Synthesis of 3-fluorofuran-2(5H)-ones based on Z/E photoisomerisation and cyclisation of 2-fluoro-4-hydroxybut-2-enoates

Article abstract of DOI:10.1002/ejoc.200700439

Mixtures of some (E)- and (Z)-2-fluoroalk-2-enoates prepared from the corresponding 2-hydroxycarbonyl compounds and ethyl 2-(diethoxyphosphoryl)-2- fluoroacetate have been transformed in high conversions into the target 3-fluorofuran-2(5H)-ones by an effi

Full text of DOI:10.1002/ejoc.200700439

FULL PAPER
DOI: 10.1002/ejoc.200700439
Synthesis of 3-Fluorofuran-2(5H)-ones Based on Z/E Photoisomerisation and
Cyclisation of 2-Fluoro-4-hydroxybut-2-enoates
[a]
[b]
[c]
[c]
ˇ
ˇ
ˇ
Karel Pomeisl,* Jan Cejka, Jaroslav Kvícala, and Oldrich Paleta
Keywords: Horner–Wadsworth–Emmons reaction / Phosphonates / Photolysis / Isomerization / Fluorofuranones
Mixtures of some (E)- and (Z)-2-fluoroalk-2-enoates prepared
from the corresponding 2-hydroxycarbonyl compounds and
ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate have been
transformed in high conversions into the target 3-fluoro-
furan-2(5H)-ones by an efficient Z/E photoisomerisation of
noncyclisable Z isomers followed by acid-catalysed cycli-
sation. In contrast, the acid-catalysed deprotection of ethyl
(E)- and (Z)-4-[tert-butyl(dimethyl)silyloxy]-2-fluoro-4-phen-
ylbut-2-enoates resulted in the displacement of vinylic
fluorine, affording ethyl (E)-2-oxo-4-phenylbut-3-enoate. 3-
Fluoro-4-phenylfuran-2(5H)-one was transformed into 2-
[tert-butyl(dimethyl)silyloxy]-3-fluoro-5-methylfuran as
a
novel fluorinated building block.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
ponent of several classes of bioactive natural compounds
and that fluoro substituents such as F, CF3 or OCF3 are
generally powerful modifiers of the chemical and biological
properties of organic compounds,[11,12] as evidenced by
hundreds of pharmaceuticals and biocides. Some fluori-
nated analogues of tetronic and -ascorbic acids have re-
cently been prepared[13] for biochemical studies and 2-
fluoro-4-hydroxy-3-styrylbut-2-en-4-olide was even found
to exhibit a phospholipase inhibitory effect.[14]
In this present study, we directed our research efforts
towards the synthesis of some alkyl- and phenyl-substituted
2-fluorobut-2-en-4-olides (28 and 37–39) as fluorinated de-
rivatives of the above-mentioned angelicalactone or natural
mintlactone and (–)-incrustoporine (Figure 1). The combi-
nation of a fluorine substituent with an alkyl- and phenyl-
substituted butenolide ring could thus afford compounds
with new and interesting properties. Therefore, our study
focused on their rapid preparation.
Introduction
The furan-2(5H)-one (but-2-en-4-olide) ring is a compo-
nent of several classes of bioactive natural compounds.
Some natural butenolides exhibit antitumour activity,[1]
cytotoxic properties towards human tumour cells,[2] intesti-
nal carcinogenicity inhibition,[3] significant activity against
lymphotic leukemia systems[4] and also HIV-1 protease-in-
hibitor activity.[5] Some analogues of natural butenolides
have also been proven to have antitumour[6] and antitu-
mour-promoter activity.[7]
Furthermore, alkyl-substituted butenolides are appropri-
ate building blocks in the synthesis of bioactive compounds.
As an example, angelicalactone[8a,8b] has been utilised as a
simple chiral butenolide precursor for the preparation of
(+)-himbacine,[8c] known to be a significant inhibitor of M2
receptors. The presence of several alkyl and aryl groups in
one structure is also an essential feature of terpenoides that
exhibit antifungal activity,[10] such as mintlactone[9] and de-
rivatives of (–)-incrustoporine, or powerful pharmacoph-
ores, for example, in antitumour drugs Tamoxiphen and
Droloxifene or in coronary vasodilator Amotriphene.
Our investigation into fluorine-containing butenolides
was stimulated by the fact that the butenolide ring is a com-
[a] Institute of Organic Chemistry and Biochemistry, Academy of
Sciences of the Czech Republic,
Flemingovo nám. 2, 16610 Prague, Czech Republic
Fax: +420-220-183-560
E-mail: pomeisl@uochb.cas.cz
[b] Department of Solid State Chemistry, Prague Institute of
Chemical Technology,
Figure 1. Alkyl and phenyl-substituted but-2-enolides as the bioac-
tive compounds and building blocks.
Technická 5, 16628 Prague 6, Czech Republic
[c] Department of Organic chemistry, Prague Institute of Chemical
Technology,
The synthesis of 2-fluorobut-2-enolides has usually been
accomplished by deprotection of 2-fluoro-4-hydroxyalk-2-
enoates followed by the spontaneous closure of the lactone
ring.[14,15] A simple synthetic pathway leading to these
Technická 5, 16628 Prague 6, Czech Republic
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 5917–5925
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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K. Pomeisl, J. Cejka, J. Kvícˇala, O. Paleta
FULL PAPER
hydroxyalkenoates has appeared to be the Horner–
Wadsworth–Emmons (HWE) synthesis involving the reac-
tion of 2-(diethoxyphosphoryl)-2-fluoroacetate (10) with an
appropriate α-hydroxycarbonyl compound.[14,15]
However, we have found that this method for the synthe-
sis of 3-fluoro-4,5-diphenylfuran-2(5H)-one prepared from
benzoin ethers[16] has its limitations as the intermediate 4-
alkoxybutenoates are formed predominantly in a noncyclis-
able configuration. It seems the stereoselectivity of the
HWE reaction depends on the structure of the starting α-
hydroxycarbonyl compound. However, the structure of
some α-hydroxycarbonyl compounds can be modified by in-
cluding the tert-butyl(dimethyl)silyl protecting group, as
documented in this paper. Secondly, the noncyclisable con-
figuration of some 2-fluoroalkenoates can be transformed
by using a suitable Z/E isomerisation method which has not
so far been studied in detail by this process. Therefore, we
decided to isomerise the α,β double bond of 2-fluoroalk-
enoates in the synthesis of target butenolides 28 and 37–39
by using UV irradiation followed by acid-catalysed cycli-
sation.
Scheme 1. HWE synthesis of 2-fluoroalkenoates from protected α-
hydroxy aldehydes.
Table 1. Stereoselectivity of the reaction of aldehydes 1–4 with
phosphonates 9 and 10.
Starting esters
Products
Yields
a[a]
b[a]
a+b[b]
R
A
X
(%, rel.) (%, rel.)
(%)
1
1
2
3
4
(S)-Me
(S)-Me
(S)-Me
Ph
Me
Me
TBS
Me
TBS
11
12
13
14
15
H
F
F
F
F
35
96
84
91
85
65
4
16
9
54
52
79
69
52
Results and Discussion
Ph
15
[a] The relative content of the E and Z isomers was determined by
19F NMR spectroscopic analysis of the reaction mixture. [b] Iso-
lated yield.
For the synthesis of the target but-2-enolide 28 we fol-
lowed the above-described methodology, exploiting the
HWE reaction synthetic sequence and then hydrolysing the
resulting intermediates. Aldehydes 5–8, prepared in situ by
the selective reduction of easily available esters[17] 1–4 using
diisobutylaluminium hydride at –78 °C, were selected as the
starting carbonyl compounds. The precursor of the HWE
reagent, ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (10),
was prepared from chlorotrifluoroethene using our op-
timised synthetic protocol.[15d]
The reaction of derivatives 5–8 with the HWE reagent
prepared in situ by the reaction of fluorophosphonate
10[15d] with n-butyllithium at –78 °C afforded the corre-
sponding products 11–15 as E–Z mixtures (Scheme 1,
Table 1). Data show the stereoselective course of the HWE
reaction; the desired cyclisable E isomers 12a–15a were
highly prevalent in the stereoisomeric mixtures, forming in
amounts of 84–96%. In this case, the influence of aldehyde
structures and their protecting groups is only marginal with
respect to the stereoselectivity of the HWE reaction.
To compare some of the stereochemical results, we car-
ried out an analogous HWE reaction of aldehyde 5 with a
nonfluorinated HWE reagent prepared from ethyl 2-(di-
ethoxyphosphoryl)acetate (9). The reaction afforded the
noncyclisable Z isomer 11b in a relative amount of 65%
(monitoring of the reaction mixtures by 1H NMR). In com-
parison with the content of the E and Z isomers in the
mixture of fluoroalkenoate 12, this result indicates that a
fluorine atom in place of a hydrogen in the phosphonate
agent could significantly influence the stereochemistry of
the HWE reaction.
(Scheme 2). Methoxyacetophenone 16 and methoxycy-
clohexanone 19, which are industrially available, were trans-
formed as well as compounds 17, 18 and 20 into the corre-
sponding fluoroalkenoates 22–26 in good yields of 66–86%
(Table 2). In most cases the desired cyclisable E isomers 22a
and 24a–26a prevailed slightly in the stereoisomeric mix-
tures but only in amounts of 52–65%. Furthermore, the
stereoselectivity can be decreased or reversed by replace-
ment of the ether functionality with the sterically hindered
tert-butyl(dimethyl)silyloxy protecting group (products 22/
23 and 26/27, Table 2) or influenced in different directions
by using fluorophosphonate 10 instead of 9 (products 21/
22 and 25/27, Table 2).
Scheme 2. HWE synthesis of 2-fluoroalkenoates from protected α-
hydroxy ketones.
The transformation of 4-alkoxybut-2-enoates 12, 14, 22
A similar procedure was chosen for the preparation of and 27 into the corresponding intermediate 4-hydroxybut-
22–26, the intermediates leading to butenolides 37–39 2-enoates, which usually cyclise in acidic media to afford
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Eur. J. Org. Chem. 2007, 5917–5925

Synthesis of 3-Fluoro-2(5H)-furanones
Table 2. Stereoselectivity of the reaction of ketones 16–20 with
phosphonates 9 and 10.
Starting compounds
Products
Yields
a[a]
b[a]
a+b[b]
R1
R2
A
X
(%, rel.) (%, rel.)
(%)
16
16
17
18
19
20
19
Ph
Ph
Ph
Me
–(CH2)4–
–(CH2)4–
–(CH2)4–
H
H
H
Me
Me
TBS
TBS
Me
21
22
23
24
H
F
F
F
H
F
F
75
59
10
52
65
60
82
25
41
90
48
35
40
18
93
77
80
78
66
86
65
Me
25
TBS
Me
26
27[c]
[a] The content of E and Z isomers was determined by 19F NMR
spectroscopic analysis of the reaction mixture. [b] Isolated yield. [c]
Analytical data for 27 and reaction details for the HWE reaction
of 19 with ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (10) are re-
ported in ref.[16]
.
Scheme 3. The result of acid-catalysed deprotection of 4-alk-
yl(phenyl)-2-fluoroalkenoates with TsOH·H2O: a) cyslisation; b)
defluorination and allyl rearrangement of the π system.
the target butenolides, required the cleavage of the ether
bond. Because the cleavage of the ether bond in 4-alkoxybu-
tenoates using boron tribromide results in an increase in
unfavoured products[16] we applied bromine-catalysed radi-
cal Z/E isomerisation followed by cleavage of the in-situ-
formed hydrobromide, as reported in our previous paper.[16]
Unfortunately, the selective closure of 2-fluoroalkenoates to
the but-2-enolide ring did not proceed, probably owing to
the absence of bulky substituents at positions C-3 and C-4
of the alkenoate moiety, as shown in the Z/E isomerisation
of ethyl 2-alkoxy-2-fluoro-3,4-diphenylbut-2-enoates.[16] In
this case, the steric effect of aryl groups could influence, for
example, the efficient flexibility of the bond system during
the cyclisation as an important reaction step of the Z/E
isomerisation sequence. Instead, mixtures of unfavoured
products were observed by 19F NMR spectroscopy.
sation of some of the 2-fluoroalkenoates was carried out
by several methods including by photochemical[19,20] and
thermal[21,22] processes. In contrast, irradiation of the E–Z
mixtures of the precursor 23 using unfiltered UV light from
a medium-pressure mercury lamp led to a complex mixture
of products 32a and 32b (Scheme 4). As shown in Scheme 4,
the Z isomer 32b further decomposed to oxo ester 33 due
to defluorination of the alkenoate. This was probably
caused by a selective interaction of the fluorine atom with
the silyl group in the cis position of the alkenoate. There-
fore, characterisation of the proposed intermediate isomer
32b by analysis was not entirely successful.
In contrast to the ether functionality, the tert-butyl(di-
methyl)silyloxy group in compounds 13, 15, 23, 24 and 26
was easily removed by acid-catalysed hydrolysis using p-tolu-
enesulfonic acid. However, the hydrolysis of phenyl deriva-
tives 15a and 15b resulted in an unexpected defluorination
reaction although the deprotection of 2-fluoroalkenoate 13a
readily afforded the desired butenolide 28 and siloxane 29
(Scheme 3). The defluorination reaction is probably the re-
sult of an allyl rearrangement of 15 exclusively to (E)-4-
phenyl-2-oxobut-3-enoate (30) in which the double bond
system is more extensive due to the phenyl substituent at
the C-4 position. The displacement of the vinylic fluorine
is in accord with the monitoring of the reaction mixture
content by 19F NMR analysis in which tert-butyl(dimethyl)-
fluorosilane (31) was found to be a single fluorinated
product with
a characteristic chemical shift (septet,
–170.1 ppm),[18] while the signals of the starting phenyl de-
rivatives 15a and 15b had completely disappeared.
In this study we found that the unfavourable Z configu-
ration of the 2-fluoro-2-hydroxyalkenoates can be trans-
formed into the E configuration, which is suitable for cycli-
sation, by an appropriate Z/E isomerisation reaction during
Scheme 4. Photoinduced isomerisation and defluorination of 3-
phenyl-2-fluorobut-2-enoates.
However, the mild photosensitised Z/E isomerisation of
which the ester group and the more bulky hydroxyalkyl our HWE precursor 23 using UV light with a wavelength
group are placed in the cis position. Such Z-to-E isomeri- above 280 nm (selected by a Simax® filter) in the presence
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K. Pomeisl, J. Cejka, J. Kvícˇala, O. Paleta
FULL PAPER
of acetone as a sensitiser was partly efficient, giving the de-
Fluorinated furanone 37 was transformed into the corre-
sired E isomer 23a in a maximum relative yield of only sponding silyloxyfuran 41 as a novel building block
20%. The results of these photoinduced isomerisaton reac- (Scheme 6). Nonfluorinated silyloxyfurans have been em-
tions led us to focus our research on influencing the pro- ployed in electrophilic reactions[23] and pheromone synthe-
portion of Z and E isomers that can be formed which has sis.[23c] Among fluorinated analogues, only 4-chloro-3-
allowed us to obtain significant amounts of cyclisable 2- fluoro-2-(trimethylsilyloxy)furan has been previously re-
fluoroalkenoates (see below).
ported,[24] but it appeared to be unstable above about
To date photochemical methods have been used only for –30 °C. However, we recently reported that use of the tert-
the Z/E isomerisation of fluorinated cinnamates[15] and (Z)- butyl(dimethyl)silyl protecting group could increase the sta-
2-fluoro-3-phenylprop-2-enoate.[20] As shown in Scheme 5, bility of 3-fluoro-4,5-diphenyl-2-(trialkylsilyloxy)furan.[16]
this method can be also used for the isomerisation of 4- We carried out the transformation of furanone 37 into fu-
hydroxy-2-fluoroalkenoates 34b–36b which were obtained ran 41 by applying our improved protocol,[16] that is, low-
by deprotection of silyl derivatives 23, 24 and 26 in the pres- temperature lithiation to enolate 40 and subsequent si-
ence of p-toluenesulfonic acid. In this case, the relative lylation, to obtain furan 41 in a yield of 70%. It was stable
amounts of Z and E isomers formed was influenced by at 0–4 °C as was the reported 3-fluoro-4,5-diphenyl-2-(trial-
spontaneous acid-catalysed cyclisation of the intermediates kylsilyloxy)furan (checked by 19F NMR for 2 weeks). Based
34a–36a during UV irradiation (see electronic supporting on both results, we assume that the effect of the higher con-
information). Thus the corresponding butenolides 37–39 jugation of phenyl-substituted furans also increases their
were prepared with high conversion of the deprotected hy- stability and this will be investigated in further research.
droxy derivatives, as verified by 19F NMR analysis, but only
in 41–54% preparative yields, probably due to losses caused
by difficulties in purification (Table 3). From this point of
view, only the unoptimised yields for the cyclisation reac-
tions are presented.
Scheme 6. Synthetic exploitation of 2-fluorobutenolides.
A series of synthesised 3-fluorobutenolides were investi-
gated for their ability to possess various kinds of biochemi-
cal activities. We have found that the fluorinated mintlac-
tone derivative 39 exhibits significant inhibitory activity on
cyclin-dependent kinase[25] (CDK) (IC50 = 10 µ) in com-
parison with olomoucine (IC50 = 7 µ), but lower activity
than that of roscovitine (IC50 = 0.1 µ) (see Figure 1).
On other hand, the antifungal effect of fluorobutenolide
37 was marginal[26] in comparison with that of known 3-
aryl-substituted but-2-enolides[10,27] [e.g., (–)-incrustoporine
as the lead structure, see Figure 1]. The lower antifungal
activity could be caused, for example, by a different aryl
substitution and is probably favoured by substitution at the
C-3 position of the furan-2(5H)-one moiety as demon-
strated in a series of incrustoporine derivatives.[10]
None of the presented compounds possess cytostatic ac-
tivity in K-562 (chronic myeloid leukemia) and MCF7
(breast carcinoma) cells in contrast to olomoucine and ros-
covitine.
Scheme 5. Photoisomerisation and cyclisation of 2-fluoro-4-hy-
droxy-but-2-enoates.
Table 3. Results of the E–Z photoisomerisation of fluoroalkenoates
23, 24 and 26.
Starting compounds
Products
a[a]
b[a]
Content in reac- Yield[c]
tion mixture[b]
(%, rel.)
(%, rel.)
(%, rel.)
(%)
Conclusions
23
24
26
7
52
62
93
48
38
37
38
39
95
89
77
42
41
54
In summary, we have developed methods for the rapid
preparation of alkyl- and phenyl-substituted 2-fluorobut-2-
enolides synthesised either as derivatives of bioactive com-
pounds (e.g., fluorinated mintlactone derivative 39) or as
fluorinated building blocks (see compound 28, the fluori-
nated derivative of angelicalactone).
In some cases, we have found that the stereoselectivity of
the HWE synthesis can be significantly influenced by steric
hindrance of the substituents at C-1 and C-2 and/or the
[a] Content of E and Z isomers in isolated fluoroalkenoates. [b]
The content of the butenolides was determined by 19F NMR spec-
troscopic analysis of the resulting reaction mixture. [c] All products
were isolated and characterised by NMR and MS spectroscopy;
yields are unoptimised. In addition, the structure of 37 was deter-
mined by X-ray analysis. CCDC-646554 contains the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Eur. J. Org. Chem. 2007, 5917–5925

Synthesis of 3-Fluoro-2(5H)-furanones
(14.6 mmol) in THF (50 mL) cooled to around –75 °C under nitro-
gen. After 1–5 h of stirring, a solution of n-butyllithium (2.5 ,
21.9 mmol) in hexane was separately added through a septum to a
solution of the phosphonate 9 or 10 (21.9 mmol) in THF (70 mL)
cooled to around –75 °C under nitrogen. After 20 min of stirring,
the mixture containing aldehyde 5–8 was added dropwise by sy-
ringe at the same temperature to the flask charged with a phos-
phonate salt. The resulting mixture was stirred for 1 h, then slowly
allowed to warm to room temp. for 6 h and stirred for another
14 h. THF was removed on a rotary evaporator under reduced
protecting groups at C-2 of the starting carbonyl com-
pound. In addition, some noncyclisable 2-fluoroalkenoates
can undergo ring-closure to the but-2-enolide ring with high
conversions by photochemical isomerisation in the presence
of p-toluenesulfonic acid. From this point of view, Z/E pho-
toisomerisation could be considered as a significant alterna-
tive tool for the preparation of alkyl- and aryl-substituted
2-fluorobut-2-enolides with regard to its simplicity and effi-
ciency.
On the other hand, the reactions reported in this paper pressure, the residue was dissolved in dichloromethane and 1  HCl
was added to the mixture at 5 °C. The mixture was filtered through
a Celite pad under pressure and concentrated on a rotary evapora-
tor to a minimum volume. The residue was diluted with dichloro-
methane, a solution was dried with MgSO4 and the solvent was
removed on a rotary evaporator. The residue was purified by
chromatography on a silica gel column or by microdistillation to
afford the products 11–15 as mixtures of E/Z isomers (see below).
show that the annulation of the α-fluorobut-2-enolide ring
by acid-catalysed deprotection of the silyl group in 4-
phenyl-substituted HWE intermediates 15a,b may com-
pletely fail due to allyl rearrangement of their double bond
systems.
Ethyl (S)-4-Methoxypent-2-enoate (11): Yield 1.26 g (54.4%) of the
mixture 11a/11b (31:69). Column chromatography was performed
on silica gel (benzene/ethyl acetate, 10:1); slightly yellow oil.
C8H14O3 (158.2): calcd. C 60.74, H 8.92; found C 60.57, H 8.81.
Experimental Section
General Remarks: Melting points were determined with a Kofler
block and are uncorrected. Optical rotations were measured with
an Opton PPP 0.005 polarimeter at 20 °C; [α]D values are given in
10–1 degcm2 g–1. NMR spectra were measured with a Bruker 400
AM (FT, 19F at 376.5 MHz) and a Gemini 300 (1H at 300.1 MHz
and 13C at 75.5 MHz using 1H decoupling) spectrometer in CDCl3.
Chemical shifts (δ, ppm) and coupling constants (J, Hz) obtained
by first-order analysis of the spectra were measured relative to tet-
ramethylsilane and fluorotrichloromethane. IR spectra were re-
corded with a FTIR Spec Nicolet 740 in CHCl3. Mass spectra were
scanned with an Autospec Ultima (Micromass) spectrometer using
GC (HP 6890, ionisation with electron impact at 70 eV) and a
ZAB-EQ (VG Analytical) spectrometer using FAB (Xe ionisation,
accelerating voltage 8 kV, glycerol matrix). E and Z configurations
were assigned on the basis of 19F-{1H} and 1H-{1H} NOE Dif.
NMR experiments carried out with a Bruker Avance DRX 500.1
(at 470.4 MHz) apparatus on stereoisomeric mixtures. Irradiation
was performed by using a polychromatic UV medium-pressure
mercury lamp (TESLA, RVK 400 W, system S1) and the same lamp
using a wavelength above 280 nm (selected by a Simax® filter, sys-
tem S2). The distance between the UV lamp and the silicious cell
was 40 mm (diameter 50 mm; thickness 10 mm) equipped with a
magnetic stirrer and loaded with alkenoate 23, 24 or 26 dissolved
in solvent (see below).
1
MS (EI): m/z (%) = 158 (13) [M]+. 11a (Z): H NMR (CDCl3): δ
= 1.31 (m, 6 H); 3.30 (d, J = 0.6 Hz, 3 H), 4.21 (q, J = 7.1 Hz, 2
H), 4.93 (pent, J = 7.1 Hz, 1 H), 5.84 (dd, J = 11.8, J = 1.2 Hz, 1
H), 6.13 (dd, J = 8.0, J = 1.2 Hz, 1 H) ppm. 13C NMR (CDCl3): δ
1
= 14.5, 20.1, 56.6, 60.2, 73.2, 120.5, 152.0, 165.8 ppm. 11b (E): H
NMR (CDCl3): δ = 1.31 (m, 6 H), 3.33 (d, J = 0.6 Hz, 3 H), 3.90
(pent, J = 6.3 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 5.96 (d, J =
15.7 Hz, 1 H), 6.82 (dd, J = 15.7, J = 0.8 Hz, 1 H) ppm. 13C NMR
(CDCl3): δ = 14.2, 20.3, 56.6, 60.4, 76.2, 121.3, 148.9, 166.3 ppm.
Ethyl (S)-2-Fluoro-4-methoxypent-2-enoate (12): Yield 1.34 g
(52.0%) of the mixture 12a/12b (81:19). Microdistillation, b.p.
54 °C/2.0 kPa; colourless liquid. IR (CHCl ): νmax = 2888 (w), 1729
˜
3
(s), 1667 (w), 1375 (s), 1311 (m-s), 1151 (m), 1108 (m), 1078
(m) cm–1. C8H13FO3 (176.2): calcd. C 54.54, H 7.44; found C 54.25,
H 7.60. 12a (E): 1H NMR (CDCl3): δ = 1.31 (dd, J = 6.3, J =
1.1 Hz, 3 H), 1.37 (t, J = 7.1 Hz, 3 H), 3.30 (s, 3 H), 4.31 (q, J =
7.1 Hz, 2 H), 4.77 (dqd, J = 8.8, J = 6.3, J = 1.1 Hz, 1 H), 5.98
(dd, J = 20.8, J = 8.9 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 14.2,
21.0, 57.4, 61.8, 71.3 (J = 6 Hz), 125.4 (J = 5 Hz), 147.2 (J =
260 Hz), 160.2 (J = 37 Hz) ppm. 19F NMR (CDCl3): δ = –120.1
(d, J = 20.4 Hz, 1 F) ppm. 12b (Z): 1H NMR (CDCl3): δ = 1.31
(dd, J = 6.3, J = 1.1 Hz, 3 H), 1.37 (t, J = 7.1 Hz, 3 H), 3.30 (s, 3
H), 4.30 (q, J = 7.1 Hz, 2 H), 4.77 (dqd, J = 8.8, J = 6.3, J =
1.1 Hz, 1 H), 6.17 (dd, J = 33.2, J = 8.9 Hz, 1 H) ppm. 13C NMR
(CDCl3): δ = 14.1, 20.6, 55.9, 61.0, 70.2 ppm; the signals of C=CF,
CF and COO were not found due to their very low intensity. 19F
NMR (CDCl3): δ = –127.2 (d, J = 33.4 Hz, 1 F) ppm.
The chemicals that were used are as follows. Ethyl 2-(diethoxyphos-
phoryl)acetate (9) was prepared according to ref.[28] and ethyl 2-
(diethoxyphosphoryl)-2-fluoroacetate (10) was synthesised from
trifluorochloroethene by our improved procedure.[15d] Compounds
2, 4, 17, 18 and 20 were prepared by reaction of tert-butyl(dimeth-
yl)silyl chloride with ethyl (S)-2-hydroxypropanoate,[29a] ethyl 2-hy-
droxy-2-phenylacetate,[29b] 2-hydroxyacetophenone,[29c] 3-hydroxy-
2-butanone[29d] and 2-hydroxycyclohexanone (a similar procedure
to that reported in ref.[29d]) purchased as well as 2-methoxy ketones
16 and 19 and standard chemicals from Sigma–Aldrich. Com-
pounds 1 and 3 were prepared according to ref.[30]. Isooctane and
dioxane as appropriate solvents used for the UV irradiation of 23,
24 and 26 were obtained from Lachema. Tetrahydrofuran and
dichloromethane were dried and purified according to standard
procedures.
Ethyl (S)-4-[tert-Butyl(dimethyl)silyloxy]-2-fluoropent-2-enoate (13):
Yield 3.18 g (78.8%) of the mixture 13a/13b (95:5). Column
chromatography was performed on silica gel (benzene); slightly yel-
low oil. IR (CHCl ): ν
= 3031 (w), 2982 (w), 2959 (m), 2931
˜
3
max
(m), 2888 (w), 2859 (m-w), 1728 (s), 1668 (w), 1472 (m-w), 1446
(w), 1377 (m-w), 1318 (m), 1259 (s), 1145 (m), 1079 (s), 834
(s) cm–1. C13H25FO3Si (276.4): calcd. C 56.49, H 9.12; found C
1
56.22, H 9.05. 13a (E): H NMR (CDCl3): δ = 0.04, 0.06 (2ϫs, 3
H), 0.88 (s, 9 H), 1.29 (dd, J = 6.1, J = 1.1 Hz, 3 H), 1.36 (t, J =
7.1 Hz, 3 H), 4.30 (q, J = 7.1 Hz, 2 H), 5.26 (dqd, J = 8, J = 6.3,
J = 1.1 Hz, 1 H), 5.90 (dd, J = 20.9, J = 8.5 Hz, 1 H) ppm. 13C
NMR (CDCl3): δ = –4.8, –4.6, 14.2, 18.2, 24.3 (J = 3 Hz), 25.8,
61.6, 63.7 (J = 6 Hz), 128.2 (J = 15 Hz), 144.8 (J = 257 Hz), 160.5
General Procedure for the HWE Synthesis of Alkenoates 11–15: A
solution of diisobutylaluminium hydride (1.2 , 24.9 mmol) in tol-
uene was added through a septum to a solution of compound 1–4
Eur. J. Org. Chem. 2007, 5917–5925
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5921

ˇ
K. Pomeisl, J. Cejka, J. Kvícˇala, O. Paleta
FULL PAPER
(J = 36 Hz) ppm. 19F NMR (CDCl3): δ = –125.3 (d, J = 20.7 Hz,
1 F) ppm. 13b (Z): H NMR (CDCl3): δ = 0.06, 0.08 (2ϫs, 6 H),
Compounds 22, 23 and 26 were then purified by microdistillation
(see below).
1
0.88 (s, 9 H), 1.28 (dd, J = 6.1, J = 1.1 Hz, 3 H), 1.34 (t, J = 7.1 Hz,
3 H), 4.28 (q, J = 7.1 Hz, 2 H), 4.80 (dqd, J = 8.6, J = 6.3, J =
1.4 Hz, 1 H), 6.10 (dd, J = 33.6, J = 8.3 Hz, 1 H) ppm. 13C NMR
Ethyl 4-Methoxy-3-phenylbut-2-enoate (21): Yield 974 mg (93.1%)
of the mixture 21a/21b (77:23). Column chromatography was per-
formed on silica gel (benzene/ethyl acetate, 10:1); slightly yellow
(CDCl3): signals were not found due to their very low intensity. 19
F
oil. IR (CHCl ): νmax = 2984 (w), 2902 (w), 2826 (w), 1710 (s), 1631
˜
3
NMR (CDCl3): δ = –129.2 (d, J = 33.7 Hz, 1 F) ppm.
(w-m), 1577 (w), 1494 (w), 1448 (w), 1372 (w), 1339 (w), 1180 (s),
1099 (w), 1039 (w), 697 (w-m) cm–1. MS (EI): m/z (%) = 220 (100)
[M]+. C13H16O3 (220.3): calcd. C 70.89, H 7.32; found C 70.43, H
7.48. 21a (Z): 1H NMR (CDCl3): δ = 1.07 (t, J = 6.9 Hz, 3 H),
3.43 (s, 3 H), 4.01 (q, J = 7.2 Hz, 2 H), 4.15 (d, J = 1.7 Hz, 2 H),
6.14 (t, J = 1.9 Hz, 1 H), 7.20 (m, 2 H), 7.36 (m, 3 H) ppm. 13C
NMR (CDCl3): δ = 13.0, 58.7, 59.9, 76.0, 116.5, 127.4, 128.0, 128.1,
137.0, 154.5, 165.9 ppm. 21b (E): 1H NMR (CDCl3): δ = 1.32 (t, J
= 7.1 Hz, 3 H), 3.32 (s, 3 H), 4.23 (q, J = 7.1 Hz, 2 H), 4.94 (s, 2
H), 6.20 (s, 1 H), 7.37 (m, 3 H), 7.51 (m, 2 H) ppm. 13C NMR
(CDCl3): δ = 14.2, 58.2, 60.3, 68.1, 120.1, 127.1, 128.4, 129.1, 154.6,
166.0 ppm.
Ethyl 2-Fluoro-4-methoxy-4-phenylbut-2-enoate (14): Yield 2.40 g
(69.0%) of the mixture 14a/14b (93:7). Column chromatography
was performed on silica gel (benzene); slightly yellow oil.
C13H10FO3 (238.3): calcd. C 65.54, H 6.35; found C 65.61, H 6.54.
1
MS (EI): m/z (%) = 238 (32) [M]+. 14a (E): H NMR (CDCl3): δ
= 1.39 (t, J = 7.1 Hz, 3 H), 3.35 (s, 3 H), 4.35 (q, J = 7.1 Hz, 2 H),
5.78 (dd, J = 9.4, J = 1.4 Hz, 1 H), 6.02 (dd, J = 20.4, J = 9.6 Hz,
1 H), 7.28–7.43 (m, 5 H) ppm. 13C NMR (CDCl3): δ = 14.2, 56.5,
61.9, 76.6, 123.4 (J = 17 Hz), 126.5, 128.1, 128.5, 140.0 (J = 3 Hz),
147.3 (J = 261 Hz), 160.5 (J = 35 Hz) ppm. 19F NMR (CDCl3): δ
1
= –119.4 (d, J = 20.8 Hz, 1 F) ppm. 14b (Z): H NMR (CDCl3): δ
= 1.32 (t, J = 7.1 Hz, 3 H), 3.37 (s, 3 H), 4.27 (qd, J = 7.1, J =
2.2 Hz, 2 H), 5.22 (dd, J = 8.2, J = 1.1 Hz, 1 H), 6.24 (dd, J =
32.2, J = 9.1 Hz, 1 H), 7.28–7.43 (m, 5 H) ppm. 13C NMR (CDCl3):
the signals were not found due to their very low intensity. 19F NMR
(CDCl3): δ = –126.4 (d, J = 33.1 Hz, 1 F) ppm.
Ethyl 2-Fluoro-4-methoxy-3-phenylbut-2-enoate (22): Yield 868 mg
(76.7%) of the mixture 22a/22b (60:40). Microdistillation, b.p. 120–
122 °C/133 Pa; colourless liquid. Column chromatography was per-
formed on silica gel (benzene/ethyl acetate, 10:1). IR (CHCl ): ν
˜
3
max
= 3014 (w), 2934 (w), 2828 (w), 1726 (s), 1651 (w), 1493 (w), 1465
(w), 1371 (m), 1276 (s) cm–1. C13H15FO3 (238.3): calcd. C 64.31, H
Ethyl 4-[tert-Butyl(dimethyl)silyloxy]-2-fluoro-4-phenylbut-2-enoate
(15): Yield 2.49 g (52.2%) of the mixture 15a/15b (93:7). Column
chromatography was performed on silica gel (benzene); slightly yel-
1
6.38; found C 64.15, H 5.98. 22a (E): H NMR (CDCl3): δ = 1.03
(t, J = 6.9 Hz, 3 H), 3.32 (s, 3 H), 4.06 (q, J = 7.1 Hz, 2 H), 4.39
(d, J = 4.2 Hz, 2 H), 7.19–7.25, 7.30–7.47 (2ϫm, 5 H) ppm. 13C
NMR (CDCl3): δ = 13.6, 58.3, 61.4, 69.5 (J = 7 Hz), 127.86, 127.92,
128.01, 128.05, 128.11, 128.31, 128.36, 128.46, 129.8, (J = 13 Hz),
134.8 (J = 5 Hz), 145.6 (J = 259 Hz), 160.2 (J = 37 Hz) ppm. 19F
NMR (CDCl3): δ = –120.80 (t, J = 3.7 Hz, 1 F) ppm. 22b (Z): 1.40
(t, J = 7.1 Hz, 3 H), 3.34 (s, 3 H), 4.36 (q, J = 7.1 Hz, 2 H), 4.75
(d, J = 2.5 Hz, 2 H), 7.19–7.25, 7.30–7.47 (2ϫm, 5 H) ppm. 13C
NMR (CDCl3): δ = 14.2, 58.1, 61.8, 69.0 (J = 5 Hz), 127.86, 127.92,
128.01, 128.05, 128.11, 128.31, 128.36, 128.46, 129.9 (J = 10 Hz),
134.1 (J = 1 Hz), 145.5 (J = 264 Hz), 160.9 (J = 35 Hz) ppm. 19F
NMR (CDCl3): δ = –119.61 (s, 1 F) ppm.
low oil. IR (CHCl ): ν
= 1728 (s), 1376 (s), 1063 (s), 840
˜
3
max
(s) cm–1. C17H27FO3Si (326.5): calcd. C 63.87, H 8.04; found C
1
63.61, H 7.91. 15a (E): H NMR (CDCl3): δ = 0.04, 0.09 (2ϫs, 6
H), 0.92 (s, 9 H), 1.41 (t, J = 7.1 Hz, 3 H), 4.38 (q, J = 7.1 Hz, 2
H), 5.96 (dd, J = 20.4, J = 9.4 Hz, 1 H), 6.35 (dd, J = 9.4, J =
1.7 Hz, 1 H), 7.22–7.47 (m, 5 H) ppm. 13C NMR (CDCl3): δ =
–4.8, –4.5, 14.3, 18.3, 25.9, 61.9, 68.1 (J = 9 Hz), 125.6, 126.2 (J =
16 Hz), 127.5, 128.3 (J = 1 Hz), 142.7 (J = 3 Hz), 145.4 (J =
259 Hz), 160.7 (J = 35 Hz) ppm. 19F NMR (CDCl3): δ = –123.1
1
(d, J = 22.0 Hz, 1 F) ppm. 15b (Z): H NMR (CDCl3): δ = 0.06,
0.10 (2ϫs, 6 H), 0.92 (s, 9 H), 1.32 (t, J = 7.1 Hz, 3 H), 4.26 (q, J
= 7.1 Hz, 2 H), 5.73 (d, J = 9.1 Hz, 1 H), 6.19 (dd, J = 32.8, J =
9.1 Hz, 1 H), 7.22–7.47 (m, 5 H) ppm. 13C NMR (CDCl3): signals
were not found due to their very low intensity. 19F NMR (CDCl3):
δ = –123.1 (d, J = 22.0 Hz, 1 F) ppm.
Ethyl 4-[tert-Butyl(dimethyl)silyloxy]-2-fluoro-3-phenylbut-2-enoate
(23): Yield 1.29 g (80.3%) of the mixture 23a/23b (7:93). Micro-
distillation, b.p. 136–138 °C/240 Pa; colourless liquid. Column
chromatography was performed on silica gel (benzene). HRMS
(EI): calcd. for C14H18FO3Si 281.1009; found 281.1015. MS (EI):
m/z (%) = 281 (32) [M – tBu]+, 253 (96), 233 (14), 207 (5), 159 (9),
131 (11), 115 (12), 105 (9), 103 (24), 77 (75) [C6H5]+, 73 (25)
[C3H5O2]+, 57 (13) [tBu]+, 29 (21) [C2H5]+. 23a (E): 1H NMR
(CDCl3): δ = –0.08 (s, 6 H), 0.77 (s, 9 H), 0.99 (t, J = 7.1 Hz, 3 H),
4.03 (q, J = 7.1 Hz, 2 H), 4.56 (d, J = 3.9 Hz, 2 H), 7.15–7.21,
7.29–7.39 (2ϫm, 5 H) ppm. 13C NMR (CDCl3): δ = –5.7, 13.5,
18.1, 25.6, 60.2, 60.5 (J = 9 Hz), 127.56, 127.61, 128.43, 128.47,
133.0, 134.9 (J = 4 Hz), 144.0 (J = 256 Hz), 160.5 (J = 37 Hz) ppm.
19F NMR (CDCl3): δ = –124.32 (t, J = 3.7 Hz, 1 F) ppm. 23b (Z):
1H NMR (CDCl3): δ = –0.04 (s, 3 H), 0.75 (s, 9 H), 1.37 (t, J =
7.1 Hz, 3 H), 4.34 (q, J = 7.1 Hz, 2 H), 4.96 (d, J = 2.8 Hz, 2 H),
7.15–7.21, 7.29–7.39 (2ϫm, 5 H) ppm. 13C NMR (CDCl3): signals
were not found due to their very low intensity. 19F NMR (CDCl3):
δ = –123.6 (s, 1 F) ppm.
General Procedure for the HWE Synthesis of Alkenoates 21–26: A
solution of n-butyllithium (2.5 , 6.25 mmol) in hexane was added
through a septum to a solution of phosphonate 9 or 10 (6.16 mmol)
in THF (70 mL) cooled to around –75 °C under nitrogen. The mix-
ture was stirred for 20 min and then ketone 16–19 (4.75 mmol) in
THF (20 mL) was added dropwise by syringe at the same tempera-
ture into the flask. The resulting mixture was stirred for 20 min,
allowed to warm to room temp. for 2 h and then stirred overnight.
Separation of Compounds 21, 23, 25 and 26: The mixtures were
filtered through neutral Al2O3 (dichloromethane) and the residues
purified by chromatography on a silica gel column (benzene fol-
lowed by benzene/ethyl acetate, 10:1) or purified by microdistilla-
tion to afford products as mixtures of E/Z isomers (see below).
Separation of Compounds 22 and 24: THF was removed on a rotary
evaporator under reduced pressure, the residue was dissolved in
dichloromethane and 1  HCl was added to the mixture at 5 °C.
The mixture was neutralised with a solution of NaHCO3 and satu-
rated with a solution of NaCl. The organic layer was dried with
MgSO4. The solvent was removed (rotary evaporator) and the resi-
due purified by chromatography on a silica gel column to afford
products as mixtures of E/Z isomers (see below).
Ethyl 4-[tert-Butyl(dimethyl)silyloxy]-2-fluoro-3-methylpent-2-eno-
ate (24): Yield 1.1 g (77.8%) of the mixture 24a/24b (52:48). Col-
umn chromatography was performed on silica gel (benzene);
slightly yellow oil. IR (CHCl ): ν
= 3030 (w), 2982 (w), 2958
˜
3
max
(m), 2932 (m), 2859 (m-w), 1728 (s), 1660 (w), 1472 (w), 1446 (w),
1371 (m-w), 1297 (s), 1090 (s), 836 (s) cm–1. HRMS (EI): calcd. for
5922
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5917–5925

Synthesis of 3-Fluoro-2(5H)-furanones
C14H27FO3Si 290.1714; found 290.1719. MS (EI): m/z (%) = 290
volume (rotary evaporator). The lower layer of 29 was separated
from the residue containing butenolide 28 which was further puri-
fied by chromatography whereas the residue containing compound
(8) [M]+. C14H27FO3Si (290.5): calcd. C 57.89, H 9.37; found C
1
57.53, H 9.28. 24a (E): H NMR (CDCl3): δ = 0.01, 0.05 (2ϫs, 6
H), 0.88 (s, 9 H), 1.24 (d, J = 6.3 Hz, 3 H), 1.35 (t, J = 7.1 Hz, 3 30 on a silica gel column (see below).
H), 1.86 (d, J = 4.7 Hz, 3 H), 4.28 (q, J = 7.1 Hz, 2 H), 5.56 (dq,
3-Fluoro-5-methylfuran-2(5H)-one (28): Yield 605 mg (57%) of a
J = 6.3, J = 1.9 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = –4.95,
–4.89, 9.7 (J = 8 Hz), 14.3, 18.2, 22.8, (J = 4 Hz), 25.82, 61.2, 64.7
(J = 5 Hz), 137.4 (J = 9 Hz), 142.0 (J = 251 Hz), 160.7 (J =
35 Hz) ppm. 19F NMR (CDCl3): δ = –127.0 (s, 1 F) ppm. 24b (Z):
1H NMR (CDCl3): δ = 0.03, 0.07 (2ϫs, 6 H), 0.89 (s, 9 H), 1.22
(d, J = 6.3 Hz, 3 H), 1.36 (t, J = 7.1 Hz, 3 H), 2.05 (d, J = 3.0 Hz,
3 H), 4.28 (q, J = 7.1 Hz, 2 H), 4.98 (dq, J = 6.3, J = 1.2 Hz, 1
H) ppm. 13C NMR (CDCl3): δ = –5.01, –4.94, 10.2 (J = 2 Hz),
14.3, 18.2, 22.3 (J = 1.4 Hz); 25.81, 61.2, 64.5 (J = 11 Hz), 136.4
(J = 10 Hz), 141.3 (J = 247 Hz), 161.2 (J = 35 Hz) ppm. 19F NMR
(CDCl3): δ = –127.0 (s, 1 F) ppm.
colourless liquid obtained by microdistillation, b.p. 52–54 °C/80 Pa,
[α]D = +72.1 at 20 °C (c = 0.140 g/100 mL, CHCl3). Column
chromatography was performed on silica gel (benzene/ethyl acetate,
10:1). IR (CHCl ): ν
= 1784 (s), 1682 (m) cm–1. MS (EI): m/z
max
˜
3
(%) = 116 (11) [M]+. C5H5FO2 (116.1): calcd. C 51.73, H 4.34;
1
found C 51.52, H 4.11. H NMR (CDCl3): δ = 1.51 (dd, J = 6.9,
J = 1.1 Hz, 3 H), 5.26 (dqd, J = 6.6, J = 5.6, J = 1.9 Hz, 1 H),
6.71 (dd, J = 2.2, J = 1.9 Hz, 1 H) ppm. 13C NMR (CDCl3): δ =
19.5 (J = 3 Hz), 73.0 (J = 7 Hz), 126.7 (J = 5 Hz), 148.2 (J =
279 Hz), 164.4 (J = 32 Hz) ppm. 19F NMR (CDCl3): δ = –141.5
(d, J = 4.9 Hz, 1 F) ppm.
Ethyl 2-(2-Methoxycyclohexylidene)acetate (25): Yield 618 mg
(65.7%) of the mixture 25a/25b (65:35). Column chromatography
was performed on silica gel (benzene/ethyl acetate, 10:1); slightly
Bis[tert-butyl(dimethyl)]siloxane (29): Yield 1.2 g (93.6%) of a
colourless liquid. MS (EI): m/z (%) = 246 (1) [M]+. 1H NMR
(CDCl3): δ = 0.03 (s, 3 H), 0.87 (s, 9 H) ppm.
yellow oil. IR (CHCl ): ν
= 3025 (w), 2986 (w), 2941 (m), 1709
˜
3
max
Ethyl (E)-2-Oxo-4-phenylbut-3-enoate (30):[31] Yield 884 mg
(49.8%) of a slightly yellow oil. Column chromatography was per-
formed on silica gel (benzene). The conversion of compound 15 to
30 was complete based on 19F and 1H NMR spectroscopy. IR
(s), 1653 (m-w), 1464 (w), 1447 (w), 1381 (w), 1198 (w), 1167 (s),
1143 (m), 1095 (m), 1036 (w) cm–1. HRMS (EI): calcd. for
C11H18O3 198.1256; found 198.1248. MS (EI): m/z (%) = 198 (34)
[M]+. 25a (Z): 1H NMR (CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3 H),
1.31–2.02 (m, 6 H), 2.54 (m, 1 H), 3.05 (m, 1 H), 3.29 (s, 3 H), 4.15
(q, J = 7.2 Hz, 2 H), 5.79 (dd, J = 11.0, J = 0.8 Hz, 1 H) ppm. 13C
NMR (CDCl3): δ = 14.3, 22.7, 28.5, 32.9, 34.6, 55.7, 59.7, 82.5,
112.8, 166.0. 166.7 ppm. 25b (E): 1H NMR (CDCl3): δ = 1.27 (t, J
= 7.1 Hz, 3 H), 1.31–2.02 (m, 6 H), 2.54 (m, 1 H), 3.24 (s, 3 H),
3.56 (m, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 5.24 (t, J = 6.8 Hz, 1
H) ppm. 13C NMR (CDCl3): δ = 14.3, 20.1, 27.2, 27.7, 32.8, 56.6,
59.8, 72.5, 116.5, 160.9, 166.1 ppm.
(CHCl ): ν
= 1730 (m), 1608 (s), 1083 (s) cm–1. HRMS (EI):
˜
3
max
calcd. for C12H21O3 204.0786; found 204.0780. MS (EI): m/z (%) =
204 (4) [M]+. 1H NMR (CDCl3): δ = 1.42 (t, J = 7.1 Hz, 3 H), 4.40
(q, J = 7.1 Hz, 2 H), 7.36 (d, J = 16.0 Hz, 1 H), 7.43 (m, 3 H), 7.63
(m, 2 H), 7.86 (d, J = 16.0 Hz, 1 H) ppm. 13C NMR (CDCl3): δ =
14.2, 62.5, 120.4, 128.9, 131.5, 133.9, 148.3, 162.0, 182.6 ppm.
tert-Butyl(fluoro)dimethylsilane (31):[18] The product was deter-
1
mined by 19F and H NMR analysis of the relevant reaction mix-
1
ture. H NMR (CDCl3): δ = 0.18 (s, 3 H), 0.91 (s, 9 H) ppm. 19F
Ethyl 2-[2-tert-Butyl(dimethyl)silyloxycyclohexylidene]-2-fluoroace-
tate (26): Yield 883 mg (86.0%) of the mixture 26a/26b (62:38).
Microdistillation, b.p. 119–120 °C/240 Pa; colourless liquid. Col-
umn chromatography was performed on neutral Al2O3 (dichloro-
NMR (CDCl3): δ = –170.1 (sept, J = 7.3 Hz, 1 F) ppm.
Photoinduced Z/E Isomerisation and Defluorination of Alkenoate
23: A mixture of alkenoate 23 (23a/23b = 97:3; 100 mg, 0.29 mmol)
and acetone (110 mg, 1.89 mmol) in isooctane (8 mL) was vigor-
ously stirred at room temp. in a silicious cell under UV irradiation
(S1). After stirring for 1 h, the content of 23a/23b was 80:20 and
the ratio of E/Z isomers did not change further (checked by 19F
NMR of the reaction mixture). The mixture was irradiated by UV
light (S2) for another 2 h leading to the complete decomposition
of alkenoate 23 to 32, formed in a ratio of 32a/32b = 60:40 (checked
by 19F NMR of the reaction mixture). The mixture was allowed
to stand for 2 days at room temperature during which time the
decomposition of 32b [19F NMR (CDCl3): δ = –169.13 ppm (dd, J
= 48.8, J = 6.1 Hz, 1 F)] to oxo ester 33 was observed (conversion
of 32b checked by 19F NMR of the reaction mixture). The solvent
was removed (rotary evaporator) and the residue purified by
chromatography on a silica gel column (benzene/ethyl acetate10:1)
to afford products 32a and 33.
methane). IR (CHCl ): ν
= 2938 (m), 2858 (m-w), 1720 (m),
˜
3
max
1660 (m), 1463 (m), 1446 (w), 1370 (w), 1295 (s), 1254 (s), 1048 (s),
1018 (s) cm–1. C16H2FO3Si (216.3): calcd. C 61.72, H 9.24; found
C 60.98, H 9.43. 26a (E): 1H NMR (CDCl3): δ = –0.02, 0.05 (2ϫs,
6 H), 0.88 (s, 9 H), 1.33 (m, 2 H), 1.33 (t, J = 7.1 Hz, 3 H), 1.48
(dm, J = 12.6 Hz, 2 H), 1.87 (m, 2 H), 2.28 (m, 1 H), 2.68 (d, J =
12.9 Hz, 1 H), 4.28 (m, 2 H), 5.61 (m, 1 H) ppm. 13C NMR
(CDCl3): δ = –5.13, –4.90, 14.17, 17.95, 19.46, 22.6 (J = 8 Hz),
25.7, 27.1 (J = 2 Hz), 35.5 (J = 3 Hz), 61.2, 64.1 (J = 6 Hz), 137.7
(J = 11 Hz), 140.7 (J = 252 Hz), 161.2 (J = 36 Hz) ppm. 19F NMR
1
(CDCl3): δ = –131.4 (s, 1 F) ppm. 26b (Z): H NMR (CDCl3): δ =
0.01, 0.06 (2ϫs, 6 H), 0.88 (s, 9 H), 1.33 (m, 2 H), 1.33 (t, J =
7.1 Hz, 3 H), 1.48 (dm, J = 12.6 Hz, 2 H), 1.87 (m, 2 H), 2.28 (m,
1 H), 3.30 (d, J = 13.5 Hz, 1 H), 4.28 (m, 2 H), 4.93 (m, 1 H) ppm.
13C NMR (CDCl3): δ = –5.23, –5.10, 14.11, 17.98, 19.53, 22.9 (J =
2 Hz), 25.7, 27.4 (J = 2 Hz), 35.2 (J = 2 Hz), 61.2, 63.3 (J = 11 Hz),
137.1 (J = 10 Hz), 140.0 (J = 249 Hz), 161.6 (J = 37 Hz) ppm. 19F
NMR (CDCl3): δ = –131.2 (d, J = 2.7 Hz, 1 F) ppm.
Ethyl (E)-4-[tert-Butyl(dimethyl)silyloxy]-2-fluoro-3-phenylbut-3-en-
oate (32a): Yield 22 mg (22.0%) of a slightly yellow oil. HRMS
(FAB): calcd. for C18H27FO3Si 338.1710; found 338.1705. MS
(FAB): m/z (%) = 338 (10) [M + H]+. 1H NMR (CDCl3): δ = 0.22,
0.24 (2ϫs, 6 H), 0.97 (s, 9 H), 1.07 (t, J = 7.1 Hz, 3 H), 4.12 (m,
J = 7.1, J = 2.5 Hz, 2 H), 6.15 (d, J = 47.6 Hz, 1 H), 6.81 (d, J =
3.6 Hz, 1 H), 7.14–7.42 (m, 5 H) ppm. 13C NMR (CDCl3): δ =
–5.43, –5.32, 13.9, 18.3, 25.4, 61.2, 85.3 (J = 181 Hz), 117.0 (J =
16 Hz), 127.0, 127.6, 128.3, 135.7, 145.1 (J = 8 Hz), 169.2 (J =
28 Hz) ppm. 19F NMR (CDCl3): δ = –181.37 (dd, J = 47.6, J =
3.7 Hz, 1 F) ppm.
General Procedure for the Acid-Catalysed Cyclisation and the Re-
arrangement of Alkenoates 13 and 15: A mixture of alkenoate 13 or
15 (8.7 mmol) and p-toluenesulfonic acid (17.4 mmol) in dichloro-
methane (20 mL) was vigorously refluxed for 2–4 h until the con-
version of the alkenoate to products was complete (checked by 19
F
NMR). After cooling, the mixture was diluted with dichlorometh-
ane (20 mL) and washed with water (2 mL). The organic solution
was dried with MgSO4 and the solvent was removed to a minimum
Eur. J. Org. Chem. 2007, 5917–5925
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5923

ˇ
K. Pomeisl, J. Cejka, J. Kvícˇala, O. Paleta
FULL PAPER
Ethyl (E)-3-Phenyl-4-oxobut-2-enoate (33): Yield 30 mg (50.7%) of 135.4 (J = 9 Hz), 141.2 (J = 251 Hz), 161.3 (J = 36 Hz) ppm. 19F
a slightly yellow oil. HRMS (EI): calcd. for C12H12O3 204.0786:
found 204.0779. MS (EI): m/z (%) = 204 (34) [M]+. 1H NMR
(CDCl3): δ = 1.12 (t, J = 7.1 Hz, 3 H), 4.13 (q, J = 7.1 Hz, 2 H),
6.70 (s, 1 H), 7.20–7.26 (m, 3 H), 7.39–7.41 (m, 2 H), 9.77 (s, 1
H) ppm. 13C NMR (CDCl3): δ = 13.8, 61.3, 128.0, 128.9, 129.0,
136.2, 149.5, 165.0, 192.8 ppm.
NMR (CDCl3): δ = –130.4 (s, 1 F) ppm.
3-Fluoro-4-phenylfuran-2(5H)-one (37): Yield 296 mg (41.5%) of a
solid which was crystallised in hexane/acetone to afford white crys-
tals, m.p. 127–129 °C. IR (CHCl ): ν
= 1779 (s), 1684 (w) cm–1.
˜
3
max
MS (EI): m/z (%) = 178 (98) [M]+. C10H7FO2 (178.2): calcd. C
1
67.42, H 3.96, F 10.66; found C 67.43, H 3.91, F 10.52. H NMR
(CDCl3): δ = 5.17 (d, J = 5.5 Hz, 2 H), 7.50 (m, 3 H), 7.58 (m, 2
H) ppm. 13C NMR (CDCl3): δ = 66.3 (J = 7 Hz), 127.06, 127.14,
129.4, 131.3 (J = 2 Hz), 127.2, 133.6 (J = 3 Hz), 142.7 (J = 277 Hz),
165.4 (J = 32 Hz) ppm. 19F NMR (CDCl3): δ = –144.5 (t, J =
4.9 Hz, 1 F) ppm.
General Procedure for the Photoisomerisation and Cyclisation of Al-
kenoates 23, 24 and 26: Synthesis of 3-Fluorofuran-2(5H)-ones 37–
39: A mixture of alkenoate 23, 24 or 26 (4 mmol) and p-toluenesul-
fonic acid (4.8 mmol) in solvent (23/dioxane 8.4 mL, 24/isooctane
8 mL, 26/dioxane 3.5 mL) was vigorously refluxed for 1 h until the
conversion of alkenoate to intermediates 34, 35 or 36 was complete
(checked by 19F NMR). After cooling, the mixture was irradiated
at room temperature in a silicious cell by UV light (S2) for 20–
26.5 h until the complete isomerisation and cyclisation of 34–36 to
37–39 was observed (checked by 19F NMR of the reaction mix-
ture). The solvent was removed (rotary evaporator) and the residue
was codistilled with hexane. The mixture was diluted with dichloro-
methane and neutralised with a solution of NaHCO3. The organic
solution was dried with MgSO4 and the solvent was removed (ro-
tary evaporator). The residue was purified by chromatography on
a silica gel column (benzene/ethyl acetate, 10:1) to afford butenol-
ides 37–39.
3-Fluoro-4,5-dimethylfuran-2(5H)-one (38): Yield 215 mg (41.3%)
of a colourless oil. C6H7FO2 (130.1): calcd. C 55.38, H 5.42, F
14.60; found C 55.25, H 5.71, F 14.78. 1H NMR (CDCl3): δ = 1.47
(dd, J = 6.6, J = 1.4 Hz, 3 H), 1.98 (dd, J = 2.2, J = 0.9 Hz, 3 H),
4.86 (qd, J = 6.3, J = 1.1 Hz, 2 H) ppm. 13C NMR (CDCl3): δ =
8.9 (J = 2 Hz), 18.1 (J = 2 Hz), 76.1 (J = 7 Hz), 138.7 (J = 5 Hz),
143.9 (J = 271 Hz), 164.4 (J = 35 Hz) ppm. 19F NMR (CDCl3): δ
= –152.7 (s, 1 F) ppm.
3-Fluoro-5,6,7,7a-tetrahydro-1-benzofuran-2(4H)-one (39): Yield
338 mg (54.1%) of a colourless liquid. IR (CHCl ): ν
= 1773
˜
3
max
(s), 1719 (w) cm–1. MS (FAB): m/z (%) = 157 (49) [M + H]+.
C8H9FO2 (156.2): calcd. C 61.53, H 5.81, F 12.17; found C 61.25,
1
H 5.67, F 12.16. H NMR (CDCl3): δ = 1.26 (m, 3 H), 1.88 (m, 2
Ethyl (Z)-2-Fluoro-4-hydroxy-3-phenylbut-2-enoate (34b): Yield
418 mg (50.2%) of a colourless oil obtained for analytical purposes
by deprotection of alkenoate 23b without further UV irradiation.
Column chromatography was performed on silica gel (benzene/
H), 2.03 (m, 1 H), 2.45 (m, 1 H), 2.28 (m, 1 H), 2.87 (dm, J =
14.6 Hz, 1 H), 4.58 (2ϫdd, J = 11.3, J = 5.5 Hz, 1 H) ppm. 13C
NMR (CDCl3): δ = 23.0, 24.1 (J = 2 Hz), 26, 34.4 (J = 2 Hz),
77.0 (J = 7 Hz), 141.2 (J = 7 Hz), 141.5 (J = 271 Hz), 165.7 (J
= 32 Hz) ppm. 19F NMR (CDCl3): δ = –155.7 (d, J = 3.7 Hz, 1
F) ppm.
ethyl acetate, 10:1). IR (CHCl ): ν
= 3608 (w), 1728 (s), 1465
˜
3
max
(w), 1319 (m), 1260 (s), 1166 (m), 1019 (m) cm–1. MS (EI): m/z (%)
= 224 (29) [M]+. C12H13FO3 (224.2): calcd. C 64.28, H 5.86; found
Synthesis of 2-[tert-Butyl(dimethyl)silyloxy]-3-fluoro-4-phenylfuran
(41): A solution of n-butyllithium in hexane (2.5 , 123 µL,
0.309 mmol) was added dropwise under nitrogen through a syringe
into the flask charged with diisopropylamine (32 mg 0.309 mmol)
and dry THF (5 mL) and cooled to 0 °C. The mixture was stirred
for 20 min and then cooled to around –75 °C. Compound 37
(46 mg, 0.258 mmol) in THF (3 mL) was then added dropwise
through a syringe while stirring. After 45 min, a solution of tert-
butyl(dimethyl)silyl chloride (55 mg, 0.365 mmol) in THF (2 mL)
was added through a syringe, the mixture was stirred for 20 min
and then allowed to warm to room temp. The solvent was removed
under reduced pressure at room temp. (rotary evaporator) and the
residue purified by flash chromatography on neutral Al2O3 (light
petroleum/dichloromethane, 1:1) to give 53 mg (70.2%) of 41 as a
slightly yellow oil. No decomposition of the product was found
during a week at 0–4 °C (checked by 19F NMR). HRMS (FAB):
calcd. for C16H21FO2Si 292.1295; found 292.1930. MS (EI): m/z
1
C 64.48, H 5.79. H NMR (CDCl3): δ = 1.01 (t, J = 7.1 Hz, 3 H),
1.62 (br. s, 1 H), 4.04 (q, J = 7.1 Hz, 2 H), 4.57 (d, J = 3.6 Hz, 2 H),
7.20–7.25 (m, 2 H), 7.34–7.40 (m, 3 H) ppm. 13C NMR (CDCl3): δ
= 13.5, 60.5 (J = 9 Hz), 61.4 (J = 0.8 Hz), 128.26, 128.27, 128.30,
128.34, 132.4 (J = 14 Hz), 134.1 (J = 5 Hz), 144.5 (J = 258 Hz),
160.4 (J = 36 Hz) ppm. 19F NMR (CDCl3): δ = –123.5 (t, J =
3.7 Hz, 1 F) ppm.
Ethyl (Z)-2-Fluoro-4-hydroxy-3-methylpent-2-enoate (35b): Yield
251 mg (74.3%) of a colourless oil obtained for analytical purposes
by deprotection of alkenoate 24b without further UV irradiation.
Column chromatography was performed on silica gel (benzene/
ethyl acetate, 10:1). IR (CHCl ): ν
= 3612 (w), 1721 (s), 1307
˜
3
max
(s), 1230 (m), 1073 (m) cm–1. HRMS (EI): calcd. for C8H13FO3
176.0849; found 176.0838. MS (EI): m/z (%) = 176 (1) [M]+. 1H
NMR (CDCl3): δ = 1.27 (d, J = 6.6 Hz, 3 H), 1.32 (t, J = 7.1 Hz,
3 H), 2.05 (d, J = 3.0 Hz, 3 H), 4.26 (q, J = 7.1 Hz, 2 H), 5.0 (q,
J = 6.3 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 9.9 (J = 2 Hz), 14.0,
20.7 (J = 1 Hz), 61.2, 64.0 (J = 11 Hz), 135.1 (J = 10 Hz), 142.2 (J
= 249 Hz), 161.2 (J = 35 Hz) ppm. 19F NMR (CDCl3): δ = –128.4
(s, 1 F) ppm.
1
(%) = 292 (20) [M]+. H NMR (CDCl3): δ = 0.28 (s, 6 H), 1.00 (s,
9 H), 6.22 (J = 4.1 Hz), 7.29 (m, J = 6.3 Hz, 1 H), 7.36 (t, J =
7.4 Hz, 2 H), 7.52 (d, J = 7.4 Hz, ????) ppm. 13C NMR (CDCl3): δ
= –4.7, 18.0, 25.3, 119.0 (J = 13 Hz), 124.9 (J = 7 Hz), 126.00,
126.04, 127.3, 128.7, 127.5, 130.3 (J = 4 Hz), 130.7 ppm. 19F NMR
(CDCl3): δ = –189.73 (d, J = 3.4 Hz, 1 F) ppm.
Ethyl (Z)-2-Fluoro-2-(2-hydroxycyclohexylidene)acetate (36b): Yield
32 mg (10.7%) of a colourless oil. IR (CHCl ): ν
= 3609 (w),
˜
3
max
Supporting Information (see also the footnote on the first page of
this article): Further details of the monitoring by 19F NMR spec-
troscopy of the Z/E isomerisation of 23b to the butenolide 37.
2944 (m), 1723 (m), 1661 (w), 1301 (s), 1256 (m), 1219 (m), 1027
(m), 998 (w), 974 (w) cm–1. HRMS (EI): calcd. for C10H15FO3
1
202.1005; found 202.1001. MS (EI): m/z (%) = 202 (12) [M]+. H
NMR (CDCl3): δ = 1.30 (m, 1 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.50
(m, 2 H), 1.80 (m, 2 H), 1.95 (d, J = 12.0 Hz, 1 H), 2.20 (br. s, 1
H), 2.33 (m, 1 H), 3.28 (d, J = 15.0 Hz, 1 H), 4.24 (q, J = 7.1 Hz,
Acknowledgments
2 H), 4.95 (s, 1 H) ppm. 13C NMR (CDCl3): δ = 14.0, 19.4, 22.8 This study was performed as a part of a research project of the
(J = 1 Hz), 26.9 (J = 2 Hz), 33.6 (J = 2 Hz), 61.3, 62.9 (J = 11 Hz),
Institute of Organic Chemistry and Biochemistry (project
5924
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5917–5925

Synthesis of 3-Fluoro-2(5H)-furanones
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The authors thank Prof. Dr. Miroslav Strnad (Palacký Univer-
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Received: May 16, 2007
Published Online: October 5, 2007
Eur. J. Org. Chem. 2007, 5917–5925
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5925