthetic usefulness of the title compound is demonstrated through its reactivity towards thio and amino nucleophiles as well as tin-
centred radicals. The synthesis of a 2-¯uoro analogue of a natural fungicide (Sinharine) is reported. We also show that 3-aryl-2-
¯uoropropenoates could be obtained via Stille coupling between an aryl iodide and a 3-tributylstannyl-2-¯uoropropenoate. # 1998 Elsevier
Science S.A. All rights reserved.
Keywords: 2-Fluoro-3-(phenylthio)acrylate; 2-Fluoroacrylate; 2-Fluoroacrylamide; Stille coupling
Owing to the growing applications of ¯uorinated mole-
cules in agro and pharmaceutical chemistry, several groups
have proposed new multifunctional ¯uorinated synthons
which are very useful as building blocks [1]. From this
point of view 2-¯uoro-3-(leaving group) substituted acryl-
ates 1 are of great interest, since they can be functionalised
via a 1,2- or 1,4-nucleophilic addition (path a or path b, then
c, respectively) as well as via an addition±elimination
process (path b then d) Scheme 1.
1. Reaction of amines and thiols: synthesis of a
fluorinated analogue of a natural fungicide
Whatever the conditions used, nitrogen nucleophiles
usually react with alkenoate derivatives through a conjugate
addition [6]. However, as observed previously from the 3-
methoxy derivative [4], n-propylamine and phenethylamine
reacted exclusively with (Z)-1a via an 1,2-addition to afford
1
2
the ¯uoroamides (Z)-2a and (Z)-2a , respectively, as indi-
cated in Scheme 2.
Owing to these possibilities, several ¯uoroheterocycles
have been synthesized by reaction of 1,2- or 1,3-bis nucleo-
philes on 2,3-di¯uoroacrylates [2] or 5-¯uoro-1,3-dioxin-4-
ones [3]. On the other hand, the synthetic potentiality of
On the other hand, it is also known that the thio-moiety of
some vinylsul®des could be stereospeci®cally exchanged
via a vinylic substitution [7]. Interestingly, the ¯uoroacrylate
(Z)-1a reacted smoothly with sodium thioglycolate in
methanol to provide the corresponding sul®de (Z)-1c
(Scheme 3, conditions i). Therefore, the preparation of
the 2-¯uoro analogue (Z)-2d of the natural fungicide Sin-
harine [8] was easily achieved from (Z)-1a in 56% overall
yield, via two 100% regioselective successive reactions
[Scheme 3: (Z)-1a ) (Z)-1d ) (Z)-2d]. The phenylthio
group of (Z)-1a was ®rst exchanged with methanethiolate
using preferentially CH Cl as solvent (conditions ii). Ami-
1
2
methyl (Z)-3-methoxy-2-¯uoroacrylate 1 (R ˆH, R ˆMe,
YˆOMe) has been examined by Schlosser and co-workers
[
4] who also obtained the corresponding 3-phenylthio deri-
1
2
vative 1a (R ˆH, R ˆMe, YˆSPh) upon treatment of 3-
methoxy 2-¯uoroacrylate with thiophenol and subsequent
thermal elimination of MeOH. Having proposed at the same
time a general methodology for the synthesis of 2-¯uoro-3-
phenylthio-2,3-unsaturated carbonyl compounds [5], this
result prompts us to report our work about the reactivity
2
2
1
2
of (Z)-1a and (Z)-1b (R ˆH, R ˆEt, YˆSPh) towards
heteronucleophiles. The utility of these reactions will also
be demonstrated suggesting an easy synthetic pathway to a
dation of (Z)-1d was then performed by reaction with
phenethylamine (conditions iii), as mentioned above.
¯
uorinated analogue of a natural product.
2
. Reaction with tin radicals followed by Stille coupling
*
1
Corresponding author.
Among organometallic species, only mixed organo-cup-
rates reagents allow the selective substitution of the thio
Part of the Ph. D. Dissertation of Didier Andr e s (N8 214±96 -
Universit e Claude Bernard-Lyon I)
0022-1139/98/$ ± see front matter # 1998 Elsevier Science S.A. All rights reserved.
P I I : S 0 0 2 2 - 1 1 3 9 ( 9 8 ) 0 0 2 4 9 - 8

6
4
D.F. Andr eÁ s et al. / Journal of Fluorine Chemistry 92 (1998) 63±67
Scheme 1.
Scheme 2.
Scheme 3.
group of 3-alkyl-3-[alkyl(or aryl) thio]alkenoates [9±12].
However, it should be noted that this coupling methodology
fails from less bulky 3-monothiosubstituted enoates like
cation equivalent. The thio group can be stereoselectively
exchanged via an addition±elimination. Moreover, the sub-
stitution of this thio group by a tributyltin one leads to a
reversal polarity allowing the Stille reaction to be success-
fully applied. Finally, such ¯uoroacrylate moiety synthetic
methodology is an alternative towards more classical Hor-
ner±Wadsworth±Emmons or Reformatsky reactions invol-
ving ¯uoroacetate anion [21].
ethyl 3-(phenylthio)propenoate (PhSCH=CH±CO Et)
2
which gave only a doubly alkylated product by reaction
with (Bu CuSCN)Li in THF at � 308C [10].
2
2
In order to avoid such dif®culties, 2-¯uoro-3-phe-
nylthioenoates (Z)-1a and (Z)-1b were converted [13] under
classical conditions, into the new corresponding (2-¯uoro-
acrylyl)stannanes [14±17] (E/Z)-5a and (E/Z)-5b, respec-
tively (Scheme 4). Pure (Z)-stereomers were then isolated
3. Experimental
by ¯ash chromatography on SiO (with petroleum ether as
2
1
eluent).
All melting points were uncorrected. H NMR spectra
(TMS, CDCl , ppm, Hz) were recorded on a BRUKER AC
Then as depicted in Scheme 4, (Z)-5a has been stereo-
selectively coupled with para-iodoanisole via a Stille reac-
tion under Farina's conditions to give (Z)-6 [18]. The diene
(Z,Z)-7, isolated as minor by-product was also selectively
prepared in good yield from treatment of (Z)-5a with copper
3
200 (200 MHz) spectrometer. 19F NMR (CFCl , CDCl )
spectra were measured at 188.2 MHz on a BRUKER AC
3
3
200 whilst 13CNMR spectra (TMS, CDCl ) were recorded
3
on the same apparatus at 50.3 MHz. Mass spectra were
taken on a NERMAG R10-10S (70 eV) coupled with a
capillary GC DELSI-DI 700 using DB5 column:
30 mÂ0.25 nm. Chromatography was carried out on silica
gel (Merck, 230±400 mesh).
(
II) nitrate trihydrate in tetrahydrofuran [19,20].
To conclude, the title compound which was easily pre-
pared by one electro¯uorination step from their respective-
hydrogeno analogues, are very useful as a 2-¯uoroacrylate

D.F. Andr eÁ s et al. / Journal of Fluorine Chemistry 92 (1998) 63±67
65
Scheme 4.
19
F NMR: � 125.0 (d, 3JHFˆ31.6) 13C
3
3
.1. Preparation of (Z)-1b
3JHFˆ31.6);
NMR: 34.5 (s, CH ), 52.5 (s, CH ), 53.0 (s, CH ), 119.3
2
3
3
2
1
(
d, C , JCFˆ13.5), 145.2 (d, C , JCFˆ253.7), 169.1 (d,
3
2
2
.1.1. Ethyl 2-fluoro-3-(phenylthio)acrylate
It was obtained by electrochemical ¯uorination of the
C ˆO, JCFˆ32.8).
1
corresponding 2-hydrogeno analogue as previously
1
3.2.2. Methyl 2-fluoro-3-(methylthio)prop-2-enoate (Z)-1d
To a stirred solution of 500 mg (2.35 mmol) of (Z)-1a in
5 ml of dichloromethane was added 214 mg (3.06 mmol) of
MeSNa. The resulting heterogeneous mixture was then kept
under nitrogen for 10 h and the ®nal work-up was carried
out as described as (Z)-1c. The crude oil (668 mg) was then
puri®ed by column chromatography using pure petroleum
3
described [5]. H NMR: 1.34 (t, 3H, JHHˆ7.1), 4.30 (q,
3
3
2
5
H, J ˆ7.1), 7.07 (d, 1H, J ˆ31.5), 7.37±7.51 (m,
9 3 13
HF
HH
HF
Harom); 1 F NMR: � 124.4 (d, J ˆ31.5); C NMR: 14.2
2
(
C ), 129.6 (s, 2 C ), 130.9 (s, 2 C ), 132.6 (s, C ), 144.8
s, CH ), 6.17 (s, CH ), 121.0 (d, C , J ˆ13.5), 128.4 (s,
3
2
3
CF
p
o/m
o/m
i
1
2
(
d, C , JCFˆ254.2), 159.2 (d, C ˆO, JCFˆ32.5).
2
1
1
ether and 207 mg (59%) of (Z)-1d was isolated. (Z)-1d: H:
3
3
.2. Preparation of (Z)-1c and (Z)-1d from (Z)-1a
HF
NMR 2.44 (s, 3H), 3.81 (s, 3H), 6.82 (d, 1H, J ˆ31.9);
1
9
3
13
F NMR: � 128.2 (d, JHFˆ31.9); C NMR: 16.9 (s, CH ),
3
4
2
5
2.3 (d, CH , J ˆ0.7), 122.9 (d, C , J ˆ13.6), 144.6 (d,
1 2
2 1
CF CF
3
CF
3
CF
3
.2.1. Methyl 2-fluoro-3-[(methoxycarbonyl)methylthio]-
prop-2-enoate (Z)-1c
To a stirred solution of 125 mg (1.18 mmol) of
C , J ˆ251.8), 159.7 (d, C ˆO, J ˆ32.5).
1
2
3.3. Preparation of 2-fluoro acrylamides: (Z)-2a , (Z)-2a
and (Z)-2d
methylthioglycolate and 64 mg (1.18 mmol) of MeONa
in 10 ml of MeOH, under nitrogen atmosphere, was slowly
added (15 min) a solution of 250 mg (1.18 mmol) of (Z)-1a
in 7 ml of methanol. The mixture was then stirred at room
temperature and its evolution followed by GC. After 20 h,
the reaction medium was hydrolysed with water (10 ml) and
acidi®ed by 6N HCl up to pH 1. Methanol was then
evaporated under reduced pressure and the aqueous phase
was extracted with dichloromethane. After drying on
3.3.1. N-phenethyl-2-fluoro-3-(methylthio)prop-2-enamide
(Z)-2d
3 ml of dry dichloromethane was placed in a small ¯ask
and kept under nitrogen. Then 60 mg (0.4 mmol) of (Z)-1d
and 55 ml (0.44 mmol) of phenethylamine were introduced.
The homogeneous mixture was stirred under re¯ux for 4 h
and the solvent was evaporated under reduced pressure
giving 91 mg (95%) of the crystallised product (Z)-2d:
which was not more puri®ed. (Z)-2d: m.p.: 111±1128C;
MgSO , evaporation of the solvent gave a crude oil
4
(
280 mg) which was puri®ed by column chromatography
1
3
using petroleum ether (b.p. 45±608C)/acetone (95/5) as
eluent. 90 mg (36%) of starting material (Z)-1a and
H NMR: 2.40 (s, 3H), 2.88 (t, 2H, JHHˆ7.0), 3.58 (dt, 2H,
3
3
J
HH
HH
ˆ7.0, J ˆ13.4), 6.18 (s, 1H, NH), 6.73 (d, 1H,
1
3J ˆ35.4), 7.20±7.31 (m, 5H
19
1
3
10 mg (45%) of (Z)-1c were isolated. (Z)-1c: H NMR:
.53 (s, 2H), 3.78 (s, 3H), 3.82 (s, 3H), 6.95 (d, 1H,
); F NMR: � 130.8
3 2
HF
(d, 3
arom
13
J
ˆ35.4); C NMR: 17.0 (s, CH ), 35.6 (CH ),
HF

6
6
D.F. Andr eÁ s et al. / Journal of Fluorine Chemistry 92 (1998) 63±67
2
3
4
(
0.5 (CH ), 117.5 (d, CHˆ, J ˆ13.4), 126.6 (s, C ), 128.7
1.22±1.60 (m, 18H), 4.28 (q, 2H, J ˆ7.50), 6.55 (d, 1H,
HH
2
CF
p
1
3
19
3
13
2Â2 C ), 138,4 (C ), 147.8 (d, CF, JCFˆ261.2), 158.8 (d,
JHFˆ65.1); F NMR: � 99.1 (d, JHFˆ65.1); C NMR:
3 3 3
o/m
i
2
‡
CO, JCFˆ27.3). MS m/z (%): 239 (M , 2), 192 (37), 148
10.2 (s, 3 CH ), 13.6 (s, 3 CH ), 14.2 (s, CH ), 27.2 (s, 3
CH ), 29.0 (s, 3 CH -Sn), 61.7 (s, CH ), 116.4 (d,
(
(
33), 135 (14), 120 (15), 119 (100), 105 (12), 104 (47), 91
28), 65 (15). Anal. Calc. for C H SNOF: C, 60.23; H,
2
2
2
2
1
JCFˆ41.2), 156.1 (d, JCFˆ249.8). 159.6 (d, CO,
JCFˆ45.8). (E)-5b: F NMR: � 88.3 (d, JHFˆ30.3).
1
2 14
2
19
3
5.90; S, 13.40; F, 7.54%. Found: C, 60.13; H, 5.92; S, 13.35;
F, 7.78%.
3
.5. Preparation of (Z)-6 by Stille coupling
3
.3.2. N-propyl-2-fluoro-3(phenylthio)prop-2-enamide
1
(
According to the procedure described above for (Z)-2d, it
Z)-2a
Under dried nitrogen atmosphere, 132 mg (0.56 mmol) of
iodoanisol, 35 mg (0.12 mmol, 20%) of triphenylarsine,
11 mg (10%) of Cul, 27 mg (5%) of Pd dba , CHCl and
1
1
was isolated as a white solid. (Z)-2a : m.p.: 62±648C, H
2
3
3
3
NMR: 0.94 (t, 3H, JHHˆ7.1), 1.42±1.67 (m, 2H), 3.17±3.39
220 mg (0.56 mmol) of (Z)-5a were dissolved in anhydrous
degassed dioxane (4 ml). After 10 h at 508C under stirring,
the solvent was evaporated and the crude oil (405 mg) was
3
(
m, 2H), 6.31 (s, 1H, NH), 7.01 (d, 1H, J ˆ34.9), 7.14±
HF
); 19F NMR: � 127.4 (d, J ˆ34.9). MS m/z
3
7.55 (m, 5H
%): 239 (M , 84), 182 (10), 181 (100), 161 (12), 153 (10),
arom
‡
HF
ꢀ
(
chromatographed on SiO (petroleum ether/acetone: 95/5)
2
1
(
52 (15), 133 (18), 130 (15), 110 (10), 109 (33), 93 (18), 89
11), 65 (14), 51 (10), 43 (10).
giving 57 mg (0.27 mmol) of (Z)-6 then 10 mg (0.05 mmol)
of (Z,Z)-7.
3
.3.3. N-phenethyl-2-fluoro-3(phenylthio)prop-2-enamide
2
3.5.1. Methyl 2-fluoro-3-(4-methoxyphenyl)prop-2-enoate
(Z)-6 [22]:
(
According to the procedure described above for (Z)-2d, it
Z)-2a
1
H NMR: 3.84 (s, 3H), 3.87 (s, 3H), 6.88 (d, 1H,
19
2
1
3
was isolated as a white solid. (Z)-2a : m.p.: 91±938C; H
JHFˆ35,7), 6.94±7.62 (m, 4Harom); F NMR: � 129.6
‡
ꢀ
3
3
3
NMR: 2.89 (t, 2H, JHHˆ7.0); 3.62 (dd, 2H, JHHˆ7.0,
(d, JHFˆ35.7). MS m/z (%): 210 (M , 100), 179 (17),
159 (11), 152 (10), 150 (11), 136 (14), 132 (34), 108 (20),
107 (32).
3
JHHˆ13.3); 6.18 (broad s, 1H, NH); 7.01 (d, 1H,
3
3
19
JHFˆ34.8); 7.22±7.48) (m, 10H); F NMR: � 127.9 (d,
‡
ꢀ
JHFˆ34.8). MS m/z (%): 301 (M , 45), 210 (17), 197 (54),
1
(
92 (23), 182 (12), 181 (100), 133 (28), 109 (34), 93 (20), 91
21), 89 (17), 77 (16), 65 (26).
3.6. Preparation of (Z,Z)-7 by intermolecular coupling of
(Z)-5a
3
.4. Preparation of (Z)-5a and (Z)-5b by stannylation of
Z)-1a and (Z)-1b, respectively
3.6.1. (Z,Z)-Dimethyl 2,5-difluorohex-2,4-diene-1,6-dioate
(Z,Z)-7
(
To a solution of 105 mg (0.43 mmol) of Cu(NO ) Á3H O
3
2
2
3
.4.1. Methyl 2-fluoro-3-(tributyltin)prop-2-enoate (Z)-5a
A solution of 1074 mg (3.69 mmol) of tributyltinhydride,
80 mg (1.80 mmol) of (Z)-1a and 36 mg (0.22 mmol, 5%)
in 0.5 ml of THF at room temperature was added 170 mg
(0.43 mmol) of (Z)-5a. The resulting mixture was stirred for
20 mn at the same temperature then treated as described in
[20]. The puri®cation of the crude oil (250 mg) by column
chromatography afforded 65 mg (0.32 mmol, 74%) of
(Z,Z)-7. H NMR: 3.88 (s, 6H), 6.87±7.03 (m, 2H); 19F
NMR: � 118.4 to � 118.1 (m); 3C NMR: 52.9 (s, 2 CH3),
3
of azaisobutyronitrile (AIBN) in 15 ml of benzene was
re¯uxed for 6 h, under a nitrogen atmosphere. Then, ben-
zene was evaporated under reduced pressure, giving
1
1
1
330 mg of crude oil which was puri®ed by column chro-
2
3
matography (petroleum ether). 552 mg of 5a (Z/E: 80/20)
was ®rstly isolated and pure (Z)-5a was obtained after a
second column chromatography. (Z)-5a: H NMR: 0.89 (t,
108.5 (dd, JCFˆ7.0, JCFˆ4.6, 2 CHˆ) 149.5 (d,
1
2
JCFˆ269.3, 2 CFˆ), 162.1 (d, JCFˆ33.9, 2 CO). MS
ꢀ
m/z (%): 206 (M , 21), 175 (10), 147 (100), 59 (15).
1
‡
3
3
9
1
H, JHHˆ7.1), 1.02 (t, 6H, JHHˆ8.2), 1.19±1.52 (m, 6H),
3
.56±1.69 (m, 6H), 3.82 (s, 3H), 6.56 (d, 1H, JHFˆ65.2);
19
3
13
F NMR: � 99.3 (d, JHFˆ65.2); C NMR: 10.2 (s, 3 CH ),
2
References
1
3.5 (s, 3 CH ), 27.1(s, 3 CH ), 28.9 (s, 3 CH -Sn), 52.4 (s,
3
2
2
2
CH ), 116.6 (d,ˆCHSnBu , J ˆ41.2), 155.7 (d, CF,
3
3
CF
[
1] J.M. Percy, in: R.D. Chambers (Ed.), Topics in Current Chemistry
933: Organofluorine Chemistry, Techniques and Synthons, Spring-
er, Berlin, 1997, pp. 131±195.
1
2
1
JCFˆ249.5), 159.8 (d, CO, JCFˆ46.4). (E)-5a:
NMR: 0.89 (t, 9H, JHHˆ7.1), 0.98 (t, 6H, JHHˆ8.1),
.21±1.47 (m, 6H), 1.51±1.67 (m, 6H), 3.83 (s, 3H), 6.01
H
1
3
3
1
[2] B. Dondy, P. Doussot, M. Iznaden, M. Muzard, C. Portella,
Tetrahedron Lett. 35 (1994) 4357.
3
19
3
(
d, 1H, JHFˆ32.0); F NMR: � 88.3 (d, JHFˆ32.0).
[
3] M. Sato, C. Kanuko, T. Iwaoka, Y. Kobayashi, T. Lida, J. Chem.
Soc., Chem. Commun., (1991) 699.
3
.4.2. Ethyl 2-fluoro-3-(tributyltin)prop-2-enoate (Z)-5b
Prepared by the same procedure used for (Z)-5a. (Z)-5b:
[
[
4] G. Shi, Q. Wang, M. Schlosser, Tetrahedron 52 (1996) 4403.
5] D. Andres, U. Dietrich, E. Laurent, B. Marquet, Tetrahedron 53
(1997) 647.
1H NMR: 0.85 (t, 9H, 3JHHˆ7.1), 0.98 (t, 3H, JHHˆ7.50),
3

D.F. Andr eÁ s et al. / Journal of Fluorine Chemistry 92 (1998) 63±67
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6] P. Permultter, in: J.E. Baldwin, P.D. Magnus (Eds.), Conjugate
Addition Reactions in Organic Synthesis, Tetrahedron Organic
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7] L. Testaferri, L. Tiecco, M. Tingoli, D. Chianelli, Tetrahedron 41
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Lett. 35 (1994) 1027 and [15±17].
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(
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[
[
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[
[
10] K. Dieter, L. Silks III, J. Org. Chem. 51 (1986) 4687.
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3
4 (1993) 7895.
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[
[
12] K. Mori, M. Fujiwhara, Tetrahedron 44 (1988) 343.
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