Studies on a three-step preparation of β-fluoroalkyl acrylates from fluoroacetic esters

Article abstract of DOI:10.1016/j.tet.2006.12.045

β-Fluoroalkyl-acrylic esters are valuable building blocks for the synthesis of organofluorine compounds. Although the preparation of several β-fluoroalkyl-acrylates is known, a general and straightforward lab-scale methodology for the preparation of multigram amounts of these compounds from fluoroacetic esters is not available, and the related chemistry has not been investigated in detail. We now describe an optimized three-step protocol relying on: (1) Claisen-type condensation of fluoroacetic esters with ethyl acetate, using LDA as base; (2) reduction of the resulting γ-fluoro-β-keto esters by NaBH₄, using toluene or benzene as solvents; (3) P₂O₅-promoted dehydration of the intermediate γ-fluoro-β-hydroxy esters. The methodology affords preparatively useful yields of the target compounds incorporating only fluorine atoms (CF₃, CHF₂, C₂F₅), whereas the γ-halodifluoromethyl (CClF₂, CBrF₂, CIF₂) acrylates could not be obtained in analytically pure form from the dehydration step.

Full text of DOI:10.1016/j.tet.2006.12.045

Tetrahedron 63 (2007) 2042–2046
Studies on a three-step preparation of b-fluoroalkyl acrylates
from fluoroacetic esters
*
Monika Jagodzinska, Florent Huguenot and Matteo Zanda
*
C.N.R.—Istituto di Chimica del Riconoscimento Molecolare, sezione ‘A. Quilico’, and Dipartimento di Chimica, Materiali ed
Ingegneria Chimica ‘G. Natta’ del Politecnico di Milano, via Mancinelli 7, I-20131 Milano, Italy
Received 23 October 2006; revised 1 December 2006; accepted 14 December 2006
Available online 17 December 2006
Abstract—b-Fluoroalkyl-acrylic esters are valuable building blocks for the synthesis of organofluorine compounds. Although the preparation
of several b-fluoroalkyl-acrylates is known, a general and straightforward lab-scale methodology for the preparation of multigram amounts of
these compounds from fluoroacetic esters is not available, and the related chemistry has not been investigated in detail. We now describe an
optimized three-step protocol relying on: (1) Claisen-type condensation of fluoroacetic esters with ethyl acetate, using LDA as base; (2) re-
duction of the resulting g-fluoro-b-keto esters by NaBH4, using toluene or benzene as solvents; (3) P2O5-promoted dehydration of the inter-
mediate g-fluoro-b-hydroxy esters. The methodology affords preparatively useful yields of the target compounds incorporating only fluorine
atoms (CF3, CHF2, C2F5), whereas the g-halodifluoromethyl (CClF2, CBrF2, CIF2) acrylates could not be obtained in analytically pure form
from the dehydration step.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
of remarkable usefulness, such as Diels–Alder and 1,3-di-
polar cycloadditions,2 Friedel–Crafts and Michael-type
reactions,3 dihydroxylation and epoxidation,4 carboxylate
reduction and hydrolysis,5 and Heck-type reactions,6 can
give access to a wide range of fluorinated analogs of biolog-
ically important structures like amino-acids, alkaloids, pep-
tidomimetics, and sugars, just to mention some examples.
The synthesis of versatile and reactive fluorinated building
blocks has remarkable interest, due to the wide range of
applications of fluoroorganic compounds in a number of
important fields such as drug discovery, materials science,
and nanotechnology. Among the vast range of structurally
simple and suitably functionalized fluorinated compounds,
which can be used as starting building blocks for the synthe-
sis of complex fluorinated molecules, b-fluoroalkyl acrylic
acid esters 1 (Scheme 1) are of particular interest.1 Indeed,
their high versatility and reactivity in a number of reactions
Recently, we became interested in compounds 1a–f as start-
ing materials for the preparation of fluorinated peptidomi-
metics and protease inhibitors.7 Inspection of the literature
revealed that there are two main routes to the target com-
pounds, which are all known except for the iodo-derivative
1f (Scheme 1). The first one (route A) is based on the de-
hydration of the corresponding g-fluoro-b-hydroxy esters 2,
and has been preferentially used for the preparation of
1a–c.8,5b The intermediate carbinols 2 were generally ob-
tained either by Reformatsky reaction of bromoacetate or
by Knoevenagel reaction of malonates with fluoroacet-
aldehydes or their hemiacetals.
OH
O
−H2O
OEt
RF
2
O
Zn/BrCH2CO2Et
(for 1a-c)
Route A
OEt
RF
1
OH
OR
R = H, alkyl
(EtO)2P(O)CH2CO2Et
RF
The second (route B) relies on the Horner–Wadsworth–
Emmons reaction of fluoroacetaldehydes with triethyl phos-
phonoacetate that was used to prepare 1d,e.9
Route B
(for 1d,e)
RF = (a) CF3, (b) CHF2, (c) C2F5, (d) CClF2, (e) CBrF2, (f) CIF2
Scheme 1. Known preparations of g-fluoroalkyl-acrylates 1.
Recent work has also demonstrated the possibility of using
Pd-catalyzed Heck-type chemistry, although the yields are
currently rather modest.10 Alternatively, 1a in pure Z-form
was obtained by Lindlar-type hydrogenation of CF3–
C^C–CO2Et.11
* Corresponding authors. Tel.: +39 02 2399 3084; fax: +39 02 2399 3080;
e-mail: matteo.zanda@polimi.it
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.045

M. Jagodzinska et al. / Tetrahedron 63 (2007) 2042–2046
2043
Table 1. Tautomeric composition of compounds 3 in different solvents
Both routes A and B rely on fluoroacetaldehyde derivatives
as starting materials. These compounds are not easily avail-
able from commercial sources, except for the trifluoro deriv-
ative, and are remarkably expensive. Alternatively, one has
to prepare them by reduction of the corresponding esters.
Moreover, fluoroacetaldehyde derivatives are somewhat
unstable and reactive, particularly in the strongly electro-
philic oxo form. We therefore reasoned that the direct use
of fluoroacetic esters, which represent by far the cheapest
and most readily available starting materials in a wide range
of fluorination degrees, would be extremely advantageous,
particularly on preparative multigram scale (Scheme 2). Sur-
prisingly, we found that little is published about steps 1 and
2, namely the Claisen-type preparation of g-fluoro-b-keto
esters 3 and their hydride reduction to 2, which we deemed
more suitable for a lab-scale preparation.12
at rta,b
H
O
O
O
RO OR
RF
O
O
ROH
OEt
OEt
RF
−ROH
slow
fast
OEt
RF
3C
3A
3B
RF = (a) CF3, (b) CHF2, (c) C2F5, (d) CClF2, (e) CBrF2, (f) CIF2
b-Keto CDCl3
ester
C6D6
(R¼H)
CD3OD Acetone-d6 DMSO-d6
(R¼CD3, D) (R¼H) (R¼H)
(R¼H)
3ad
3b
3c
3d
3e
3f
10:60:30 11:68:21 2:6:92
33:27:40 36:26:38 8:2:90
28:50:22
33:17:50
24:73:3
21:14:65
40:38:22
48:17:35
27:36:37
15:28:57
23:68:9
20:10:70
39:38:23
70:4:26
11:86:3
25:25:50 15:25:60 5:28:67
9:87:4
9:54:37
30:33:37 32:39:29 n.d.c
42:37:21 44:39:17 18:20:62
a
Ratio of compounds A/B/C.
The compound was dissolved in a solvent taken from a freshly opened
b
bottle, allowed to stand for 5–10 min, then analyzed by 19F, 1H, and 13
C
LDA
AcOEt
Toluene or
benzene
O
O
OH
O
O
NMR. Little or no variations were observed after longer times, confirming
that the equilibrium was actually reached.
The spectrum displayed a very complex pattern with a number of signals,
which could not be assigned.
Compound 3a was reported to have ca. 20:70:10 ratio in THF-d8 under the
same conditions (Ref. 18).
OEt
RF
OEt
RF
OMe
RF
NaBH4
r.t.
−70 °C
(STEP 1)
3a-f
c
2a-f
(STEP 2)
d
P2O5
(STEP 3)
O
OEt
1a-c
RF
constant for each compound in a given solvent.17 On the
other hand formation of the hemiketal or gem-diol form C
from A is a slow process, which is accelerated by the pres-
ence of acids or other catalysts, and can be obviously shifted
toward C by increasing the amount of water. The data por-
trayed in Table 1 are obtained by 1H, 19F and 13C NMR anal-
ysis at rt, by dissolving each compound in the appropriate
solvent (freshly opened, untreated) and recording the spectra
after 5 min. The data demonstrate that tiny structural differ-
ences in g-position, such as the number of fluorine atoms or
a change of halide, are able to bring about strong differences
in terms of tautomeric behavior. From the substrate point of
view, it clearly appears that the pentafluoroethyl derivative
3c has a remarkable proclivity to the b-enol ester form B, al-
most independently of the solvent. Less marked prevalence
of B was determined for the trifluoro compound 3a. The
chlorodifluoro compound 3d showed a strong preference
for the gem-diol or hemiketal form C, and the same ten-
dency, albeit less pronounced, was evidenced for the difluoro
compound 3b. The tautomeric population of the iododifluoro
compound 3f showed a shift toward the b-keto form A,
whereas the bromodifluoro 3e featured a borderline behavior
with a general equivalence of population among the three
tautomeric forms. In terms of solvent, the trend was that
expected and already reported in the literature,17 namely
low-polarity aprotic solvents like benzene favor the intramo-
lecularly hydrogen-bonded tautomer B, whereas more polar
solvents shift the tautomerism toward the keto form A, and
methanol favors the formation of the hemiketal form C. It
is also worth noting that for the halodifluoro compounds
3d–f, the rate of keto form A decreases with increasing the
electronegativity of the halogen (Cl>Br>I). Finally, it
should be noticed that polar hygroscopic solvents like
DMSO and acetone lead to an increase in gem-diolic form C.
RF = (a) CF3, (b) CHF2, (c) C2F5, (d) CClF2, (e) CBrF2, (f) CIF2
Scheme 2. Three-step preparation of b-fluoroalkyl acrylates 1 from fluoro-
acetates.
In this paper, we describe the results of a study on the feasibil-
ity of a synthesis of b-fluoroalkyl acrylic acid esters (E)-1a–f
in three steps from the corresponding fluoroacetic esters.
2. Results and discussion
Step 1, the preparation of g-fluoro-b-keto esters 3 from fluo-
roacetic esters, has been reported to occur under different
conditions such as Reformatsky-type (bromoacetate, Zn),13
or Claisen-type using acetic esters as nucleophiles and
EtONa/EtOH,14 or NaH,15 or LDA16 in ethereal solvents as
base. In our hands, the latter proved to be by far the best, in-
variably affording good yields of 3b–f, generally within the
70–80% range (only 3a was purchased from commercial
sources). These molecules, upon NMR analysis, showed
quite complex spectral patterns revealing the presence of
three different tautomeric forms often in comparable ratios,
depending on the solvent. Although it is known that some
g-fluoro-b-keto esters 3 have a rather peculiar tautomeric
distribution, with an unusually high ratio of the b-enol ester
form as compared to the unfluorinated counterparts, a de-
tailed study about this aspect is not present, to the best of
our knowledge, in the literature.17 This issue is even more
important considering that it is known that the different tau-
tomers of 3a can have dramatically different reactivity upon
reductive conditions.18 We therefore decided to investigate
the tautomeric composition of the whole set of compounds
3a–f in different solvents, as shown in Table 1.
It should be mentioned that the equilibrium between b-enol
ester (B) and b-keto ester form (A) has been reported to be
a fast reaction, and the A/B ratio is therefore substantially
The next transformation (step 2, Scheme 2) was the hydride
reductionoftheb-ketoesters3tothecarbinols2. Thisreaction
is reported only occasionally in the literature, and in some

2044
M. Jagodzinska et al. / Tetrahedron 63 (2007) 2042–2046
cases little experimental information was provided.19,14,15
Ethereal solvents (diethyl ether, THF) or alcohols (MeOH,
EtOH), with or without water, are conventionally the most
used solvents for the reduction of carbonyl groups with
NaBH4, therefore, we explored first the use of diethyl ether
and MeOH. Despite the apparent simplicity of the process,
the results were not very satisfactory. This was particularly
true for the substrates 3c and 3d that afforded low yields of
the target products 2c and 2d, together with relevant amounts
of the 1,3-diol by-products 4c,d (Table 2). A possible factor
contributing to the low performance of the NaBH4 reductions
of 3c,d is that these compounds have a very low population of
the b-keto tautomers (A), and generally large amounts of b-
enol ester (B) and hemiketal or gem-diol (C) forms, respec-
tively (see Table 1). Even worse were the results obtained
with 3a in MeOH, where the hemiketal form C is largely
predominant that resulted in a complex mixture of unidenti-
fied products.
dehydration took place to a very small extent. Analogously,
attempts to obtain the bromodifluoro and iododifluoro
derivatives 1e,f by dehydration of 2e,f over P2O5 failed,
producing extended decomposition. A number of other de-
hydration procedures were attempted for the transformation
of 2d into 1d, including a variant of an optimized procedure
recently reported for the dehydration of 2a to 1a (mesyl
chloride, triethylamine),22 H2SO4, H2SO4/AcOH, SOCl2,23
and DBU/CHCl3,8b but the product 1d was always obtained
as a minor product in mixture with the carboxylic acids
formed by hydrolysis of 2d and 1d, together with several
other unidentified by-products. The reasons for the dramatic
difference in reactivity of 2d–f in comparison with 2a–c are
unclear. However, we suspect that the presence of halogens
other than fluorine has an important role. This hypothesis is
supported by the observation that, to our knowledge, none of
the g-halodifluoromethyl acrylates 1d–f have been hitherto
prepared by dehydration of the corresponding b-hydroxy
esters 2d–f.
Table 2. NaBH4 reductions of 3a–f in different solvents
NaBH4
O
O
OH
O
In conclusion, we have carried out a detailed study on the fea-
sibility of the preparation of b-fluoroalkyl acrylates 1a–f in
three steps from commercially available and inexpensive
fluoroacetic esters. The procedure works very well for com-
pounds 1a–c containingonlyfluorineatoms, whereas thefinal
dehydration step could not be performed successfully for the
preparation of 1d–f, which also contain chlorine, bromine,
and iodine, respectively. In those cases, we recommend the
use of an alternative methodology, described in the literature,
relying on the Horner–Wadsworth–Emmons reaction of fluo-
roacetaldehydes with triethyl phosphonoacetate.9 Finally,
a detailed study on the tautomeric population of g-fluoro-
b-keto esters 3a–f in different solvents has been performed.
OH
solvent
+
OEt
RF
OEt
RF
OH
RF
r.t.
(STEP 2)
3
4
2
RF = (a) CF3, (b) CHF2, (c) C2F5, (d) CClF2, (e) CBrF2, (f) CIF2
a
Product
Et2Oa
MeOHa
Toluene or C6H6
2a
2b
2c
2d
2e
2f
78 [2.5]
80 [1.5]
29 [2.0]c
44 [3.0]e
77 [1.5]
72 [1.5]
ꢀ [2.0]b
72 [0.5]
<2 [1.5]d
40 [3.0]f
76 [1.5]
71 [0.5]
94 [2.5]
80 [2.0]
89 [3.5]
92 [4.5]
80 [4.5]
73 [4.5]
a
Yield (%) [reaction time (h)].
Complex mixture.
By-product 4c was isolated in 29% yield.
Complex mixture, containing low amounts (<5%) of 4c.
By-product 4d was isolated in 30% yield.
By-product 4d was isolated in 20% yield.
b
c
d
e
f
3. Experimental
3.1. General details
To our surprise, the use of toluene or benzene (which pro-
vided identical results) as solvent proved to be extremely re-
warding, affording the desired alcohols 2a–f in high yields
(Table 2), in spite of the poor solubility of NaBH4 in these
solvents. All of the substrates 3a–f were reduced with very
clean reactions, according to TLC and NMR analysis of
the crude reaction mixtures, suggesting that nearly quantita-
tive yields could be obtained simply by further prolonging
the reaction times. An interpretation of these results in terms
of tautomeric ratios of the substrates 3 in benzene is difficult
(see Table 1), as the difference with respect to the other sol-
vents is not dramatic. We believe that the improved perfor-
mance should mainly depend on the reactivity of NaBH4
in benzene or toluene, which is not commonly used for the
reduction of carbonyl groups.20
Commercially available reagent-grade solvents were em-
ployed without purification. TLC was run on silica gel 60
F254 Merck. Flash chromatographies (FC) were performed
1
with silica gel 60 (60–200 mm, Merck). H, 13C, and 19F
NMR spectra were run at 250, 400, or 500 MHz. Chemical
shifts are expressed in parts per million (d), using tetra-
1
methylsilane (TMS) as internal standard for H and 13C
nuclei (dH and dC¼0.00), while C6F6 was used as external
standard (dF¼ꢀ162.90) for 19F. Compound 3a was pur-
chased from commercial sources.
3.2. Synthesis of b-keto esters 3b–f
3.2.1. Typical experimental procedure. To a solution of
diisopropylamine (22.5 mL, 161 mmol) in dry THF
(100 mL), a 2.5 M solution of n-butyl lithium in THF
(64.4 mL, 161 mmol) was added at ꢀ40 ꢁC, under nitrogen
atmosphere. The temperature was allowed to increase slowly
until 0 ꢁC over 1 h, then the flask was cooled again to
ꢀ78 ꢁC and a solution of EtOAc (15.7 mL, 161 mmol) in
THF (10 mL) was added dropwise. After 1 h a solution of
ethyl difluoroacetate (8.47 mL, 80.5 mmol) in THF (8 mL)
was added dropwise. The reaction mixture was stirred at
ꢀ78 ꢁC for 3 h, and after that time it was allowed to warm
The final transformation, step 3 (Scheme 2), was performed
by heating b-hydroxy esters 2a–c on P2O5,5b followed by
standard or bulb to bulb distillation of the dehydration prod-
ucts 1a–c, using a Kugelrohr apparatus. Compounds 1a–c
were obtained in good yields, in the range 65–75%, with
very good purity, and nearly exclusive (E)-form.21 However,
attempts to obtain the chlorodifluoro derivative 1d from 2d
according to the same procedure were unsuccessful, as the

M. Jagodzinska et al. / Tetrahedron 63 (2007) 2042–2046
2045
to rt, then the reaction was quenched with saturated aqueous
NH4Cl, and extracted two times with EtOAc. The organic
layer was washed with 1 M HCl, brine, dried over
Na2SO4, and then the solvent was removed in vacuo afford-
ing 3b (10.07 g, 80%) as a yellowish oil. The compound was
used without further purification for the next step.
3.3.1.2. Ethyl 4,4-difluoro-3-hydroxybutanoate (2b).
Physical, spectral, and analytical properties matched with
those described in the literature.24
3.3.1.3. Ethyl 4,4,5,5,5-pentafluoro-3-hydroxypenta-
noate (2c). Physical, spectral, and analytical properties
matched with those described in the literature.16
3.2.1.1. Ethyl 4,4-difluoro-3-oxobutanoate (3b). Physi-
cal, spectral, and analytical properties matched with those of
the commercial compound obtained from Fluorochem Ltd
(cat. Code 001566).
3.3.1.4. Ethyl 4-chloro-4,4-difluoro-3-hydroxybuta-
noate (2d). Physical, spectral, and analytical properties
matched with those described in the literature.24
3.2.1.2. Ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate
(3c). Physical, spectral, and analytical properties matched
with those of the commercial compound obtained from
Sigma–Aldrich.
3.3.1.5. Ethyl 4-bromo-4,4-difluoro-3-hydroxybuta-
noate (2e). Yellow oil. [Found: C, 29.26; H, 3.55.
C6H9BrF2O3 requires C, 29.17; H, 3.67%.] Rf ¼0.41 (Hex/
1
EtOAc 8:2); nmax (film) 3447, 2987, 1723, 1106; H NMR
(400 MHz, CDCl3) d: 1.28 (3H, t, J¼7.2 Hz, Me), 2.68 (1H,
dd, J¼9.2 and 16.4 Hz, CHaHbCO), 2.79 (1H, dd, J¼2.7
and 16.4 Hz, CHaHbCO), 3.9 (1H, s, OH), 4.21 (2H, q,
J¼7.2 Hz, OCH2), 4.41 (1H, m, CHCF2Br); 13C NMR
(100.6 MHz, CDCl3) d: 13.9, 36.0, 61.5, 73.1 (t,
J¼25.6 Hz), 123.6 (t, J¼309.3 Hz), 170.5; 19F NMR
3.2.1.3. Ethyl 4-chloro-4,4-difluoro-3-oxobutanoate
(3d). Physical, spectral, and analytical properties matched
with those described in the literature.24
3.2.1.4. Ethyl 4-bromo-4,4-difluoro-3-oxobutanoate
(3e). Physical, spectral, and analytical properties matched
with those described in the literature.25
(235.3 MHz, CDCl3) d: ꢀ58.7 (1F, dd, JFH¼10.1 Hz, JFF
¼
172.9 Hz), ꢀ61.1 (1F, dd, JFH¼10.1 Hz, JFF¼172.9 Hz);
m/z (EI) 246.8 [M+H+], 268.8 [M+Na+], 284.9 [M+K+].
3.2.1.5. Ethyl 4,4-difluoro-4-iodo-3-oxobutanoate (3f).
Reddish oil. [Found: C, 24.78; H, 2.54. C6H7F2IO3 requires
C, 24.68; H, 2.42%.] Rf¼0.42 (Hex/EtOAc, 8:2); nmax (film)
3446, 2986, 1739, 1373, 1098; 1H NMR (400 MHz, CDCl3).
Keto form A d: 1.27 (3H, t, J¼7.2 Hz, Me), 3.77 (2H, s,
COCH2), 4.18 (2H, q, J¼7.2 Hz, OCH2). Enol form B:
1.24 (3H, t, J¼7.2 Hz, Me), 4.23 (2H, q, J¼7.2 Hz,
OCH2), 4.61 (1H, br s, OH), 5.51 (1H, s,]CH). gem-Diol
form C: 1.24 (3H, t, J¼7.2 Hz, Me), 2.86 (2H, s,
C(OH)2CH2), 4.61 (2H, br s, (OH)2), 4.23 (2H, q,
J¼7.2 Hz, OCH2). For all forms: 13C NMR (100.6 MHz,
CDCl3) d: 13.7, 13.8, 35.2, 40.1, 47.8, 49.8, 61.5, 61.6 (t,
J¼25.9 Hz), 61.8, 62.0, 87.3, 87.4 (t, J¼312.1 Hz), 95.5 (t,
J¼326.3 Hz), 108.2, 164.5, 165.9 (t, J¼25.5 Hz), 171.2,
185.3 (t, J¼25.6 Hz); 19F NMR (235.3 MHz, CDCl3) d:
form A: ꢀ62.4 (2F, s), form B: ꢀ55.8 (2F, s), form C:
ꢀ57.9 (2F, s); m/z (EI) 314.9 [M+Na+].
3.3.1.6. Ethyl 4,4-difluoro-3-hydroxy-4-iodobutanoate
(2f). Reddish oil. [Found: C, 24.63; H, 3.19. C6H9F2IO3 re-
quires C, 24.51; H, 3.09%.] Rf¼0.37 (Hex/EtOAc 8:2); nmax
(film) 3446, 2986, 1723, 1095; 1H NMR (400 MHz, CDCl3)
d: 1.28 (3H, t, J¼7.2 Hz, Me), 2.62 (1H, dd, J¼9.2 and
16.4 Hz, CHaHbCO), 2.75 (1H, dd, J¼2.4 and 16.4 Hz,
CHaHbCO), 3.77 (1H, s, OH), 4.02 (1H, m, CHCF2I), 4.21
(2H, q, J¼7.2 Hz, OCH2); 13C NMR (100.6 MHz, CDCl3)
d: 14.0, 36.5, 61.5, 74.6 (t, J¼24.2 Hz), 109.2 (t,
J¼316.2 Hz), 170.2; 19F NMR (235.3 MHz, CDCl3) d:
ꢀ50.8 (1F, dd, JFH¼10.1 Hz, JFF¼183.1 Hz), ꢀ55.1 (1F,
dd, JFH¼10.1 Hz, JFF¼183.1 Hz); m/z (EI) 294.8 [M+H+],
316.8 [M+Na+].
3.4. Dehydration of b-hydroxy esters 2a–c to
b-fluoroalkyl acrylates 1a–c
3.3. Reduction of b-keto esters 3a–f to b-hydroxy
esters 2a–f
3.4.1. Typical experimental procedure. Alcohol 2a
(10.76 g, 57.8 mmol) was placed in a 50 mL flask and phos-
phorus pentoxide (4.1 g, 28.9 mmol) was added in one por-
tion. The flask was shaken intermittently for 1 h (by hand).
During this time a brown colored liquid was formed and
heat was evolved. Distillation of the mixture yielded
6.68 g (39.7 mmol, 69% yield) of trifluorocrotonate 1a (bp
113–117 ꢁC) as colorless liquid.
3.3.1. Typical experimental procedure. To a solution of 3d
(0.74 mmol) in toluene (5 mL) at 0 ꢁC, NaBH4 (0.78 mmol)
was added portionwise and then the mixture was allowed to
warm at rt. The slurry was stirred for 4.5 h at rt and then the
reaction was quenched by careful addition of aqueous HCl
(10%) at 0 ꢁC. The phases were separated, and the aqueous
phase was extracted twice with EtOAc, then the collected
organic phases were dried over Na2SO4, filtered, and the sol-
vent was removed in vacuo. Compound 2d was obtained in
very good purity, without further purification, in 92% yield.
Spectral and analytical data of 2d matched with those
described in the literature.
3.4.1.1. Ethyl 4,4,4-trifluorobut-2-enoate (1a). Physi-
cal, spectral, and analytical properties matched with those
of the commercial compound obtained from Sigma–Aldrich.
3.4.1.2. Ethyl 4,4-difluorobut-2-enoate (1b). Physical,
spectral, and analytical properties matched those described
in the literature.8a
3.3.1.1. Ethyl 4,4,4-trifluoro-3-hydroxybutanoate (2a).
Physical, spectral, and analytical properties matched with
those of the commercial compound obtained from Sigma–
Aldrich.
3.4.1.3. Ethyl 4,4,5,5,5-pentafluoropent-2-enoate (1c).
Physical, spectral, and analytical properties matched with
those described in the literature.8a

2046
M. Jagodzinska et al. / Tetrahedron 63 (2007) 2042–2046
11. Leroy, J.; Fischer, N.; Wakselman, C. J. Chem. Soc., Perkin
Trans. 1 1990, 1281–1287.
Acknowledgements
12. For some examples of catalytic hydrogenation of 3, see: (a)
Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.;
Genet, J.-P.; Champion, N.; Dellis, P. Angew. Chem., Int. Ed.
2004, 43, 320–325; (b) Jeulin, S.; Duprat de Paule, S.;
Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.;
Dellis, P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5799–
5804; (c) Diezi, S.; Mallat, T.; Szabo, A.; Baiker, A. J. Catal.
2004, 228, 162–173; (d) Spindler, F.; Malan, C.; Lotz, M.;
Kesselgruber, M.; Pittelkow, U.; Rivas-Nass, A.; Briel, O.;
Blaser, H.-U. Tetrahedron: Asymmetry 2004, 15, 2299–2306;
We thank the European Commission (IHP Network grant
‘FLUOR MMPI’ HPRN-CT-2002-00181, and Integrated
Project ‘STROMA’ LSHC-CT-2003-503233), MIUR (Cofin
2002, Project ‘Peptidi Sintetici Bioattivi’), Politecnico di
Milano, and C.N.R. for economic support.
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