Synthesis of γ-Fluoro-α,β-unsaturated Carboxylic Esters from Saturated α-Fluoro Aldehydes

Article abstract of DOI:10.1002/(sici)1521-3897(200001)342:1<52::aid-prac52>3.0.co;2-h

γ-Fluoro-α,β-unsaturated carboxylic esters 7a, 7b and 7d and 4-fluoro-4-phenylbut-3-enoic ester (8) are obtained by two alternative pathways from 2-fluoro aldehydes 5a-d, either by Horner-Wadsworth-Emmons reaction or by Wittig reaction. The aldehydes 5a-d are prepared by Swern oxidation of the corresponding fluorohydrins 4a-d. These are available from α-olefins by bromofluorination, bromine-by-acetate replacement and subsequent hydrolysis.

Full text of DOI:10.1002/(sici)1521-3897(200001)342:1<52::aid-prac52>3.0.co;2-h

FULL PAPER _________________________________________________________________________
Synthesis of γ-Fluoro-α,β-unsaturated Carboxylic Esters from
Saturated α-Fluoro Aldehydes
Jens Oldendorf and Günter Haufe*
Münster, Organisch-Chemisches Institut der Westfälischen Wilhelms-Universität
Received September 06th, 1999
Keywords: Aldehydes, C–C coupling, Fluorine, Oxidations, Fluorohydrins
Abstract. γ-Fluoro-α,β-unsaturated carboxylic esters 7a, 7b
and 7d and 4-fluoro-4-phenylbut-3-enoic ester (8) are ob-
tained by two alternative pathways from 2-fluoro aldehydes
5a–d, either by Horner–Wadsworth–Emmons reaction or by
Wittig reaction. The aldehydes 5a–d are prepared by Swern
oxidation of the corresponding fluorohydrins 4a–d. These
are available from α-olefins by bromofluorination, bromine-
by-acetate replacement and subsequent hydrolysis.
Partially fluorinated organic materials – both analogues
of naturally occurring compounds and synthetic sub-
stances – gain a continuously growing interest by or-
ganic chemists, medicinal chemists, material scientists
and others due to the unique chemical properties and
biological activity [1]. Hence, there is an enormous de-
mand of synthetic methods for the introduction of a flu-
orine atom at a specific position in the molecule [2].
Among the carbonyl compounds α-fluorinated ketones
and carboxylic acids are fully characterized [3]. Also
α-fluoro-α,β-unsaturated aldehydes are well known and
widely used, e.g. in synthesis of fluorinated analogues
of vitamin A or derivatives [4]. Saturated 2-fluoro alde-
hydes have also been synthesized by different methods
[5, 6]. However, these compounds are described to be
rather unstable [6b, 6e, 6i]. 2-Fluoro aldehydes are ex-
pected to be useful building blocks joining the carbonyl
group with the attribute of having a fluorine substitu-
ent. Thinking of the numerous well known reactions
with non-fluorinated aldehydes, fluorinated molecules
should be versatile building blocks.
potassium acetate in dimethyl formamide led to β-fluoro
acetates 3a–d in moderate yields (62–69%), with the
exception of 3c (28%). This procedure is superior to
that one we used in the past [9]. The main reason for
low yield in the latter case is the favoured elimination
of HBr to α-fluoro styrene. Hydrolysis of 3a–d under
basic conditions yielded the 2-fluoro alcohols 4a–d
(66 –91%) (Scheme 1).
R1
R1
R2
R1
R2
F
F
ii
i
Br
OAc
R2
1a-d
2a-d
3a-d
R1
R2
F
R1
R2
F
iii
iv
O
OH
H
4a-d
5a-d
We like to report on synthesis of different types of
2-fluoro aldehydes and their application as starting ma-
terials for the synthesis of γ-fluoro-α,β-unsaturated carb-
oxylic esters by Horner–Wadsworth–Emmons (HWE)
reaction or by Wittig reaction, respectively.
a
b
F
c
d
R1
R2
CH3
C6H5
H
C6H5
H
C8H17
C6H5
Scheme 1 Syntheses of 2-fluoroaldehydes; reagents and con-
ditions: (i) NBS, Et3N·3HF, CH2Cl2, 12 h, r.t.; (ii) KOAc,
DMF, 26 h, 153 °C; (iii) KOH, methanol, 0.5–6 h, 0 °C or
20 °C; (iv) Oxalyl chloride/DMSO, Et3N, CH2Cl2, 15 min,
–60 °C.
Results and Discussion
According to our well established procedure [7] the ter-
minal olefins 1a–d react in high yields to the bromo
fluoro adducts 2a–d by using N-bromosuccinimide
(NBS) as a source of electrophilic bromine and triethyl-
amine tris(hydrofluoride) [8] (Et3N·3HF) or trimethyl-
amine bis(hydrofluoride) (Me3N·2HF) as a very mild
nucleophilic fluorinating agent. Heating of 2a–d with
Better yield of 4c was obtained by ring opening of
styrene oxide (6) with Et3N·3HF in the presence of
20 mol% of BF3·Et2O at room temperature according
to a procedure described for α-alkylstyrene oxides [9a]
(Scheme 2).
52
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000 1436-9966/99/3410X-52 $ 17.50 + .50/0
J. Prakt. Chem. 2000, 342, No. 1

Synthesis of γ-Fluoro-α,β-unsaturated Carboxylic Esters
___________________________________________________________________________ FULL PAPER
F
the thermodynamically more stable styrene derivative,
the γ-fluoro-β,γ-unsaturated carboxylic ester 8, which
was isolated in quite low yields (34% and 25% respec-
tively, over two steps) (Scheme 4). No (E)-isomer was
found by 1H and 19F NMR spectroscopy.
O
Et3N·3HF,
BF3·Et2O
OH
CH2Cl2, 12 h, r.t.
6
4c
Scheme 2 Synthesis of 2-fluoro-2-phenylethanol
H
F
H
H
F
The selective oxidation of the fluorohydrins to 2-
fluoro aldehydes 5a–d is a key step of the shown se-
quence (Scheme 1). However, methods by Corey [10]
according to a modified procedure [11] or Pfitzner and
Moffatt [12] failed or gave low yield. Finally Swern
oxidation [13] was found to be the most effective
method. The handling is quite simple, there is no ob-
structing by-product and the yields are high (83–95%),
except for 4c (65%). All attempts to purify the 2-fluoro
aldehydes 5a–d failed (vacuum distillation at low tem-
perature and liquid chromatography) as already report-
ed by other authors [6b, 6e, 6i]. Thus, we used the freshly
prepared crude products for further reactions. Treatment
of triethyl phosphono acetate with sodium hydride
formed the phosphonate anion [14] which on reaction
with 2-fluoro aldehydes 5a, 5b and 5d gave the γ-fluoro-
α,β-unsaturated carboxylic esters 7a, 7b and 7d in 52 –
76% yields over two steps (Scheme 3), similarly to a
transformation Davis et al. reported for a 2-fluoropro-
pionic aldehyde [6i]. As an alternative method the Wit-
tig reaction yielded the same products (57–72% over
two steps). In all cases the HWE reactions gave the (E)-
isomers (1H and 19F NMR spectroscopy) and also in the
Wittig reactions the (E)-isomers were formed almost
exclusively (except for 7d, (E):(Z) = 85:15).
O
Ph
Ph
CO2Et
H
H
5c
7c
F
Ph
CO2Et
8
Scheme 4 Wittig olefination of 2-fluoro-2-phenylacetalde-
hyde
In conclusion, although the saturated 2-fluoro alde-
hydes 5a–d could not be isolated as pure compounds
they have been shown to be good building blocks for
γ-fluoro-α,β-unsaturated carboxylic esters 7a, 7b and
7d or the γ-fluoro-β,γ-unsaturated carboxylic ester 8.
Financial support by the Fonds der Chemischen Industrie is
greatfully acknowledged. We thank the Hoechst AG, Frank-
furt/Main, and the Bayer AG, Leverkusen, for kind donation
of chemicals.
Experimental
R1
R2
H
R1
R2
F
F
1
General: H- (300 MHz), 13C- (75.5 MHz) and 19F- (282.3
O
v or vi
CO2Et
MHz) NMR spectra were recorded using a Bruker WM 300
spectrometer with CDCl3 as solvent and tetramethylsilane
(TMS) or CFCl3, respectively, as internal standards. – Mass
spectra (electron impact ionization 70 eV, chemical ioniza-
H
H
7
5
+
tion with NH4 ) were determined using a GC/MS system:
a
b
d
Varian GC 3400/MAT 8230 and data system of Finnigan/
MAT. – Column chromatography was performed using silica
gel (Merck, particle size 0.022–0.063 mm). – Thin layer chro-
matography was taken with TLC plates 60 F 254 by Merck. –
Gas chromatographical analyses were performed with a
Hewlett Packard 5890 II gas chromatograph (quartz capil-
lary column 0.32 mm × 30 m, 0.25 µm SPB-1, Supelco). –
Infrared spectra were recorded using a Nicolet 5DXC-FT-
spectrophotometer. – Elemental analyses were taken at the
Mikroanalytisches Laboratorium, OC, Universität Münster,
with a Heraeus Elementaranalysator CHN–O-Rapid. – Tri-
ethylamine tris(hydrofluoride) and trimethylamine bis-
(hydrofluoride) were provided by Hoechst AG, Frankfurt/
Main, and Bayer AG, Leverkusen. All other starting materi-
als and reagents were obtained from Fluka, Merck, Aldrich,
R1
R2
CH3
C6H5
F
C6H5
H
C8H17
Scheme 3 Wittig-olefinations of 2-fluoroaldehydes; reagents
and conditions: (v) (EtO)2P(O)CH2CO2Et, NaH, pentane,
2 h, 36 °C; (vi) [Ph3PCH2CO2Et]+Br–, NaH, DMSO, 2 h,
80 °C.
However, the γ-fluoro-α,β-unsaturated carboxylic
ester 7c could not be isolated following the same proce-
dures. This compound could not even be detected by
NMR or other analytical methods in the crude product
mixture. Under the conditions of the HWE or Wittig
reactions, respectively it is obviously rearranged into
J. Prakt. Chem. 2000, 342, No. 1
53

J. Oldendorf, G. Haufe
FULL PAPER __________________________________________________________________________
Riedel deHaen and Janssen chemicals; dichloromethane and
N,N-dimethyl formamide were purified by distillation and
dried by storage over molecular sieves 0.4 nm.
1-Acetoxy-2-fluoro-2-phenylpropane (3a)
Prepared from 7.00 g (32 mmol) of 1-bromo-2-fluorophenyl-
propane (2a); yield 4.04 g (20.6 mmol, 64%, 98% purity, GC).
– TLC (cyclohexane/ethyl acetate, 10:1): Rf = 0.24. – IR
~
Synthesis of Vicinal Bromo Fluoro Compounds 2a–d
(NaCl): /cm–1 = 1 749 (C=O). – All other analytical and
v
spectroscopic data agree with published values [9a].
According to the general procedure [7b] a mixture of 20 mmol
of the α-olefin 1 and 5 ml (31 mmol) of Et3N·3HF or 4.7 ml
(45 mmol) of Me3N·2HF in 50 ml of dry CH2Cl2 is cooled to
0 °C and treated in portions with 3.90 g (22 mmol) of NBS.
After stirring for 15 min the solution is allowed to warm up at
room temp. and stirred for another 4–6 hours. After the reac-
tion has finished the mixture is poured into 500 ml of ice/
water. It is neutralized with 25% aq. NH3 and extracted with
50 ml of CH2Cl2 three times. The combined organic phases
are washed two times with 50 ml of 0.1N HCl and subse-
quently with 5% aq. NaHCO3 (3 × 50 ml), and dried with
MgSO4. After evaporation of the solvent under reduced pres-
sure the products are purified by distillation or liquid chro-
matography (silica gel, cyclohexane (2b), cyclohexane/ethyl
acetate, 10:1 (2a, 2c), cyclohexane/ethyl acetate, 20:1 (2d)).
2-Acetoxy-1,1-difluoro-1-phenylethane (3b)
Prepared from 1.97 g (8.9 mmol) of 2-bromo-1,1-difluoro-1-
phenylethane (2b); yield 1.23 g (69%, 98% purity, GC). –
TLC (cyclohexane/ethyl acetate, 10:1): Rf = 0.22. – IR (NaCl):
~
1
/cm–1 = 1756 (C=O). – H NMR: δ/ppm = 2.07 (s, 3H,
v
CH3), 4.48 (t, 3JH,F = 13.1 Hz, 2H, CH2), 7.40–7.54 (m, 5H,
aromatic H). – 13C NMR: δ/ppm = 20.5 (q, CH3), 65.1 (tt,
2JC,F = 33.1 Hz, CH2), 119.2 (ts, 1JC,F = 244.1 Hz, CF2), 125.4
(td, 3JC,F = 7.6 Hz, C-o), 128.5 (d, C-p), 130.5 (d, C-m), 134.0
(ts, JC,F = 17.8 Hz, C-i), 169.8 (s, C(O)CH3). – 19F NMR:
2
δ/ppm = –104.9 (m). – GC/MS (70 eV), m/z (%): 201 (10)
[MH+], 200 (62) [M+], 141 (6) [MH+ – CH3CO2H], 140 (20)
[M+ – CH3CO2H], 128 (10) [MH+ – CH2OAc], 127 (100)
[M+ – CH2OAc], 91 (12) [C7H7 ], 77 (16) [C6H5 ], 73 (26)
+
+
[CH2OAc+], 51 (10) [C4H3 ], 43 (70) [C2H3O+].
+
1-Bromo-2-fluoro-2-phenylpropane (2a)
Prepared from 11.81 g (100 mmol) of 2-phenylprop-1-ene
(1a) using 19.50 g (110 mmol) of NBS and 23.5 ml (225 mmol)
of Me3N·2HF; yield 20.40 g (94%, 95% purity, GC). – TLC
(cyclohexane/ethyl acetate, 10:1): Rf = 0.45. Analytical and
spectroscopic data agree with published values [7a].
2-Acetoxy-1-fluoro-1-phenylethane (3c)
Prepared from 1.50 g (7.4 mmol) of 2-bromo-1-fluoro-1-phe-
nylethane (2c); yield 0.38 g (28%, 96% purity, GC). – TLC
(cyclohexane/ethyl acetate, 10:1): Rf = 0.26. – IR (NaCl):
~
1
/cm–1 = 1 748 (C=O). – H NMR: δ/ppm = 2.11 (s, 3H,
v
CH3), 4.26–4.43 (m, 2H, CHAHB), 5.65 (ddd, 3JX,A = 4.3 Hz,
2-Bromo-1,1-difluoro-1-phenylethane (2b)
3JX,B = 6.7 Hz, JX,F = 48.4 Hz, 1H, CHXF), 7.31–7.45 (m,
2
Prepared from 6.30 g (31 mmol) of 1-fluoro-1-phenylethene
[15] (1b) using 6.04 g (34 mmol) of NBS and 7.3 ml
(69.8 mmol) Me3N·2HF; yield 5.02 g (77%, 98% purity, GC).
– TLC (cyclohexane): Rf = 0.28. Analytical and spectros-
copic data agree with published values [16].
5H, aromatic H). – 13C NMR: δ/ppm = 20.7 (q, CH3), 66.8
2
1
(dt, JC,F = 22.9 Hz, CHAHB), 91.7 (dd, JC,F = 178.0 Hz,
CHXF), 125.8 (dd, 3JC,F = 7.6 Hz, C-o), 128.7 (d, C-p), 129.0
(d, C-m), 135.9 (ds, 2JC,F = 20.3 Hz, C-i), 170.6 (s, C(O)CH3).
–
19F NMR: δ/ppm = –184.9 (m). – GC/MS (70 eV),
m/z (%): 181 (0.1) [M+ – H], 162 (2) [M+ – HF], 123 (46) [M+
2-Bromo-1-fluoro-1-phenylethane (2c)
– CH3COO], 122 (100) [M+ – CH3CO2H], 109 (100) [M+ –
Prepared from 15.62 g (150 mmol) of styrene (1c) using
29.25 g (165 mmol) of NBS and 35.3 ml (338 mmol) of
Me3N·2HF; yield 26.14 g (85%, 98% purity, GC). – TLC
(cyclohexane/ethyl acetate, 10:1): Rf = 0.41. Analytical and
spectroscopic data agree with published values [17].
+
+
CH2CO2CH3], 91 (16) [C7H7 ], 77 (22) [C6H5 ], 51 (28)
[C4H3 ], 43 (100) [COCH3 ], 39 (16) [C3H3 ].
+
+
+
1-Acetoxy-2-fluorodecane (3d)
Prepared as a 93:7 mixture of regioisomers with 2-acetoxy-
1-fluorodecane from 21.80 g (91 mmol) of 1-bromo-2-fluoro-
decane (2d) (as a 87:13 mixture of regioisomers with 2-bro-
mo-1-fluorodecane); yield 12.33 g (62%, 93% purity, GC). –
TLC (cyclohexane/ethyl acetate, 20:1): Rf = 0.19. – IR (NaCl):
1-Bromo-2-fluorodecane (2d)
Prepared from 14.02 g (100 mmol) of dec-1-ene (1d) as a
87:13 mixture of regioisomers with 2-bromo-1-fluorodecane
using 19.50 g (110 mmol) of NBS and 25.0 ml (155 mmol) of
Et3N·3HF; yield 20.92 g (88%, 87% purity, GC). – TLC (cyc-
lohexane/ethyl acetate, 20:1): Rf = 0.55. Analytical and spec-
troscopic data agree with published values [16b,17b].
~
v /cm–1 = 1747 (C=O). – 13C NMR: δ/ppm = 14.0 (q, C-10),
20.7 (q, C-12), 22.6, 24.7, 24.8, 29.1, 29.3, 31.8 (t, C-4–C-
2
2
9), 31.4 (dt, JC,F = 20.3 Hz, C-3), 65.9 (dt, JC,F = 22.9 Hz,
1
C-1), 91.4 (dd, JC,F = 172.9 Hz, C-2), 170.7 (s, C-11). –
19F NMR: δ/ppm = –187.5 (m). – GC/MS (70 eV), m/z (%):
Synthesis of 2-Fluoroalkyl Acetates 3a–d
156 (5) [M+ – C2H3OF], 96 (15) [C7H12+], 82 (18) [C6H10+],
A mixture of 10 mmol of the respective bromo fluoro com-
pound 2 and 3.93 g (40 mmol) of KOAc in 50 ml of dry DMF
is heated for 26 h at 153 °C under argon. After the reaction
has been cooled down to room temp. 50 ml of a 1:1 mixture
of cyclohexane and ethyl acetate is added and the solid is
filtered off and washed carefully with the same solvent. The
organic phase is washed with water (6 × 75 ml) and dried
with MgSO4. After evaporation of the solvent under reduced
pressure the products are isolated by column chromatogra-
phy (silica gel, cyclohexane/ethyl acetate, 10:1).
55 (18) [C4H7 ], 43 (100) [C2H3O+]. – H NMR spectros-
copic data agree with published values [18].
+
1
Synthesis of 2-Fluoroalkanols 4a–d
A mixture of 5 mmol of the 2-fluoro acetate 3 in 10 ml of
methanol is added to a mixture of 0.84 g (15 mmol) of KOH
in 20 ml of MeOH. After stirring (the reaction temp. and the
time of stirring depend on the reactivity of the fluoro acetate)
the solution is poured into 100 ml of ice/water and extracted
54
J. Prakt. Chem. 2000, 342, No. 1

Synthesis of γ-Fluoro-α,β-unsaturated Carboxylic Esters
___________________________________________________________________________ FULL PAPER
with CH2Cl2 (5 × 30 ml). The combined organic layers are
washed three times with 50 ml of water and dried with MgSO4.
The solvent is evaporated in vacuo, and the product is isolat-
ed by column chromatography (silica gel, cyclohexane/ethyl
acetate, 5:1).
CH2Cl2 is slowly dropped into the mixture. After 15 min
1.02 g (10 mmol) of Et3N is added slowly. After stirring for
15 min the solution is allowed to warm up at room temp.
within 1 h. After the reaction has finished the mixture is poured
into 50 ml of ice/water and extracted three times with 30 ml
of CH2Cl2. The combined organic phases are dried with
MgSO4 and the crude products are isolated by evaporation of
the solvent. Attempts to purify the 2-fluoro aldehydes by chro-
matography or vacuum distillation at low temperature result-
ed in decomposition. Therefore, the aldehydes were used in
crude form for further reactions.
2-Fluoro-2-phenylpropanol (4a)
Prepared from 0.58 g (3 mmol) of 1-acetoxy-2-fluoro-2-phe-
nylpropane (3a); reaction temp.: 0 °C, reaction time: 15 min;
yield 0.30 g (66%, 95% purity, GC). – TLC (cyclohexane/
ethyl acetate, 5:1): Rf = 0.15. – Analytical and spectroscopic
data agree with published values [9a].
2-Fluoro-2-phenylpropanal (5a)
2,2-Difluoro-2-phenylethanol (4b)
Prepared from 0.15 g (1 mmol) of 2-fluoro-2-phenylpropa-
Prepared from 1.23 g (6 mmol) of 2-acetoxy-1,1-difluoro-1-
phenylethane (3b); reaction temp.: 20 °C, reaction time: 4 h;
yield 0.88 g (91%, 98% purity, GC). – TLC (cyclohexane/
ethyl acetate, 5:1): Rf = 0.19. – GC/MS (70 eV), m/z (%): 159
(10) [MH+], 158 (84) [M+], 128 (70) [MH+ – CH3O], 127
(100) [M+ – CH3O], 107 (12) [M+ – CH3OHF], 91 (20)
[C7H7 ], 77 (70) [C6H5 ], 51 (40) [C4H3 ], 39 (10) [C3H3 ]. –
1H, 13C and 19F NMR spectroscopic data agree with published
values [6e].
nol (4a); yield 0.14 g crude product (94%, 95% purity, GC).
~
1
– IR (NaCl): /cm–1 = 1 749 (C=O). – H NMR: δ/ppm =
v
3
1.79 (d, JH,F = 22.7 Hz, 3H, CH3), 7.28–7.43 (m, 5H, aro-
matic H), 9.70 (d, 3JH,F = 4.8 Hz, 1H, CHO). – 13C NMR: δ/
ppm = 22.1 (dq, 2JC,F = 22.9 Hz, CH3), 98.7 (ds, 1JC,F = 178.0
Hz, CFCH3), 124.9 (dd, 3JC,F = 7.6 Hz, C-o), 128.4 (d, C-p),
128.9 (C-m), 136.7 (ds, 2JC,F = 22.9 Hz, C-i), 197.4 (dd, 2JC,F
= 40.7 Hz, CHO). – GC/MS (70 eV), m/z (%): 153 (0.5)
[MH+], 152 (5) [M+], 123 (100) [M+ – HF], 109 (10) [C7H6F+],
+
+
+
+
103 (42) [C8H7 ], 77 (24) [C6H5 ], 51 (15) [C4H3 ]. – 19F
NMR spectroscopic data agree with published values [6b].
+
+
+
2-Fluoro-2-phenylethanol (4c)
Prepared from 0.23 g (1.3 mmol) of 2-acetoxy-1-fluoro-1-
phenylethane (3c); reaction temp.: 20 °C, reaction time: 2 h;
yield 0.14 g (79%, 98% purity, GC). – TLC (cyclohexane/
ethyl acetate, 5:1): Rf = 0.14. – Analytical and spectroscopic
data agree with published values [19].
2,2-Difluoro-2-phenylethanal (5b)
Prepared from 0.27 g (1.7 mmol) of 2,2-difluoro-2-phenyl-
ethanol (4b); yield 0.24 g crude product (90%, 95% purity,
GC). – GC/MS (70 eV), m/z (%): 156 (10) [M+], 128 (10)
+
+
+
[C7H6F2 ], 127 (100) [C7H5F2 ], 77 (18) [C6H5 ], 51 (10)
[C4H3 ]. – 1H NMR spectroscopic data agree with published
+
2-Fluoro-2-phenylethanol (4c) by ring opening of styrene
oxide (6)
values [6e].
A mixture of 0.50 g (4.2 mmol) of styrene oxide (6), 2.0 g
(12.4 mmol) of Et3N·3HF, and 0.11 g (0.8 mmol) of BF3·Et2O
in 50 ml of dry CH2Cl2 is stirred at room temp. for 12 h. The
working up procedure is the same as described for bromofluor-
ination; yield 0.41 g (70%, 96% purity, GC).
2-Fluoro-2-phenylethanal (5c)
Prepared from 0.23 g (1.6 mmol) of 2-fluoro-2-phenyletha-
nol (4c); yield 0.21 g crude product (65% purity, GC). – IR
~
(NaCl): v /cm–1 = 1735 (C=O). – GC/MS (70 eV), m/z (%):
138 (18) [M+], 110 (20) [C7H7F+], 109 (100) [C7H6F+], 51
+
1
(6) [C4H3 ]. – H NMR spectroscopic data agree with pub-
2-Fluorodecanol (4d)
lished values [21].
Prepared from 11.50 g (52.8 mmol) of 1-acetoxy-2-fluoro-
decane (3d) (as a 93:7 mixture of regioisomers with 2-acet-
oxy-1-fluorodecane); reaction temp.: 20 °C, reaction time:
4 h; yield 7.58 g (82%, 96% purity, GC). – TLC (cyclohex-
ane/ethyl acetate, 5:1): Rf = 0.17. – 13C NMR: δ/ppm = 14.0
(q, C-10), 22.6, 24.9, 24.9, 29.1, 29.4, 31.8 (t, C-4–C-9), 31.0
(dt, 2JC,F = 20.3 Hz, C-3), 65.1 (dt, 2JC,F = 22.9 Hz, C-1), 94.7
2-Fluorodecanal (5d)
Prepared from 0.35 g (2 mmol) of 2-fluorodecanol (4d), yield
0.33 g crude product (94%, 83% purity, GC). – 13C NMR:
δ/ppm = 14.0 (q, C-10), 22.5, 24.1, 24.8, 29.4, 31.7 (t, 5-
3
CH2–9-CH2), 29.1 (dt, JC,F = 7.6 Hz, C-4), 30.3 (dt, 2JC,F
=
1
22.9 Hz, C-3), 95.0 (dd, JC,F = 178.0 Hz, C-2), 200.1 (dd,
2JC,F = 35.6 Hz, C-1). – GC/MS (70 eV), m/z (%): 174 (1)
[M+], 156 (0.2) [M+ – H2O], 131 (2) [M+ – C2H3O], 83 (20)
1
(dd, JC,F = 165.3 Hz, C-2). – GC/MS (70 eV), m/z (%): 97
(15) [C7H13+], 96 (40) [C7H14+], 83 (35) [C6H11+], 81 (40)
+
+
+
[C6H9 ], 71 (20) [C5H11+], 69 (50) [C5H9 ], 57 (60) [C4H9 ],
[C6H11+], 71 (45) [C5H11+], 69 (25) [C5H9 ], 57 (80) [C4H9 ],
+
+
+
+
+
55 (90) [C4H7 ], 43 (100) [C3H7 ], 41 (85) [C3H5 ], EI;
m/z (%): 194 (100) [M+ + NH4], 156 (8) [M+ – H2O], CI. –
1H and 19F NMR spectroscopic data agree with published
values [6d, 20].
55 (60) [C4H7 ], 43 (100) [C3H7 , C2H3O+], 41 (78) [C3H5 ].
+
+
+
1
– H and 19F NMR spectroscopic data agree with published
values [6e].
Synthesis of the γ-Fluoro-α,β-unsaturated Carboxylic
Acid Esters 7a, 7b and 7d by Horner–Wadsworth–Em-
mons Reaction
Synthesis of 2-Fluoro Aldehydes 5a–d
In a two necked round bottom flask a mixture of 0.28 g
(2.2 mmol) of oxalyl chloride in 15 ml of dry CH2Cl2 is cooled
to – 60 °C under argon. A solution of 0.37 g (4.7 mmol) of
DMSO in 5 ml of dry CH2Cl2 is added dropwise. After
15 min stirring 2 mmol of the 2-fluoroalkanol 4 in 5 ml of dry
Under an argon atmosphere and with ice cooling a mixture of
2-fluoro aldehydes 5a, 5b or 5d obtained by oxidation of
4 mmol of the corresponding 2-fluoroalkanols 4a, 4b or 4d in
J. Prakt. Chem. 2000, 342, No. 1
55

J. Oldendorf, G. Haufe
FULL PAPER __________________________________________________________________________
5 ml of dry Et2O is added dropwise to a mixture of 0.12 g
(4 mmol) of sodium hydride (80% in paraffine) and 0.90 g
(4 mmol) of triethylphosphono acetate in 50 ml of dry Et2O.
After stirring and heating at 34 °C for three hours the mixture
is poured into 50 ml of ice/water and extracted with Et2O (3 ×
30 ml). The combined organic phases are dried with MgSO4,
and after evaporation of the solvent under reduced pressure
the products are isolated by column chromatography (cy-
clohexane/ethyl acetate, 10:1).
7.39–7.52 (m, 5H, aromatic H). – 13C NMR: δ/ppm = 14.1
(q, C-6), 61.2 (t, C-5), 118.4 (ts, 1JC,F = 241.6 Hz, C-4), 124.9
(td, 3JC,F = 7.6 Hz, C-o), 125.3 (td, 3JC,F = 5.1 Hz, C-2), 128.7
(d, C-p), 130.4 (d, C-m), 135.2 (ts, 2JC,F = 25.4 Hz, C-i), 139.9
(td, 2JC,F = 30.5 Hz, C-3), 165.1 (s, C-1). – 19F NMR: δ/ppm
= –95.6 (m). – GC/MS (70 eV): m/z (%): 226 (40) [M+], 198
(10) [M+ – C2H4], 181 (30) [M+ – C2H5O], 153 (80) [M+ –
C3H5O2], 133 (100) [M+ – C3H5O2 – HF], 77 (30) [C6H5 ],
+
+
51 (15) [C4H3 ].
C12H12F2O2 Calcd.: C 63.71 H 5.35
(226.2)
Found: C 64.14 H 5.71.
Synthesis of the γ-Fluoro-α,β-unsaturated Carboxylic
Acid Esters 7a, 7b and 7d by Wittig reaction
Ethyl (E)-4-fluorododec-2-enoate (7d)
A mixture of 0.79 g (3 mmol) of triphenylphosphine and
0.50 g (3 mmol) of ethyl bromo acetate in 40 ml of DMSO is
heated for 3 hours at 80 °C. After cooling down to room temp.
0.09 g (3 mmol) of sodium hydride (80% in paraffine) is add-
ed, and the mixture is heated for another hour. A solution of
the 2-fluoro aldehyde 5a, 5b or 5d obtained by oxidation of
3 mmol of the corresponding 2-fluoroalkanol 4a, 4b or 4d in
10 ml of DMSO is added to the cooled mixture containing
the phosphonium salt and heated for another two hours. After
the reaction has finished the mixture is poured into 100 ml of
ice/water and worked up as mentioned above.
By HWE reaction: Prepared from 0.32 g (1.8 mmol) of
2-fluorodecanol (4d) via 2-fluorodecanal (5d); yield 0.23 g
(52%, 98% purity, GC); by Wittig reaction: Prepared from
0.26 g (1.5 mmol) of 2-fluorodecanol (4d) via 2-fluorodeca-
nal (5d); yield 0.25 g (70% over two steps, 98% purity, 85:15
mixture of diastereomers, GC). – TLC (cyclohexane/ethyl
~
acetate, 20:1): Rf = 0.27. – IR (NaCl): v /cm–1 = 1 725 (C=O).
1
3
– H NMR: δ/ppm = 0.88 (t, JH,H = 6.7 Hz, 3H, 12-CH3),
1.30 (t, 3JH,H = 7.2 Hz, 3H, 14-CH3), 1.27–1.78 (m, 14H, 5-
3
CH2–11-CH2), 4.21 (q, JH,H = 7.2 Hz, 2H, 13-CH2), 5.06
(dm, 2JX,F = 48.4 Hz, 1H, 4-CHX), 6.04 (ddd, 4JA,X = 1.7 Hz,
Ethyl (E)-4-fluoro-4-phenylpent-2-enoate (7a)
4JA,F = 1.7 Hz, 3JA,B = 16.0 Hz, 1H, 2-CHA), 6.89 (ddd, 3JB,X
3
3
= 4.3 Hz, JB,A = 16.0 Hz, JB,F = 20.3 Hz, 1H, 3-CH ). –
By HWE reaction: Prepared from 0.15 g (1 mmol) of 2-fluoro-
2-phenylpropanol (4a) via 2-fluoro-2-phenylpropanal (5a);
yield 0.17 g (76% over two steps, 99% purity, GC); by Wittig
reaction: Prepared from 0.23 g (1.5 mmol) of 2-fluoro-2-phe-
nylpropanol (4a) via 2-fluoro-2-phenylpropanal (5a); yield
0.24 g (72% over two steps, 99% purity, GC). – TLC (cyclo-
B
13C NMR: δ/ppm = 14.0 (q, C-12), 14.2 (q, C-14), 22.6, 24.5,
29.1, 29.3, 29.4, 31.8 (t, C-6–C-11), 34.7 (dt, 2JC,F = 20.3 Hz,
C-5), 60.5 (t, C-13), 91.3 (dd, 1JC,F = 172.9 Hz, C-4), 121.1
3
2
(dd, JC,F = 12.7 Hz, C-2), 145.1 (dd, JC,F = 17.8 Hz, C-3),
166.0 (s, C-1). – 19F NMR: δ/ppm = –184.3 (m). – GC/MS
(70 eV), m/z (%): 244 (1) [M+], 224 (2) [M+ – HF], 216 (3)
[M+ – C2H4], 199 (20) [M+ – C2H5O], 71 (25) [C5H11+], 69
~
hexane/ethyl acetate, 10:1): Rf = 0.28. – IR (NaCl): /cm–1
v
= 1717 (C=O). – 1H NMR: δ/ppm = 1.28 (t, 3JH,H = 7.2 Hz,
+
+
+
3
(25) [C5H9 ], 57 (45) [C4H9 ], 55 (40) [C4H7 ], 43 (100)
3H, 7-CH3), 1.82 (d, JH,F = 22.2 Hz, 3H, 5-CH3), 4.20 (q,
[C2H3O+, C3H7 ], 41 (95) [C3H5 ].
+
+
3JH,H = 7.2 Hz, 2H, 6-CH2), 6.09 (dd, 4JA,F = 1.0 Hz, 3JA,B
15.7 Hz, 1H, 2-CHA), 7.10 (dd, JB,A = 15.7 Hz, JB,F
=
=
3
3
18.6 Hz, 1H, 3-CHB), 7.27–7.39 (m, 5H, aromatic H). –
Ethyl (Z)-4-fluoro-4-phenylbut-3-enoate (8)
13C NMR: δ/ppm = 14.2 (q, C-7), 26.6 (dq, 2JC,F = 25.4 Hz,
1
Using the same procedures as for compounds 7. By HWE
reaction: Prepared from 0.28 g (2 mmol) of 2-fluoro-2-phe-
nylethanol (4c) via 2-fluoro-2-phenylethanal (5c); yield
0.14 g (34% over two steps, 98% purity, GC); by Wittig reac-
tion: Prepared from 0.21 g (1.5 mmol) of 2-fluoro-2-phe-
nylethanol (4c) via 2-fluoro-2-phenylethanal (5c); yield
0.08 g (25% over two steps, 98% purity, GC). – TLC (cyclo-
C-5), 60.6 (t, C-6), 95.1 (ds, JC,F = 175.5 Hz, C-4), 119.5
3
3
(dd, JC,F = 10.2 Hz, C-2), 124.6 (dd, JC,F = 7.6 Hz, C-o),
128.2 (d, C-p), 128.6 (d, C-m), 141.6 (ds, 2JC,F = 22.9 Hz, C-
i), 148.8 (dd, 2JC,F = 22.9 Hz, C-3), 166.2 (s, C-1). – 19F NMR:
δ/ppm = –145.8 (m). – GC/MS (70 eV), m/z (%): 223 (5)
[MH+], 222 (22) [M+], 204 (8) [M+ – H2O], 177 (12) [M+ –
C2H5O], 149 (100) [M+ – C3H5O2], 129 (50) [C10H9 ], 123
+
~
–1
v
(12) [C8H8F+], 91 (20) [C7H7 ], 77 (12) [C6H5 ], 51 (8)
+
+
hexane/ethyl acetate, 10:1): Rf = 0.26. – IR (NaCl): /cm =
+
1 736 (C=O). – 1H NMR: δ/ppm = 1.28 (t, 3JH,H = 7.2 Hz, 3H,
6-CH3), 3.34 (dd, 4JH,F = 1.7 Hz, 3JH,H = 7.2 Hz, 2H, 2-CH2),
4.18 (q, 3JH,H = 7.2 Hz, 2H = 5-CH2), 5.62 (dt, 3JH,H = 7.2 Hz,
3JH,F = 36.2 Hz, 1H, 3-CH), 7.31–7.42 (m, 3H, aromatic H),
7.50 – 7.54 (m, 2H, aromatic H). – 13C NMR:
[C4H3 ].
Ethyl (E)-4,4-difluoro-4-phenylbut-2-enoate (7b)
By HWE-reaction: Prepared from 0.24 g (1.5 mmol) of 2,2-
difluoro-2-phenylethanol (4b) via 2,2-difluoro-2-phenyl-
ethanal (5b); yield 0.22 g (64% over two steps, 99% purity,
GC); by Wittig reaction: Prepared from 0.24 g (1.5 mmol) of
2,2-difluoro-2-phenylethanol (4b) via 2,2-difluoro-2-phe-
nylethanal (5b); yield 0.19 g (57% over two steps, 99% puri-
ty, GC). – TLC (cyclohexane/ethyl acetate, 10:1): Rf = 0.32.
δ/ppm = 14.2 (q, C-6), 30.0 (dt, 3JC,F = 5.1 Hz, C-2), 60.9 (t,
2
C-5), 98.0 (dd, JC,F = 17.8 Hz, C-3), 124.2 (dd,3JC,F
=
7.6 Hz, C-o), 128.4 (d, C-p), 129.0 (d, C-m), 131.9 (ds, 2JC,F
1
= 28.0 Hz, C-i), 158.1 (ds, JC,F = 249.2 Hz, C-4), 171.1 (s,
C-1). – 19F NMR: δ/ppm = –117.5 (m). – GC/MS (70 eV),
m/z (%): 208 (25) [M+], 190 (2) [M+ – H2O], 162 (2) [M+ –
C2H6O], 135 (100) [M+ – C3H5O2].
~
1
– IR (NaCl): /cm–1 = 1727 (C=O). – H NMR: δ/ppm =
v
1.29 (t, 3JH,H = 7.2 Hz, 3H, 6-CH3), 4.23 (q, JH,H = 7.2 Hz,
3
2H, 5-CH2), 6.26 (dt, 4JA,F = 2.4 Hz, 3JA,B = 15.7 Hz, 1H, 2-
CHA), 7.01 (dt, 3JB,F = 10.3 Hz, 3JB,A = 15.7 Hz, 1H, 3-CHB),
C12H13FO2 Calcd.: C 69.22 H 6.29
(208.2)
Found: C 68.80 H 6.44.
56
J. Prakt. Chem. 2000, 342, No. 1

Synthesis of γ-Fluoro-α,β-unsaturated Carboxylic Esters
___________________________________________________________________________ FULL PAPER
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Address for correspondence:
Prof. Dr. Günter Haufe
Organisch-Chemisches Institut
Universität Münster
Corrensstraße 40
D-48149 Münster
[7] a) G. Alvernhe, A. Laurent, G. Haufe, Synthesis 1987, 562;
b) G. Haufe, G. Alvernhe, A. Laurent, T. Ernet, O. Goj, S.
Kröger, A. Sattler, Org. Synth. 1998, 76, 159
Fax: Internat. code (0) 251-8339772
e-mail: haufe@uni-muenster.de
J. Prakt. Chem. 2000, 342, No. 1
57