Phosphonium supported triphenylphosphine reagent: an improved access to α-fluoro-α,β-unsaturated esters

Article abstract of DOI:10.1016/j.tetlet.2006.09.008

α-Fluoro-α,β-unsaturated esters 2 were efficiently synthetized via diethylzinc-promoted Wittig reaction using a phosphonium-supported triphenylphosphine SCG-PPh₃ 1, which possesses similar reactivity as its parent analog triphenylphosphine. The

Full text of DOI:10.1016/j.tetlet.2006.09.008

Tetrahedron Letters 47 (2006) 7931–7933
Phosphonium supported triphenylphosphine reagent:
an improved access to a-fluoro-a,b-unsaturated esters
a
a
a
´
Ludivine Zoute, Celine Lacombe, Jean-Charles Quirion,
b
a,
*
´
Andre B. Charette and Philippe Jubault
a
`
Laboratoire d’He´te´rochimie Organique associe´ au CNRS, IRCOF, INSA et Universite´ de Rouen, 1 rue Tesniere,
76821 Mont Saint-Aignan Cedex, France
bDe´partement de Chimie, Universite´ de Montre´al, PO Box 6128, Station Downtown, Que., Canada H3C 3J7
Received 19 July 2006; revised 1 September 2006; accepted 1 September 2006
Available online 25 September 2006
Abstract—a-Fluoro-a,b-unsaturated esters 2 were efficiently synthetized via diethylzinc-promoted Wittig reaction using a phospho-
nium-supported triphenylphosphine SCG–PPh3 1, which possesses similar reactivity as its parent analog triphenylphosphine. The
main advantage of this system is the use of a novel low-molecular-weight support that is soluble in solvents of medium polarities
for the attachment of reagents and insoluble in solvents of low polarities.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
In particular, we developed an efficient synthesis of
a-fluoro acrylates from aldehydes or ketones using
triphenylphosphine, ethyl dibromofluoroacetate and
diethylzinc. The main drawback of such a process is
the difficult separation, in some cases, of triphenylphos-
phine and triphenylphosphine oxide from the expected
a-fluoro acrylate. We report herein the use of SCG–
PPh3 1 for the synthesis of a-fluoro-a,b-unsaturated
esters (see Scheme 1).
Very important efforts have been devoted during the
past few decades towards the development of novel sup-
ports to facilitate organic synthesis. This research area
includes the development of insoluble1 or soluble poly-
mers2 as solid supports, silica-bound scavengers or
reagents.3 Other approaches such as the use of ionic
liquids4 and fluorous phases5 have been applied with
success in organic synthesis.
The initial process for the synthesis of such compounds
was carried out in THF but SCG–Ph3 1 presents low
solubility in such a solvent. As 1 is soluble in solvents
One of us recently described the synthesis of new stable
entities which are soluble in well-defined solvents but
that precipitate completely with a minimum amount of
an orthogonal solvent.6 Tetraarylphosphonium salts
can be used effectively as solubility control group
(SCG). SCG–PPh3 1, which has been synthesized, is
totally insoluble in diethyl ether, is robust and possesses
similar reactivity as its parent analog triphenylphos-
phine. Another unique property of 1 is its little propen-
sity to trap organic compounds upon precipitation.
New process
R1
PPh2
ClO4
Ph3P
O
R1
R2
CO2Et
F
R2
+ Br2FCCO2Et + Et2Zn
CH2Cl2
2a-j
1
R1
R2
We also recently described an efficient synthesis of
fluoroolefins via diethylzinc-promoted Wittig reaction.7
Initial process
PPh3 + Br2FCCO2Et + Et2Zn
O
R1
R2
CO2Et
F
Keywords: Phosphonium-supported triphenylphosphine; Wittig reac-
THF
tion; Diethylzinc; Fluorine.
2a-j
*
Corresponding author. Fax: +33 2 35 52 29 59; e-mail: philippe.
jubault@insa-rouen.fr
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.008

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L. Zoute et al. / Tetrahedron Letters 47 (2006) 7931–7933
Table 1. Synthesis of a-fluoro a,b-unsaturated esters using SCG–PPh31
Entry
Compound
R1
R2
Phosphine
Yield (%)a
Z/Eb
1
2
3
4
5
6
7
8
9
2a
2a
2a
2b
2c
2d
2e
2f
4-MeO–C6H4
4-MeO–C6H4
4-MeO–C6H4
Ph
C6H5–CH@CH
CH3(CH2)4
Ph–CH2–CH2
4–MeO2C–C6H4
Ph–CH2
H
H
H
H
H
H
H
H
PPh3
PPh3
91c
89d
93
92
93
90
92
95
90
78
85
88
68/32
68/32
68/32
70/30
70/30
60/40
85/15
70/30
55/45
60/40
—
SCG–PPh31
SCG–PPh31
SCG–PPh31
SCG–PPh31
SCG–PPh31
SCG–PPh31
SCG–PPh31
SCG–PPh31
SCG–PPh31
SCG–PPh31
2g
2h
2i
CH3
CH3
10
11
12
Ph
(CH2)5
2j
BnO–C6H4
C2H5
80/20
a Isolated yield, product characterized by 1H, 13C, 19F NMR, IR and mass spectroscopies.7
b Ratio determined by 19F NMR.
c In THF (initial process).
d In CH2Cl2.
H
CO2Et
C5H11
F
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
ppm (f1)
Figure 1. Crude 1H NMR spectrum of a-fluoro a,b-unsaturated ester 2d.
of medium polarities (CH3CN, DMSO, CH2Cl2, etc.),
we first tested our process using triphenylphosphine
in dichloromethane. A similar yield was obtained
(Table 1, entry 2). SCG–PPh31 was mixed with ethyl
dibromofluoroacetate and diethylzinc in dichlorometh-
ane prior to the aldehyde addition. Under these condi-
tions, high yields of a-fluoro-a,b-unsaturated esters
were obtained (Table 1). In all cases, equal efficiency
was obtained either using triphenylphosphine or SCG–
PPh3 1. Various aldehydes were subjected to the opti-
mized reaction conditions, giving the expected fluoro-
olefins 2 in high yields (Table 1, entries 1–8). We also
applied such a process successfully to unactivated
ketones (Table 1, entries 9–12).
phine oxide-free organic layer. Concentration under
reduced pressure afforded a quantitative recovery of a
very clean crude product for which the NMR analysis
did not show any traces of phosphonium salts (Fig. 1).
In conclusion, we performed the application of SCG–
PPh3 to the synthesis of a-fluoro-a,b-unsaturated esters
via diethylzinc-promoted Wittig reaction. The main
advantage of this system is the use of a novel low-
molecular-weight support that is soluble in solvents
of medium polarities for the attachment of reagents
and insoluble in solvents of low polarities.
References and notes
When the reaction was completed,8 ethanol was added,
and the resulting solution was concentrated under
reduced pressure. The residue was diluted with dichloro-
methane, filtered on Celite to remove zinc salts, and the
addition of diethylether to the filtrate allowed complete
precipitation of the SCG–PPh3 oxide by-product, which
was removed by filtration leading to a phosphine/phos-
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2 mL) under argon. The reaction was then stirred at room
temperature for 10 min and then the appropriate aldehyde
or ketone (0.5 mmol, 1 equiv) was rapidly added. The
reaction mixture was then stirred for 10 min. The resulting
solution was then quenched with ethanol (5 mL) and the
solution was concentrated under reduced pressure. The
residue was diluted with dichloromethane (2 mL) and
filtered on a small pad of celite to remove zinc salts.
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induced the precipitation of the phosphonium salt. The
mixture was filtered on a pad of celite. The organic phase
was concentrated in vacuo to afford the nearly pure
compound. A quick flash chromatography on silica gel
(10% ethylacetate/cyclohexane) gave the expected a-fluoro
a,b-unsaturated ester. Rf = 0.5 (cyclohexane–EtOAc, 9:1).
(Z) and (E) 3-pentyl-2-fluoroacrylic acid ester: 60/40 (2d):
1H NMR (300 MHz, CDCl3): d = 6.05 (dt, 3JH–H = 8.0 Hz,
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3
3JH–F = 33.3 Hz, 0.6H, H3Z), 5.85 (dt, JH–H = 8.3 Hz,
3JH–F = 21.6 Hz, 0.4H, H3E), 4.20–4.10 (m, 2H, H9), 2.40
(dq, J = 1.7 Hz, J = 8.6 Hz, 0.8H, H4E), 2.15 (dq, J =
2.2 Hz, J = 7.2 Hz, 1.2H, H4Z), 1.40–1.20 (m, 9H, H5,6,7,8),
0.83 (t, 3H, J = 6.8 Hz, H10). 13C NMR (75.5 MHz,
CDCl3): d = 161.1 (d, J = 36 Hz), 161.0 (d, J = 26 Hz),
148.0 (d, J = 255 Hz), 147.0 (d, J = 250 Hz), 123.8 (d,
J = 18 Hz), 121.0 (d, J = 12 Hz), 61.5, 61.3, 31.4, 29.0
(d, J = 2 Hz), 29.0 (d, J = 2 Hz), 25.5 (d, J = 5 Hz), 24.2 (d,
J = 2 Hz), 22.5, 22.4, 14.1, 14.0. 19F NMR (282.5 MHz,
CDCl3): d = À123.2 (d, J = 21.5 Hz, 0.4F), À131.6 (d,
J = 33.3 Hz, 0.6F). IR (neat): 2960, 2932, 1732, 1678, 1467,
1373, 1309, 1261, 1201, 1148, 1089, 765 cmÀ1. MS (EI):
m/z = 188 (M+), 91, 41.
8. General procedure: To a solution of SCG-PPh3 1 (2 mmol
4 equiv, 1.2 g) and ethyl dibromofluoroacetate (1 mmol,
2 equiv, 140 lL) in dichoromethane (5 mL) was rapidly
added diethylzinc (1 M solution in hexane, 2 mmol, 2 equiv,