Fluorine-containing butanolides and butenolides. Vinylic fluorine displacement in 4,4-dialkyl-2,3-difluoro-2-buten-4-olides and a novel rearrangement induced by organolithium addition to a carbonyl group

Article abstract of DOI:10.1016/S0040-4020(00)00167-8

2,3-Difluoro-4,4-dimethyl-2-buten-4-olide (1) and spirocyclic 2,3- difluoro-4,4-(pentane-1,5-diyl)-2-buten-4-olide (2) were modified by vinylic displacement of fluorine with some O- and C-nucleophiles. Sodium and lithium alkoxides, substituted phenoxides and protected glucose alkoxides reacted by 1,4-addition followed by the expulsion of fluoride ion to give 3-substituted derivatives (4-24). Softer Grignard reagents in the form of a copper (I) bromide-dimethyl sulfide complex reacted in the same way as O-nucleophiles to afford 3-alkyl- or 3-aryl derivatives (25-26). Harder organolithium reagents attacked the carbonyl group to give unstable hydroxy compounds that rearranged spontaneously to furan(2H)-3-ones (27-29) in a novel oxygen rearrangement reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00167-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3197±3207
Fluorine-Containing Butanolides and Butenolides. Vinylic
Fluorine Displacement in 4,4-Dialkyl-2,3-di¯uoro-2-buten-4-
olides and a Novel Rearrangement Induced by Organolithium
Addition to a Carbonyl Group
a,
b
Oldrich Paleta, Andrew Pelter, Josef Kebrle, Zdenek Duda and Jan Hajduch
a
a
a
*
Ï
Ï
a
Â
Department of Organic Chemistry, Institute of Chemical Technology, Technicka 5, 166 28 Prague 6, Czech Republic
bDepartment of Chemistry, University of Wales Swansea, Singleton Park, Swansea SA2 8PP, United Kingdom
Received 13 July 1998; revised 31 January 2000; accepted 17 February 2000
AbstractÐ2,3-Di¯uoro-4,4-dimethyl-2-buten-4-olide (1) and spirocyclic 2,3-di¯uoro-4,4-(pentane-1,5-diyl)-2-buten-4-olide (2) were
modi®ed by vinylic displacement of ¯uorine with some O- and C-nucleophiles. Sodium and lithium alkoxides, substituted phenoxides
and protected glucose alkoxides reacted by 1,4-addition followed by the expulsion of ¯uoride ion to give 3-substituted derivatives (4±24).
Softer Grignard reagents in the form of a copper (I) bromide-dimethyl sul®de complex reacted in the same way as O-nucleophiles to afford 3-
alkyl- or 3-aryl derivatives (25±26). Harder organolithium reagents attacked the carbonyl group to give unstable hydroxy compounds that
rearranged spontaneously to furan(2H)-3-ones (27±29) in a novel oxygen rearrangement reaction. q 2000 Elsevier Science Ltd. All rights
reserved.
Introduction
Our research on ¯uorine-containing butenolides has been
stimulated by the above mentioned biological activities
together with the fact that ¯uoro substituents (such as F,
CF3, OCF3 etc.) are powerful modi®ers of chemical and
biological properties of organic compounds17,18 as docu-
mented by hundreds of pharmaceuticals and biocides. A
combination of a ¯uorine substituent with a 2-buten-4-
olide ring could thus afford compounds with new and inter-
esting bioactivity. Some ¯uorinated analogs of tetronic and
l-ascorbic acids have recently been prepared19 for biochem-
ical studies and 2-¯uoro-4-hydroxy-3-styryl-2-buten-4-
olide exhibited phospholipase inhibitory effect.20
The 2-buten-4-olide ring is a component of several classes
of bioactive natural compounds. Well-known examples are
isoprenoids,1 piperolides2,3,4 and fadyenolides2,5 (with seda-
tive properties), cardolides (e.g digitoxin), carotenoids6 and
retinoids6 (e.g. pteridinin causing planctonic `red tide').
There are many other natural bioactive 2-buten-4-olides,
e.g. with antitumor activity,7 cytotoxic properties8 to
human tumor cells, intestinal carcinogenicity inhibition9
and also with HIV-1 protease-inhibitor activity.10 Buteno-
lides isolated from the group of Annonaceae plants11 have
exhibited a signi®cant activity against lymphocytic leuke-
mia system, and cytotoxic butenolides from Melodorum
fruticosum12 showed activities against several tumor lines.
New bioactive properties can also be created by the synth-
esis of analogues of natural butenolides, as in the case of
some retinoids that were proved to have antitumor13 and
antitumor-promoter activity.14 Numerous butenolide deriva-
tives are claimed in patent literature as drugs, pharmaceu-
ticals and biocides. 2-Buten-4-olides with halogen
substituents (chlorine, bromine) attached to the double
bond15 have been developed as cytostatics.15 However
some of them, occurring in chlorinated drinking water,
appeared to be mutagenic.16
Vinylic displacement of a halogen offers the possibility of
modifying the starting structure of a butenolide with reten-
tion of the double bond. As previously reported,15,21,22
several 2,3-dihalogeno-2-buten-4-olides underwent halogen
displacement with some nucleophiles, but ring opening as a
consequence of a series of consecutive reactions has also
been observed.22 Displacement of vinylic ¯uorine and other
halogens by a nucleophilic reagent has become a general
synthetic method in aliphatic and alicyclic organo¯uorine
chemistry.23±26 Halogen atoms have been substituted in 3-
halogeno-2-alkenoates23,26 or in per¯uoroole®ns,27 while in
the case of 2,3,3-tri¯uoroacrylate addition of alkanols took
place.28 In reaction with secondary amines, vinylic ¯uorine
displacement followed by subsequent addition of a second-
ary molecule has been reported.28,29 No such reactions have
been applied, to our knowledge, to ¯uorine containing
Keywords: vinylic ¯uorine displacement; butanolides; butenolides; organo-
lithium addition rearrangement; hard and soft nucleophiles.
* Corresponding author. E-mail: paletao@vscht.cz
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00167-8

3198
O. Paleta et al. / Tetrahedron 56 (2000) 3197±3207
Scheme 1. (1) RˆCH3; (2) R±Rˆ±(CH2)5±; MˆLi, Na, MgBr.CuBr.Me2S; RˆCH3; YˆCH3O (4), C2H5O (5), C3H7O (6), (CH3)2CHO (7), C4H9O (8),
(CH3)3CO (9), R±Rˆ±(CH2)5±, YˆCH3O (10).
2-buten-4-olides. In our preliminary communication,30 we
reported a method for the preparation of a variety of
a-¯uorinated butenolides by vinylic displacement of
¯uorine and also a novel rearrangement of the ¯uori-
nated 2-hydroxy-2,5-dihydrofuran ring. Here we discuss
all our results including the mechanism of the rearrange-
ment.
classi®ed as hard nucleophiles.31 Oxyanions of various
hydroxy compounds reacted analogously (Figs. 1 and 2),
to give 11±24.
This result is in contrast with the reactivity of similar struc-
tures, e.g. 2-¯uoro-2-buten-4-olide reacted at the carbonyl
group with ring opening,32 or methyl 2,3-di¯uoro-3-[4-(2,2-
dimethyl-1,3-dioxolanyl)]-2-propenoate33 that added
a
second methanol molecule, or methyl 2,3,3-tri¯uoroacrylate
that reacted with the addition of methanol.28 Non-
¯uorinated 2-buten-4-olides added methanol,34 while the
reaction with methanolic hydroxide35 led mainly to ring
opening.
Results and discussion
Reactions of oxyanions
All reactions with sodium and lithium alkoxides carried out
took place as in Scheme 1. The oxyanions attacked the
b-carbon in di¯uorobutenolides 1 or 2 with complete regio-
selectivity to give products (4±10) of vinylic displacement
of ¯uorine (Scheme 1). The mechanism can be formulated
(Scheme 1) as a 1,4-addition followed by the expulsion of
¯uoride ion from the intermediate metal enolate 3, which
appeared to be unable to abstract proton from the super-
¯uous methanol present in the mixture. The b-carbon of
a,b-unsaturated carbonyl compounds has been usually
considered as a softer electrophilic center31 than the carbon
of a carbonyl group. However, the presence of a ¯uorine
atom at the a-carbon can substantially change its hardness
and enable the attack of alkoxide ions that are generally
We carried out the reactions of the butenolide 2 ®rst with
sodium methoxide in various conditions (Table 1) including
excess methanol to optimise reaction yields and isolation
procedure. The best yields were obtained by the `dry pro-
cedure' based on a short-column separation of salts. The
reactions of branched alkoxides were slower than that of
primary alkoxides.
Sodium monoalkoxides of protected polyhydroxy
compounds and sugars reacted in a similar way to simple
alkoxides (products 11±13, Fig. 1). Nucleophilic displace-
ment of vinylic ¯uorine, to our knowledge, has not
previously been carried out with such oxyanions. The
Figure 1.
Figure 2.

O. Paleta et al. / Tetrahedron 56 (2000) 3197±3207
Table 1. Optimisation of yields in the reactions of some sodium alkoxides
3199
Entry
Butenolide
Alkanol
Base
Solvent
Temperature
Procedurea
Yield
Product
1
2
3
4
5
6
7
8
9
10
1
1
1
1
1
1
1
2
2
2
MeOH
MeOH
MeOH
MeOH
MeOH
ButOH
ButOH
MeOH
MeOH
MeOH
Na
NaH
Na
Na
NaH
Na
NaH
Na
Na
BuLi
MeOH
DME
55
55
rt
re¯ux
250 to rt
re¯ux
240 to rt
re¯ux
re¯ux
270 to rt
A
B
C
D
E
A
C
A
D
29b
39b
72b
79b
86b
0c
4
4
4
4
4
9
9
10
10
10
MeOH
MeOH
DME
ButOH
DME
53b
35b
83b
85b
MeOH
MeOH
MeOH
a For details, see Experimental.
b Complete conversion of the starting material 1 or 2 as checked by 19F NMR.
c No conversion of the starting material 1 was detected.
reaction took place even with sterically hindered 1,2;5,6-di-
O-isopropylidene-a-d-glucofuranose.
compounds 27 and 28 as the end products in reactions
with 1 (Scheme 2). Compounds 27 and 28 were isomeric
with the products 25 and 26, but did not contain the
2-buten-4-olide ring as shown by the absence of bands at
ca. 1775±1780 cm21 in their IR spectra. Instead, each
contained a ketone group (dC ca. 195±198 ppm; nmax
1706±1723 cm21). The pattern of the signals in the 13C
NMR were similar for the pair 27 and 28 and differed
considerably from the pair 25 and 26 (Table 2). Attempts
to use the INADEQUATE NMR technique to de®ne the
connectivity of the chain of four carbon atoms foundered on
the long relaxation times and the spread of the signals.
Sodium phenoxides reacted with 1 and 2 by vinylic ¯uorine
displacement as shown in Fig. 2 according to Scheme 1 and
moderate to good yields of phenoxide products 14±24 were
obtained. New ¯uorinated butenolide derivatives 14±24
could display some biocide properties as is known for
similar non-¯uorinated butenolides.36
Reactions of soft carbanions
The reagents used were methyl- or phenylmagnesium
bromide modi®ed with copper(I) bromide-dimethyl sul®de.
Their reactions with 1 gave exclusively b-substituted
butenolides 25, 26 (equation 1) according to Scheme 1.
Products of the attack on the carbonyl group were not
observed. The reaction thus gives the possibility of modify-
ing 1 and 2 at position 3 with various alkyl and aryl substi-
tuents using complexed Grignard reagents.
With respect to the formulae of 27 and 28 it appeared that
the carbonyl group was attacked by organolithium reagents,
which behaved in this reaction as hard C-nucleophiles. This
regioselectivity can be caused by the ablity of the lithium
ion in RLi to coordinate with the carbonyl oxygen.37 By the
addition of organolithiums, the skeleton of compounds 27
and 28 was formed (intermediates 30 and 33, Scheme 3).
X-Ray analysis of compound 28 con®rmed30 its structure
and the close overall similarity of 27 and 28 allowed the
assignment of structure 27 (Scheme 2). Similarly spiro-
cyclic 2 was observed to give 29 (Scheme 2) and thus, the
reaction has not been in¯uenced by the rigid spirocyclic
annelation at C4.
ꢀ1†
To gather further insight into the mechanistic pathway lead-
ing from 30 to the end-intermediate 36 we tried to identify
some intermediates (Scheme 3). The reaction mixture from
the reaction of 1 with phenyllithium was quenched with
tri¯uoroacetic acid followed by rapid neutralisation with
sodium bicarbonate and the resulting crude product was
rapidly puri®ed and at once examined by 1H and 13C
NMR spectroscopy. It was shown to be a mixture of three
Reactions of hard carbanions and a novel
rearrangement
Methyllithium and phenyllithium surprisingly1 afforded
Scheme 2.

3200
O. Paleta et al. / Tetrahedron 56 (2000) 3197±3207
Table 2. Some spectral data of the starting compounds 1 and 2 and products 4±29
Compound
Y
X
dF
dC
C-1
X
C-2
X
C-3
X
C-4
nmax
(CˆO s, CˆC s)
1a
F
128.1 s
165.6 s
127.4 s
166.4 s
178.8 s
162.0 dc
162.9 dc
126.4 d
1JCFˆ299
160.2 d
1JCFˆ273
159.9 d
1JCFˆ269
158.9 d
JCFˆ6.14
158.2 d
JCFˆ5.63
158.2 d
JCFˆ6.1
157.4
78.0 dc
80.5
1802, 1757
1801, 1749
1773, 1706
1775, 1703
1775, 1703
1775, 1700
1775, 1703
1773, 1693
1774, 1705
±
2b
F
127.1 d
1JCFˆ290
125.2 d
4a
MeO
164.4 d
JCFˆ26.8
78.7 d
JCFˆ4.6
JCFˆ257
5a
EtO
178.1 s
177.8 s
177.0 s
177.8 s
166.5 s
164.8 d
JCFˆ26.6
164.6 d
124.7 d
78.9 d
JCFˆ5.4
78.7 d
1JCFˆ256.5
124.7 d
6a
PrO
JCFˆ26.7
1JCFˆ266
JCFˆ5.4
7a
PriO
164.6 dc
123.9 d
78.8 d
JCFˆ5
1JCFˆ256
124.8 d
8a
BuO
164.6 d
JCFˆ26.1
158.3 d
JCFˆ5.5
154.8
78.9 d
JCFˆ5.8
1JCFˆ256
9a
ButO
165.5 dc
122.6 d
79.5 d
JCFˆ6.1
80.7 d
1JCFˆ255
126.3 d
10b
11a
12a
13b
14a
15a
16a
17a
MeO
178.7 q
JHFˆ3.5
176.0 s
165.4 d
JCFˆ26.2
159.9 d
JCFˆ6.5
157.8 d
JCFˆ6.1
156.1 d
JCFˆ6.1
157.1 d
JCFˆ6.1
156 d
JCFˆ5.5
155.6 d
JCFˆ4.7
149.0 d
JCFˆ158.6
156.9 d
JCFˆ51.1
1JCFˆ257.5
JCFˆ3.9
DMDOMOd
DIPGFe
(DIPGF)
PhO
163.0 dc
125.1 d
78.8 d
JCFˆ4.6
78.8 d
1JCFˆ258
125.3 d
173.6 s
173.6 s
165.6 s
164.8 s
165.5 s
163.0 dc
1780, 1712
1778, 1708
±
1JCFˆ260
JCFˆ4.5
164.8 d
JCFˆ26.6
164.0 d
JCFˆ26
163.6 d
JCFˆ25.8
164.1 d
JCFˆ25.8
164.2 d
JCFˆ25.7
126.4 d
80.7 d
JCFˆ3.5
79.0 d
1JCFˆ260
125.5 d
1JCFˆ265
JCFˆ3.4
4Cl-C6H4O
2,4Cl2-C6H3O
2F-5Me-C6H3O
125.6 d
79.0 d
JCFˆ3.0
79.8 s
1781, 1714
1762, 1711
1781, 1716
1JCFˆ265
124.6 d
1JCFˆ264.1
170.2 s
124.8 d
79.7 d
JCFˆ2.9
137.0 dd
JCFˆ5.2; 3.5
162.3 s
43.4 s
170.2 s
1JCFˆ302.3
18a
19b
20b
21b
22b
23b
24b
25a
26a
27d
28f
29g
4CF3S-C6H4O
2Cl-C6H4O
4Cl-C6H4O
4NO2-C6H4O
2F-5Me-C6H3O
4CF3O-C6H4O
4CF3S-C6H4O
Me
163.9 d
JCFˆ26.3
128.5 d
1JCFˆ265.1
155.6 d
JCFˆ67.6
157.5 d
JCFˆ7.5
156.7
79.8
1782, 1714
1778, 1713
1775, 1711
1779, 1714
1779, 1720
1778, 1712
1779, 1713
1778, 1744
1776, 1670
1723, 1642
1706, 1626
1705, 1625
164.6 d
JCFˆ25.7
very weak
128 d
1JCFˆ264
126.8 d
81.6 d
JCFˆ3.1
81.0
164.4 s
161.2 s
170.2 s
1JCFˆ266.4
very weak
126.9 d
157.7
157.5
80.3
81.1
81.1
81.2
1JCFˆ269.4
127 d
165 d
JCFˆ25.2
164.6 d
JCFˆ15.8
164.6 d
JCFˆ29.3
163.9 dc
1JCFˆ255
164.3 s
58.8 s
162.3 s
43.5 s
153.7 s
121.1 d
156.6 d
JCFˆ5.6
156.5
1JCFˆ257.7
127.3 d
1JCFˆ267.8
143.1 d
142.3
142.1
197.9
195.3
83.1 d
JCFˆ7.0
1JCFˆ271.6
125.3 d
Ph
145.2 s
187.7 s
180.4 s
180.5 s
163.6 dc
176.0 d
83.5 d
JCFˆ5.9
88.6 dc
1JCFˆ279.4
Me
144.1 d
1JCFˆ259
140.9 d
Ph
166.7 d
JCFˆ13.6
86.5 d
JCFˆ6.4
1JCFˆ263.2
Ph
167.3 d
JCFˆ13.6
142.3 d
195.9 d
JCFˆ10.3
88.8 d
JCFˆ6.9
1JCFˆ263.9
a
d (2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy.
e O-(1,2:5,6-diisopropylidene-a-d-glucofuranosyl).
f
b
g
c Coupling constant not determined.

O. Paleta et al. / Tetrahedron 56 (2000) 3197±3207
3201
Scheme 3.
compounds almost certainly 32, 33 and 28. After standing
for 12 h in the NMR tube the spectra corresponded to 28
only and the solution was strongly acidic; no other NMR
signals were detected.
the ring opened lithium alkoxide 31. From the lithium salts,
free hydroxy compounds 32 and 33 are liberated by quench-
ing the reaction mixture with tri¯uoroacetic acid. The dis-
appearing NMR signals mentioned above are in accord with
these unstable intermediates. Protonated hemiacetal 34 is an
unstable intermediate that rearranges to 36. The transfer of
water species on the allylic system can be intermolecular
(35) or intramolecular (37) and leads a-¯uoro hydroxy
compound 36. This immediately eliminates hydrogen
¯uoride to give the end 3(2H)-furanone 28. The liberated
HF acts as the catalyst and the rearrangement is thus auto-
catalysed. We have tried to monitor the rearrangement by
19F NMR under different conditions (mineral acid concen-
tration, solvent and concentration) to obtain a time
dependence concentration of intermediates 32, 33 but so
far without success. The study of the scope and limitations
of the rearrangement is being continued.
The structure of the primary addition product 33 is an allylic
alcohol with a ¯uorinated double bond. It is known from the
literature27,38±41 that such aliphatic compounds are unstable
and rearrange, especially in the presence of mineral acid, by
a mechanism similar to the rearrangement of substituted
allylic alcohols 39,27,38±41 as in equation 2.
ꢀ2†
Conclusions
No such reaction has been reported on the dihydrofuran
skeleton. With the facts mentioned above the mechanism
of the transformation of the starting 1 to 27 or 28 can be
formulated in Scheme 3. Hemiacetal salt 30 formed in the
reaction of 1 with RLi is very probably in equilibrium with
A general method for the nucleophilic vinylic substitution of
3-F in 4,4-dialkyl-2,3-di¯uoro-2-buten-4-olides with a
variety of oxyanions and with soft carbanionic reagents
has been developed. Organolithiums behaved as hard

3202
O. Paleta et al. / Tetrahedron 56 (2000) 3197±3207
nucleophiles reacting at the carbonyl group to give unstable
hydroxy compounds that undergo a novel rearrangement to
give 2,2,5-trisubstituted 4-¯uoro-3(2H)-furanones. The
rearrangement is not in¯uenced by rigid 4,4-spirocyclic
annelation in the starting butenolide.
ethane (DME) and N,N-dimethylformamide were puri®ed
and dried in a standard manner.42 Tetrahydrofuran was
distilled in a still from sodium-benzophenone ketyl. The
following chemicals and reagents were purchased as
follows: CFC-113 (1,1,2-trichloro-1,2,2-tri¯uoroethane)
Â
Â
Â
Â
from Spolek pro chemickou a hutnõ vurobu (Ustõ n.L.,
CR), potassium ¯uoride (Fluka); sodium hydride (in mineral
oil), cuprous bromide, dimethylsulfane, phenylmagnesium
bromide (diethyl ether), butyllithium (2.5 M in hexane),
methyllithium (diethyl ether), and phenyllithium (2 M in
benzene/ether 75/25), tri¯uoroacetic acid (all from Aldrich
or Sigma-Aldrich); phenol and 4-chlorophenol (Fluka), the
other phenols and thiophenols (Baeyer AG) were used
without further puri®cation.
Experimental
Instrumentation
The temperature data were not corrected. GC analyses were
 ÏÂ
performed on a Chrom 5 instrument (Laboratornõ prõstroje,
Prague, 1984; FID, 380£0.3 cm packed column, silicone
elastomer E-301 on Chromaton N-AW-DMCS (Lachema,
Brno), nitrogen, i.e. GCa) and on a PU 4400 instrument
(Philips Analytical, Cambridge, 1990; capillary column
500£0.02 cm, methyl silicon ®lm-layer 25 mm, i.e. GCb).
NMR spectra were recorded on a Bruker 400 AM (FT, 19F at
376 MHz), Bruker AC 400 (Forchheim,1993; FT, 19F at
376 MHz), and Bruker WP 80 SY (FT, 19F at 75.4 MHz)
instruments: tetramethylsilane (1H and 13C) and CFCl3 (19F)
as the internal standards, chemical shifts in ppm (s singlet, d
doublet, t triplet, q quartet, quin quintet, sex sextet, hep
heptet, m multiplet), coupling constants J in Hz, solvents
used were CDCl3 and DMSO-d6 as bought. For assignment
of signals in NMR spectra, the individual atoms in structures
are indicated according to the example:
Dry potassium ¯uoride was prepared as follows: Anhydrous
KF was heated in an iron bowl with a Meker gas burner for
1 h, then rapidly ground to powder, which was further dried
in the reaction ¯ask under vacuum (oil pump) at 1608C for
2 h. Cu(I)Br-dimethyl sul®de complex was prepared
according to the described procedure43 and 2,3-di¯uoro-
4,4-dimethyl-2-buten-4-olide (1) were prepared in better
yields (62±69%) than previously reported.44 The prepara-
tion of 2,3-di¯uoro-4,4-(pentane-1,5-diyl)-2-buten-4-olide
(2) will be published in another paper.45
Experimental Procedures
2,3-Di¯uoro-4,4-dimethyl-2-buten-4-olide (1). Improved
procedure:44 Powdered potassium ¯uoride (16.4 g,
0.282 mol) was dried under vacuum (oil pump) in a 50 ml
¯ask for 1 h; the ¯ask was then pressure-equalised with
argon, ®tted with a Claisen condenser and a trap that was
connected to atmosphere through a hydraulic seal (conc.
sulfuric acid). The ¯ask was then heated to 190±1958C
and 2,3,3-tri¯uoro-4,4-dimethylbutan-4-olide was added
dropwise to KF through the neck of the condenser. The
liquid distillate (bp 103±1058C/130 mm Hg), product 1
(4.32 g, 94.8%; purity 95%, GCa), was used for reactions.
dH 1.62(6H, d, JFHˆ1.0, H-5). dC, 23.9(CH3).
The bold C-atom is indicated in the butenolide structure as
C-3-3-1 (i.e. butenolide ring - aromatic ring - side chain).
Hydrogen atoms are indicated according to the correspond-
ing carbon atoms, i.e. H-atom in the CH3 group is indicated
as H-3-3-1.
Mass spectra (EI, CI) were scanned on a GC-Mass Spectro-
meter tandem VG/12-253 Masslab Quadrupole Spectro-
meter (VG, Manchester, 1986). High-resolution molecular
ion was scanned on a VG Analytical Model YAB-E High
Resolution Reverse Geometry Double Foccusing Instru-
ment (VG, Manchester, 1986). Infra-red spectra were
recorded on a Perkin-Elmer 1700X FT-IR spectrometer
(Beacons®eld, 1988; absorption bands intensity: s strong,
m medium, w weak). Molecular formulae were determined
by high resolution mass spectrometry on a sample which
was pure by tlc, hplc and NMR or by microanalysis.
Analytical TLC was performed on silica gel (Merck)
mounted on aluminium cards with ¯uorescent indicator
(254 nm) and on pre-coated glass-backed plates and
visualised by UV light or ceriumIV nitrate.
2-Fluoro-3-methoxy-4,4-dimethyl-2-buten-4-olide (4).
Reactions were carried out in a double-necked 5 ml ¯ask
equipped with a Dimroth re¯ux condenser with CaCl2
drying tube, magnetic follower and septum cap.
Procedure A. Sodium cuts (0.42 g, 18.3 mmol) were put
into a ¯ask with methanol (1.5 ml). A solution of butenolide
1 (0.27 g, 1.82 mmol) in methanol (1.5 ml) was then added
at rt and the ¯ask was heated at 558C for 30 min. The
mixture was cooled to rt and then diluted with CFC-113
(15 ml), extracted with water, which, in turn, was twice
extracted with diethyl ether. The combined organic extracts
were evaporated to give 4 (85 mg, 29%) as a white solid, mp
76±868C that was recrystallised from hexane (mp 82±
868C).
Chemicals and reagents
Procedure B. Sodium hydride (0.112 g, 4.67 mmol) was put
into a ¯ask with DME (3 ml). Butenolide 1 (0.165 g,
1.11 mmol) was then added and the ¯ask was heated at
558C for 70 min. The mixture was then diluted with
water (5 ml), acidi®ed (pH ca.1) and extracted with diethyl
ether (3£5 ml). The combined extracts were dried over
Column chromatography was carried out using Merck
Kieselgel (63±100 mm). Methanol, ethanol, propanol,
2-propanol, 1-butanol, tert-butylalcohol, petroleum ether
(bp 40±608C), dichloromethane, diethyl ether, dimethoxy-

O. Paleta et al. / Tetrahedron 56 (2000) 3197±3207
3203
magnesium sulfate and solvent removed in vacuo to give
crude 4. Puri®cation by chromatography (20 g of silica gel,
diethyl ether) gave butenolide 4 (70.3 mg, 39%) as white
crystals (mp 85±878C).
after trap-to-trap distillation at 14 mm Hg 0.516 g (37%),
purity 96% (GCa). dH, 1.40(6H, dd, JFHˆ1.0, JHHˆ6.6, H-3-
2), 1.47(6H, d, JFHˆ1.0, H-4-1), 4.89(1H, dhep, JFHˆ2.4,
JHHˆ6.6, H-3-1). dC, 22.1(C-3-2), 24.4(C-4-1), 76.4(d,
JCFˆ4.1, C-3-1). nmax (cm21): 1775, 1746, 1700, 1627.
m/z (intensity), 189(3), 188(4)M1, 174(14), 146(17),
131(8), 129(9), 128(7), 103(10), 87(10), 72(7), 69(32),
59(23), 43(100), 41(27). HRMS found 188.0849,
C9H11FO3 requires [M]1, 188.08487.
Procedure C. According to procedure A, a mixture of
methanol (1.5 ml) to which were subsequently added
sodium cuts (31 mg, 1.35 mmol) and a solution of 1
(0.20 g, 1.35 mmol) in methanol (1.5 ml) was stirred at rt
for 12.5 h and then evaporated to dryness. The solid
obtained was extracted with diethyl ether, ®ltered, centri-
fuged and the solvent was removed to give pure 4 (0.155 g,
72%) (mp 84±878C).
3-Butoxy-2-¯uoro-4,4-dimethyl-2-buten-4-olide (8). Pro-
cedure A (as for 4); 1 (0.389 g, 2.64 mmol); yield (oil) after
trap-to-trap distillation at 12 mm Hg 0.17 g (32%), purity
95% (GCb). dH, 0.98(3H, t, JHHˆ7.4, H-3-4), 1.4-1.5(2H,
m, H-3-3), 1.48(6H, d, JFHˆ0.9, H-4-1), 1.73±1.8(2H, m,
H-3-2), 4.42(2H, dt, JFHˆ2.6, JHHˆ6.6, H-3-1). dC, 13.5(C-
3-4), 18.6(C-3-3), 24.5(C-4-1), 31.2(C-3-2), 72.9(2H, d,
JCFˆ4.3, C-3-1). m/z (intensity), 203(3)M1, 148(13),
146(12), 87(7), 69(13), 59(10), 58(70, 58(100), 56(18),
43(19), 41(37). HRMS found 203.1083, C10H15FO3 requires
[M]1, 203.10835.
Procedure D. According to procedure A, a mixture of
methanol (1.5 ml) to which were subsequently added
sodium cuts (31 mg, 1.35 mmol) and a solution of 1
(0.20 g, 1.35 mmol) in methanol (1.5 ml) was re¯uxed for
1.5 h and then treated as in C. The solid crude product was
extracted with dichloromethane and puri®ed by short-
column chromatography (silica gel 5 g, dichloromethane)
to give pure 4 (0.171 g, 79%), mp 86±878C.
2-Fluoro-3-tert-butoxy-4,4-dimethyl-2-buten-4-olide (9).
Procedure E (as for 4); 1 (0.276 g, 1.86 mmol), yield (oil),
0.202 g (54%), mp 84±898C. dH, 1.45(6H, d, JFHˆ0.9, H-4-
1), 1.50(9H, d, JFHˆ0.9, H-3-2). dC, 24.5(C-3-2), 28.1(d,
JCFˆ6.0, C-4-1), 83.7(C-3-1). m/z (intensity), 203(2)M1,
147(7), 129(9), 87(5), 57(100), 43(9), 41(18). HRMS
found 203.1083, C10H15FO3 requires [M]1, 203.10835.
Procedure E. A solution of methanol (42 mg, 1.31 mmol) in
DME (1 ml) was added to sodium hydride (31 mg,
1.29 mmol and decanted with petroleum ether). After the
reaction was ®nished (0.5±1 h), the ¯ask was cooled to
2608C and 1 was added dropwise with a syringe through
a septum. The mixture was stirred for 2 h at 2608C, then
allowed to warm to rt and DME was distilled off. The resi-
due was diluted with dichloromethane and subjected to
short-column chromatography (5 g of silica gel, dichloro-
methane) that gave 4 (0.178 g, 87%) (purity check by TLC,
254 nm detection). dH, 1.48(6H, s, 2CH3), 4.18(3H, d,
JFHˆ3.4, CH3O). dC 24.4(CH3), 60.1(d, JCFˆ3.8, CH3O).
m/z (intensity), 160(25)M1, 145(100), 129(12), 117(25),
103(55), 87(15), 43(40). HRMS found 160.0536, C7H9FO3
requires [M]1, 160.05357. nmax (cm21), 1773, 1747, 1706,
1636.
2-Fluoro-3-methoxy-(1,5-pentane-1,5-diyl)-2-buten-4-
olide (10). A solution of butyllithium (0.5 ml) was added
dropwise through a septum cap to dry methanol (1.5 ml) at
2708C while stirring for 15 min. A solution of 2 (0.184 g,
0.987 mmol) in methanol (0.5 ml) was then added dropwise
and the mixture was then allowed to warm to rt. The mixture
was then quenched with tri¯uoroacetic acid and neutralised
with a solution of Na2CO3. The residue was then treated as
in Procedure E; yield of 10, 0.166 g (85%), mp 130±1328C.
dH, 1.57±1.81 (5£2H, m, H-4-1- H-4-5), 4.16(3H, d, JFHˆ
3.5, H-3-1). dC, 21.9(C-4-3), 24.8(C-4-2,4), 33.7 (C-4-1,5),
60.6(d, JCFˆ3.8, C-3-1). Anal. calcd. for C10H13FO3 C,
59.99; H, 6.54. Found C, 59.88; H, 6.47.
3-Ethoxy-2-¯uoro-4,4-dimethyl-2-buten-4-olide (5). Pro-
cedure A (as for 4); 1 (0.40 g, 2.70 mmol); yield (oil), 0.25 g
(53%), purity 95% (GCb). dH, 1.43(3H, t, JHHˆ7.1, H-3-2),
1.48(6H, d, JFHˆ0.83, H-4-1), 4.48(2H, dq, JFHˆ2.45,
JHHˆ7.1, H-3-1). dC, 14.9(C-3-2), 24.5(C-4-1), 69.0(d,
JCFˆ3.2, C-3-1). m/z (intensity), 176(3), 175(34),
174(35)M1, 159(16), 146(20), 141(8), 131(58), 103(66),
69(35), 43(100), 42(13), 39(13). HRMS found 174.0692,
C8H11FO3 requires [M]1, 174.06922.
3-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]-2-¯uoro-
4,4-dimethyl-2-buten-4-olide (11). Procedure B (as for 4;
rt); 1 (0.5 g, 3.38 mmol); yield (oil) by trap-to-trap distilla-
tion at 12 mm Hg, 0.263 g (30%), purity 94% (GCa). dH:
1.38(3H, d, JFHˆ0.6, H-4-1), 1.44(3H, d, JFHˆ0.4, H-4-1),
1.51(6H, s, H-3-1-2-1), 3.81-3.88(1H, m, H-3-1), 4.12±
4.19(1H, m, H-3-1),), 4.40±4.48(3H, m, H-3-1-4,5). dC, 0
24.4(C-4-1), 25.1, 26.6, 65.5(C-3-1-5), 72.6(d, JCFˆ3.7,
C-3-1), 73.0(C-3-1-4), 110.2(C-3-1-2). m/z (intensity),
189(8), 147(12), 146(13), 131(9), 129(15), 113(12),
103(10), 87(11), 69(38), 60(9), 59(26), 43(100), 42(15),
41(28), 39(17). Anal. calcd. for C12H17FO5 C, 55.38; H,
6.58. Found C, 55.64; H, 6.78.
2-Fluoro-4,4-dimethyl-3-propoxy-2-buten-4-olide (6). Pro-
cedure D (as for 4); 1 (0.285 g, 1.92 mmol); yield (oil)
0.301 g (83%), purity 99% (GCb). dH: 1.02(3H, t,
JHHˆ7.5, HC-3-3), 1.49(6H, s, H-4-1), 1.81(2H, sex,
JHHˆ6.9, H-3-2), 4.37(2H, dt, JHHˆ6.5, JFHˆ2.6, H-3-1).
dC, 9.8(C-3-3), 22.6(d, JCFˆ2.0, C-3-2), 24.5(d, JCFˆ1.3,
C-4-1), 74.5(d, JCFˆ3.4, C-3-1). nmax (cm21), 1775, 1747,
1703, 1632. m/z (intensity), 188(10)M1, 146(35), 131(20),
103(10), 87(8), 69(13), 43(100). HRMS found 188.0849,
C9H13FO3 requires [M]1, 188.08487.
3-O-(1,2:5,6-diisopropylidene-a-d-glucofuranosyl)-2-
¯uoro-4,4-dimethyl-2-buten-4-olide (12). Procedure B (as
for 4; rt); 1 (1.53 g, 5.88 mmol), the crude 12 was sublimed
(1.167 g) and a part of sublimate (0.71 g) was puri®ed by
chromatography (50 g of silica gel, toluene/ethanol, 20/1) to
2-Fluoro-3-isopropoxy-4,4-dimethyl-2-buten-4-olide (7).
Procedure A (as for 4); 1 (1.095 g, 7.39 mmol); yield (oil)

3204
O. Paleta et al. / Tetrahedron 56 (2000) 3197±3207
give 0.384 g (60.8%) of 22, mp 172±1758C. dH: 1.31(3H, s),
1.35(3H, s), 1.42(3H, s), 1.49(3H, s), 1.52(3H, s), 1.54(3H,
s), 4.0(1H, dd, JHHˆ8.7, JHHˆ5.2), 4.13±4.25(3H, m),
4.68(1H, dd, JHHˆ7.5, JHHˆ2.8), 5.12(1H, t, JHHˆ1.7),
5.95(1H, d, JHHˆ3.6). dC: 24.5(C-3-5), 25.1, 26.2, 26.7,
26.8, 67.7(C-3-6), 72.0, 80.4, 82.7, 84.0(d, JCFˆ3.7, C-3-
3), 105.1(C-3-1), 109.7, 112.9. m/z (intensity), 390(2),
389(7), 388(7), 373(17), 315(8), 129(10), 127(12),
113(12), 102(8), 101(100), 99(7), 86(19), 85(10), 84(30),
83(11), 81(12), 73(18), 72(12), 71(11), 69(18), 59(27),
55(20), 43(78), 42(7), 41(12). HRMS found 388.1533,
C18H25FO8 requires [M]1, 388.15335.
4-1), 117.9(C-3-5), 117.9(C-3-5), 122.8(C-3-3), 127.3(C-3-
4), 131.2(C-3-6), 133.5(C-3-2). Anal. calcd. for
C12H9Cl2FO3 C, 49.51; H, 3.12; F, 6.53. Found C, 49.46;
H, 3.08; F, 6.45.
2-Fluoro-3-(2-¯uoro-5-methylphenoxy)-4,4-dimethyl-2-
buten-4-olide (17). Procedure E (as for 4); 2-¯uoro-5-
methylphenol (200 mg, 1.53 mmol), sodium hydride (33.5
mg, 1.52 mmol), 2 (200 mg, 1.35 mmol); crude product
chromatography (see 19; dichloromethane), yield of 17,
230 mg (71 %), mp 84±868C. dH: 1.64(6H, m, JHFˆ0.8,
H-4-1), 2.348(3H, s, H-3-4-1), 7.05±7.14(3H, m, JFHˆ9.8,
JFHˆ3.8, JHFˆ3.3, arom.). dC: 21.3(C-3-5-1), 25.2(C-4-1),
117.2(d, JCFˆ18.3, C-3-3), 122.6(C-3-5), 128.8(d, JCFˆ6.3,
C-3-6), 135.6(d, JCFˆ4.1, C-3-1), 141.5(d, JCFˆ12.6, C-3-
4), 150.6(d, JCFˆ247, C-3-2). Anal. calcd. for C13H12F2O3
(254.2) C, 61.38; H, 4.72; F, 14.95. Found C, 61.24; H, 4.72;
F, 15.16.
3-O-(1,2:5,6-diisopropylidene-a-d-glucofuranosyl)-2-
¯uoro-4,4-(1,5-pentanediyl)-2-buten-4-olide (13). Pro-
cedure B (as for 4; rt); 2 (207 mg, 1.10 mmol), 1,2:5,6-
diisopropylidene-a-d-glucofuranose (337 mg, 1.30 mmol).
The crude product was puri®ed by chromatography (10 g of
silica gel, toluene/ethanol 20/1) to give white solid 13,
(346 mg, 73%), mp 153±1588C. dH: 1.21±1.76(10H, m),
1.32(3H, s), 1.34(3H, s), 1.42(3H, s), 1.54(3H, s), 4.0(1H,
dd, JHHˆ8.5, JHHˆ5.4), 4.13±4.25 (3H, m), 4.66(1H, dd,
JHHˆ7.2, JHHˆ3) 5.12(1H, t, JHHˆ1.9), 5.94(1H, d,
JHHˆ3.7). dC: 21.9(C-4-3), 24.7(C-4-2), 25.8, 26.8, 27.3,
27.4, 33.7(C-4-1), 33.9(C-4-5), 68.3(C-3-6), 72.6(C-3-5),
81.0(C-3-4), 83.3(C-3-2), 84.5(d, JCFˆ4.3, C-3-3),
105.7(C-3-1), 110.3, 113.5. Anal. calcd. for C21H29FO8 C,
58.87; H, 6.84. Found C, 58.75; H, 6.43.
2-Fluoro-4,4-dimethyl-3-[(4±tri¯uoromethylthio)phen-
oxy]-2-buten-4-olide (18). Procedure E (as for 4; tetra-
hydrofuran 8 ml, rt 16 h); (4-tri¯uoromethylthio)phenol
(200 mg, 1.12 mmol), sodium hydride 60% (50 mg,
1.25 mmol), 1 (150 mg, 1.01 mmol); silica gel (see 19;
dichloromethane/petroleum ether 1/1), yield of 18, 138 mg
(43%), mp 80±828C. dH: 1.69(6H, s, H-4-1), 7.22(1H, dd,
JHHˆ8.8, JHHˆ2.2, arom), 7.73(1H, d, JHHˆ8.8, arom.). dC:
25.3(C-4-1), 117.3(C-3-1), 120.4(C-3-2), 125(q, JCFˆ377.3,
C-3-4-1), 127.9(C-3-4), 138.9(C-3-3). Anal. calcd. for
C13H10F4O2S C, 48.45; H, 3.11; F, 23.59. Found C, 48.23;
H, 3.20; F, 23.82.
2-Fluoro-4,4-dimethyl-3-phenoxy-2-buten-4-olide (14).
Procedure B (as for 4); phenol (128 mg, 1.36 mmol), 1
(200 mg, 1.35 mmol); the crude product was twice puri®ed
by chromatography (5 and 40 g of silica gel, dichloro-
methane) to give 55 mg (83%) of 14 as white crystals, mp
97±101.58C. dH: 1.66(6H, d, JFHˆ0.8, H-4-1), 7.14±
7.18(2H, m, H-3-3), 7.25±7.30(1H, m, H-3-4), 7.39±
7.44(2H, m, H-3-2). dC: 24.6(C-4-1), 118.8(C-3-3), 126.4
(d, JCFˆ2.8, C-3-4), 129.9 (d, JCFˆ4.9, C-3-2), 153.9 (C-3-
1). Anal. calcd. for C12H11FO3 C, 64.86; H, 4.99. Found C,
64.59; H, 5.23.
3-(2-Chlorophenoxy)-2-¯uoro-4,4-(1,5-pentanediyl)-2-
buten-4-olide (19). Procedure E (as for 4; tetrahydrofuran,
2508C, rt 3 h); 2-chlorophenol (153 mg, 1.19 mmol), 2
(208 mg, 1.11 mmol), sodium hydride (32 mg, 1.45
mmol). Chromatography (silica gel 10 g, dichloromethane)
of the crude product gave 19, 102 mg (31 %), mp 86±888C.
dH: 1.22±2.14(10H, m), 7.11±7.36(2H, m), 7.47(2H, dt,
JHHˆ7.7, JHHˆ2.0). dC: 23(C-4-3), 25.5(C-4-2), 34.6(C-4-
1), 123.4(arom.), 126.9(C-3-2), 129.9(arom.), 130.5(arom.),
132.4 (arom.), 151.7(C-3-1). Anal. calcd. for C15H14FClO3
C, 60.72; H, 4.76. Found C, 60.22; H, 4.94.
3-(4-Chlorophenoxy)-2-¯uoro-4,4-dimethyl-2-buten-4-
olide (15). Procedure E (as for 4); 4-chlorophenol (291 mg,
2.26 mmol), 1 (335 mg, 2.26 mmol); the crude product was
twice puri®ed by chromatography (35 and 30 g of silica gel,
dichloromethane) to give 202 mg (35%) of 15 as white
crystals, mp 93±978C. dH: 1.65 (6H, d, JFHˆ0.8, H-4-1),
7.10±7.13 (2H, m, H-3-3), 7.36-7.39 (2H, m, H-3-2). dC:
24.6(C-4-1), 120.2(C-3-3), 129.9 (d, JCFˆ1.4, C-3-2), 131.7
(C-3-4), 152.3(C-3-1). m/z (intensity): 258(40), 257(56),
256(100), 243(16), 241(52), 201(18), 199(60), 139(17),
130(14), 129(65), 128(28), 111(16), 99(8), 87(9), 73(10),
63(13), 50(10), 43(48), 39(11). HRMS found 256.0303,
C12H10ClFO3 requires [M]1, 256.03025.
3-(4-Chlorophenoxy)-2-¯uoro-4,4-(1,5-pentanediyl)-2-
buten-4-olide (20). Procedure E (as for 4; tetrahydrofuran,
rt 5 h); 4-chlorophenol (164 mg, 1.28 mmol), 2 (201 mg,
1.07 mmol); chromatography of the crude product (see
19), gave 20, 187 mg (59.3%) as white crystals, mp 110±
1138C. dH: 1.72±2.05(10H, m), 7.09(2H, dd, JHHˆ8.9,
JFHˆ1.6), 7.37(2H, d, JHHˆ8.9). dC: 22.1(C-4-3), 24.8(C-
4-2), 33.9(C-4-1), 120.8(d, JCFˆ1.6, C-3-2), 130.6(C-3-3),
132.3(C-3-4), 153.3(C-3-3). Anal. calcd. for C15H14FClO3
C, 60.72; H, 4.76. Found C, 60.94; H, 4.99.
3-(2,4-Dichlorophenoxy)-2-¯uoro-4,4-dimethyl-2-buten-
4-olide (16). Procedure E (as for 4; tetrahydrofuran, rt 15 h);
2,4-dichlorophenol (190 mg, 1.20 mmol), sodium hydride
60% (50 mg, 1.25 mmol), THF (8 ml), butenolide 1
(150 mg, 1.01 mmol); silica gel 10 g, yield 120 mg (42%),
2-Fluoro-3-(4-nitrophenoxy)-4,4-(1,5-pentanediyl)-2-
buten-4-olide (21). Procedure E (as for 4; tetrahydrofuran,
re¯ux 5 h); 4-nitrophenol (164 mg, 1.19 mmol), 2 (200 mg,
1.06 mmol). Chromatography (see 19) of the crude product
gave 21, 110 mg (33.7%), mp 127±1298C. dH: 1.78±
2.02(10H, m), 7.28(2H, dd, JHHˆ9.1, JFHˆ1.7), 8.32(2H,
d, JHHˆ9.4). dC: 21.1(C-4-3), 23.8(C-4-2), 32.9(C-4-1),
118.7(d, JCFˆ2.2, C-3-2), 125.6(C-3-3), 145.5(C-3-1).
1
mp 92±958C (white crystals). H NMR: dH: 1.69(6H, s, H-
4-1), 6.93 (1H, d, JHHˆ10, arom.), 7.20 (1H, dd, JHHˆ10,
JHHˆ1.1, arom), 7.22(1H, s, arom.). 13C NMR: dC: 25.2(C-

O. Paleta et al. / Tetrahedron 56 (2000) 3197±3207
3205
Anal. calcd. for C15H14NFO5 C, 58.63; H, 4.59; N, 4.56.
Found C, 58.79; H, 4.75; N, 4.55.
3.075 mmol), 1 (150 mg, 1.01 mmol) in THF (8 ml). Puri-
®cation was carried out by chromatography (silica gel 30 g,
dichloromethane) to give 26, yield 160 mg (77%), mp 120±
1238C. dH: 1.73(6H, d, JFHˆ1.0, H-5), 7.45±7.54(3H, m),
7.59±7.64(2H, m). dC: 26.5(C-4-1), 127.4(d, JCFˆ4.9, C-3-
1), 128.3(d, JCFˆ6.0), 129.3, 130.5. HRMS found 206.0743,
C12H11FO2 requires [M]1, 206.07431.
2-Fluoro-3-(2-¯uoro-5-methylphenoxy)-4,4-(1,5-pen-
tanediyl)-2-buten-4-olide (22). Procedure E (as for 19); 2-
¯uoro-5-methylphenol (164 mg, 1.28 mmol), sodium
hydride (33.5 mg, 1.52 mmol), 2 (207 mg, 1.1 mmol). Chro-
matography (see 19; dichloromethane/petroleum ether 5:1)
of the crude product gave 22, 118 mg (40 %), mp 75±778C.
dH: 1.18±2.08(10H, m, H-4-1 to 4-5), 2.34(3H, s, H-3-4-1),
6.98-7.11(2H, m, arom.), 7.26(1H, s, arom). dC: 21.3(C-3-
5), 21.9(C-4-3), 24.8(C-4-2), 33.8(C-4-1), 117.4(d,
JCFˆ17.7, C-3-3), 122.6(C-3-6), 128.8(d, JCFˆ6.3, C-3-4),
135.6(d, JCFˆ4, C-3-5), 141.8(d, JCFˆ13.1, C-3-1), 152.8(d,
JCFˆ248, C-3-2). Anal. calcd. for C16H16F2O3 C, 65.30; H,
5.48. Found C, 65.19; H, 5.61.
4-Fluoro-2,2,5-trimethyl-3(2H)-furanone (27). A solution
of methyllithium (diethyl ether, 1.43 M, 5 ml, 7.150 mmol)
was added to a stirred mixture of THF (10 ml) and buteno-
lide 1 (1.056 g, 7.130 mmol) at 2708C and the mixture was
stirred for 2 h, then further stirred for 4 h at 235 to 2408C.
The reaction was quenched with tri¯uoroacetic acid and
neutralised by sodium carbonate at rt and evaporated. The
concentrate was twice puri®ed by short-column chromato-
graphy (see 25), followed by trap-to-trap distillation of the
crude product (0.7 g) to give 0.495 (48%) of oily colourless
27. Re¯uxing 27 with THF (5 ml), water (2 ml) and 1M-HCl
for 3 h caused no change (NMR, GC). dH: 1.41(6H, d,
JFHˆ0.9, H-2-1), 2.27(3H, d, JFHˆ2.4, H-5-1). dC: 13.3(d,
JCFˆ2.8, C-5-1), 23.0(C-2-1). m/z (intensity): 144(40)M1,
143(40), 129(17), 183(13), 86(14), 76(22), 69(5), 58(35),
53(10), 43(100), 39(25). HRMS found 144.0587, C7H9FO2
requires [M]1, 144.05866.
2-Fluoro-4,4-(1,5-pentanediyl)-3-[(4±tri¯uoromethoxy)-
phenoxy]-2-buten-4-olide (23). Procedure E (as for 19);
tetrahydrofuran, 2508C, rt 3 h); 4-(tri¯uoromethoxy)phenol
(200 mg, 1.12 mmol), 2 (200 mg, 1.06 mmol). Chromato-
graphy (see 19) of the crude product gave 23, 125 mg
(36.8 %), mp 79±818C. dH: 0.82±2.08(10H, m), 7.13±
7.32(2H, dm, JHHˆ3.5). dC: 22.1(C-4-3), 24.9(C-4-2),
34(C-4-1), 120.8(C-3-2), 123.2(C-3-3), 127(q, JCFˆ267,
C-3-4-1), 147.5(C-3-4), 152.8(C-3-1). Anal. calcd. for
C16H14F4O4 C, 55.49; H, 4.07. Found C, 55.13; H, 4.35.
4-Fluoro-2,2-dimethyl-5-phenyl-3(2H)-furanone (28). Same
procedure used as for 27; phenyllithium (diethyl ether,
1.97 M, 2.8 ml, 5.52 mmol), THF (10 ml), 1 (816 mg,
5.510 mmol). The mixture was allowed to warm to rt for
2 h and then additionally stirred for 2 h at rt and after
quenching and neutralisation puri®ed on a short column.
Solvents were rapidly removed rapidly in vacuo at 308C.
The residue consisted of a mixture of 28 and intermediate
33; in 12 h the 33 which disappeared from the mixture in
12 h (followed by GCb, checked by NMR) during which the
mixture became strongly acidic. After short-column chro-
matography, the product was ®nally chromatographed
(silica gel 60 g, dichloromethane) to yield 0.952 g (84%)
of pure 28 as an oil, which crystallised in 5 d (mp 35±
388C). dH: 1.52(6H, d, JFHˆ0.5, H-2-1), 7.54(3H, m),
7.97(2H, m). dC: 23.3(C-2-1), 127.2(C-5-1), 127.3(d,
JCFˆ5.8), 128.9, 132.7. m/z (intensity), 206(95)M1,
191(8), 129(10), 120(100), 105(20), 99(2), 94(8), 84(11),
77(11), 49(50), 39(11). HRMS found 206.0743,
C12H11FO2 requires [M]1, 206.07431.
2-Fluoro-4,4-(1,5-pentanediyl)-3-[(4±tri¯uoromethylthio)-
phenoxy]-2-buten-4-olide (24). Procedure E (as for 22);
4-(tri¯uoromethylthio)phenol (253 mg, 1.3 mmol),
2
(204 mg, 1.1 mmol). Chromatography (see 19; dichloro-
methane/petroleum ether 9/1) of the crude product gave
24, 151 mg (34.8 %), mp 112±1148C. dH: 1.22±2.06(10H,
m), 7.2(2H, dd, JHHˆ8.7, JFHˆ1.6), 7.7(2H, d, JHHˆ8.6).
dC: 21.8(C-4-3), 24.6(C-4-2), 33.7 (C-4-1), 120.2(C-3-2),
122.6(C-3-4), 130.0(q, JCFˆ309, C-3-4-1), 138.9(C-3-3),
156.1(C-3-1). Anal. calcd. for C16H14F4O3S C, 53.04; H,
3.90. Found C, 53.00; H, 4.04.
2-Fluoro-3,4,4-trimethyl-2-buten-4-olide (25). Dimethyl
sul®de (0.4 ml) and THF (2.5 ml) were added to CuBr.Me2S
(328 mg, 1.6 mmol) in a ¯ask (with magnetic stirring bar) in
a dry-ice bath (2308C). Methylmagnesium bromide solu-
tion (diethyl ether, 1 ml, 3.17 M, 3.17 mmol) was added to
the ¯ask and then, at 2108C, a solution of 1 (238 mg,
1.61 mmol) in THF (5 ml) was added and the mixture was
stirred for 12 h at rt. The mixture was then quenched with
tri¯uoroacetic acid, the acidic solution was neutralised with
solid sodium carbonate and after ®ltration evaporated to
dryness. Repeated short-column chromatography of the
crude product (twice on silica gel 5 g, dichloromethane)
gave 25, 128 mg (55%) of purity 97% (GCb). dH:
1.49(6H, d, JFHˆ0.8, H-4-1), 1.97(3H, d, JFHˆ2.3, H-3-1).
dC: 8.3(C-3-1), 24.7(d, JCFˆ2.2, C-4-1). m/z (intensity):
144(20) M1,129(100), 101(57), 87(8), 57(10), 43(55).
HRMS found 144.0587, C7H9FO2 requires [M]1,
144.05867.
4-Fluoro-2,2-dimethyl-2,2-(1,5-pentanediyl)-5-phenyl-
3(2H)-furanone (29). Same procedure used as for 28;
phenyllithium (diethyl ether, 1.97 M, 0.65 ml, 1.3 mmol),
THF (2.5 ml), 2 (204 mg, 1.08 mmol). Short-column chro-
matography of the crude product showed after 2 d only
signals assigned to 29 (19F NMR) and ®nal chromatography
(silicagel 15 g, dichloromethane) gave solid 29, 136 mg
(51%) of pure. dH: 1.32±1.87(10H, m), 7.3±7.6(3H, m),
7.98(2H dd, JFHˆ1.2, JHHˆ8.0). dC: 22.1(C-2-3), 24.9(C-
2-2), 32.6(C-2-1), 127.9(d, JCFˆ6.5, C-5-2), 128.1(d,
JCFˆ7.1, C-5-1), 129.5, 133.3. Anal. calcd. for C15H15FO2
C, 73.15; H, 6.14. Found C, 72.85; H, 6.06.
2-Fluoro-4,4-dimethyl-3-phenyl-2-buten-4-olide
(26).
Same procedure as for 25. Quantities were dimethyl sul®de
(0.4 ml) and THF (4 ml), CuBr.Me2S (316 mg, 1.54 mmol),
phenylmagnesium bromide solution (THF, 5 ml, 0.615 M,
Attempt to trap intermediates 32 and 33 in the formation
of 28. Same procedure used as for 28; phenyllithium
(diethyl ether, 1.97 M, 1.4 ml, 2.76 mmol), THF (10 ml),

3206
O. Paleta et al. / Tetrahedron 56 (2000) 3197±3207
13. Ito, M. Pure Appl. Chem. 1991, 63, 13.
butenolide 1 (408 mg, 2.76 mmol). After quenching, neutra-
lisation, short-column puri®cation and removal of solvent,
the mixture was immediately analysed by NMR which
showed the presence of 3 compounds, 32 and 33 together
with 28; GCb con®rmed the mixture of 3 compounds. The
signals of 32 and 33 decreased with time, while the NMR
signals of 28 increased. The time dependence of signal
14. Nishino, H.; Satomi, Y.; Tokuda, H.; Nishino, A.; Iwashima,
A.; Tanaka, Y.; Zamano, Y.; Shibata, Y.; Torihara, M. Kyoto-
furitsu Ika Daigaku Zasshi 1991, 100, 831 Chem. Abstr., 1992,
116, 50881.
Â
 ÂÏ
15. Semonsky, M.; Zikan, V.; Kakac, B.; Jelõnek, V. Coll.
Â
Â
Czech. Chem. Commun., 1970, 35, 96; Zikan, V.; Vrba, L.;
1
intensity was irreproducible. H NMR: dH: 1.52(s, 28), ca.
ÂÏ
Kakac, B.; Semonsky, M. Coll. Czech. Chem. Commun., 1972,
Â
1.6(qs, 32, 33), 4.8(OH, bs, 32), 5.8(OH, br s, 33). dF
(signals of intermediates): 2114.1(s, 32), 2143.1(s, 32),
2159.2(qd, 33) 2162.9(qd, 33). dC (signals of intermedi-
ates): 135(d, JCFˆca. 280), 142(qd, JCFˆca. 280), 163(qd,
JCFˆ284), 189.3(d, JCFˆ34, CˆO, 32).
38, 1091.
16. Franzen, J.; Kronberg, L. Tetrahedron, 1993, 49, 10945;
Â
Meier, J. R. Mutat. Res., 1988, 196, 211; Meier J. R.; DeAngelo,
A. B.; Daniel, F. B.; Schenck, K. M.; et al. in Genetic Toxicology of
Complex Mixtures; Waters, M. D., Lewtas, J., Moore, M. M.,
Newnow, S. J., Eds.; Plenum: New York, 1990; p. 185.
17. Ojima, I.; McCarthy, J. R.; Welch, J. T., Eds.; Biomedical
Frontiers of Fluorine Chemistry, ACS Symposium Series 639;
American Chemical Society: Washington, DC, 1996; Welch, J. T.
Tetrahedron, 1987, 43, 3123 (Tetrah. Rep. No. 221).
18. Filler, R.; Kobayashi, Y.; Yagupolskii, L. M., Eds.; Organo-
¯uorine Compounds in Medicinal Chemistry and Biomedical
Applications; Elsevier: Amsterdam, 1993; Banks, R. E., Lowe,
K. C., Eds.; Fluorine in Medicine in the 21st Century (Conference
Papers); UMIST: Manchester, 1994.
Acknowledgements
The authors heartily thank Dr J. M. Williams for NMR
experiments, SERCX X-ray Service (Cardiff) for the
Ï
X-ray analysis of 28, J. Het¯ejs for technical assistance in
the preparation of some phenoxy derivatives and Dr J.
ÂÁ
Kvõeala for stimulating discussions. Elemental analyses
and NMR spectra measurements were carried out in the
Central Laboratories of the Institute of Chemical Tech-
nology, Prague. The authors thank their staff members
19. Ge, P.; Kirk, K. J. Fluorine Chem., 1997, 84, 45; Ge, P.; Kirk,
K. J. Org. Chem., 1997, 62, 3340.
Ï
(Dr R. Hrabal, Dr L. Helesic) for their kind assistance.
20. Komatsu, Y.; Kitazume, T. J. Fluorine Chem. 1998, 87,
101.
The authors thank the EC Tempus Programme JEP 2139
for giving the opportunity to J. K. and O. P. to visit The
University of Wales, Swansea. The research was also
supported by grant No. 203/96/1057 of the Grant Agency
of the Czech Republic. Substituted phenols were given by
the Bayer Company.
21. Ducher, S.; Michet, A. Bull. Soc. Chim. Fr. 1976, 1923±1928.
22. Fischbein, P. L.; Moore, H. W. Org. Synth. 1990, 69, 205±209.
23. Rappoport, Z. Rec. Trav. Chim. Pays-Bas, 1986, 104, 309;
Modena, G. Acc. Chem. Res., 1971, 4, 73; Rappoport, Z. Acc.
Chem. Res., 1981, 14, 7.
24. Baasner, B.; Hagemann, H.; Tatlow, J. C., Eds.; Houben-Weyl
(Methods of Organic Chemistry): Organo-Fluorine Compounds,
References
Â
Vol. E 10b, Part 2; G. Thieme: Stuttgart, 2000; Hudlicky, M.,
Pavlath, A. E., Eds.; Chemistry of Organic Fluorine Compounds
1. Knight, D. W. Contemp. Org. Synth. 1994, 1, 287.
2. Pelter, A.; Al-Bayati, R. I. H.; Ayoub, M. T.; Lewis, W.;
Pardasani, P.; Hansel, R. J. Chem. Soc., Perkin Trans. 1 1987, 717.
3. Pelter, A.; Hansel, R. Z. Naturforsch. Teil B 1972, 27b, 1186.
4. Hansel, R.; Schultz, J. Z. Naturforsch. Teil B 1978, 33b, 688.
5. Pelter, A.; Al-Bayati, R. I. H.; Hansel, R.; Dinter, H.; Burke, B.
Tetrahedron Lett. 1981, 22, 1545.
Â
II; ACS Monograph 187: Washington, 1995; Hudlicky, M.
Chemistry of Organic Fluorine Compounds, 2nd ed., E. Horwood:
Chichester, 1992.
25. Chambers, R. D., Ed.; Organo¯uorine Chemistry: Fluorinated
Alkenes and Reactive Intermediates (Topics in Current Chemistry,
Vol. 192); Springer: Berlin, 1997. Chambers, R. D., Ed.; Organo-
¯uorine Chemistry: Techniques and Synthons (Topics in Current
Chemistry, Vol. 193); Springer: Berlin, 1997. Chambers, R. D.
Fluorine in Organic Chemistry; Durham University: Durham,
1973; p 104.
6. Pfander, H. Key to Carotenoids (2nd ed.); Birkhaeuser: Basel,
1987; Foss, P.; Guillard, R. R. L.; Liaaen-Jensen, S. Phyto-
chemistry 1986, 25, 119.
7. Triozze, P. L.; Ailabouni, J.; Rinehart, J. J.; Witiak, D. T. Int. J.
Pharmacol. 1993, 15, 47.
26. Jeong, H.; Min, Y. K.; Park, N. K.; Cho, K. Y.; Kim, B. T.
Bull. Korean Chem. Soc. 1994, 15, 1031.
27. Nguyen, T.; Wakselman, C. J. Fluorine Chem., 1995, 74, 273;
8. Fang, X. P.; Anderson, J. E.; Smith, D. L.; McLaughlin, J. L.;
Wood, K. V. J. Nat. Prod. 1992, 55, 1655.
È
Wessolowski, H.; Gard, G. L.; Roschenthaler, G.-V. J. Fluorine
Chem., 1996, 80, 149.
ÏÂ
28. Paleta, O.; Konarek, J. Collect. Czech. Chem. Commun. 1973,
38, 66.
9. Mori, H.; Yoshimi, N.; Sugie, S.; Tanaka, T.; Morishita, Y.;
Jinlong, G.; Tamai, Y.; Torihara, M.; Yamahara, J. Cancer Lett.
1992, 66, 93 (Shannon, Irel.).
10. Roggo, B. E.; Hug, P.; Moss, S; Raschorf, F.; Peter, H. H.
J. Antibiot., 1994, 47, 143; Roggo, B. E.; Petersen, F.; Delmendo,
R.; Jenny, H. B.; Peter, H. H.; Roesel, J. J. J. Antibiot., 1994, 47,
136.
Â
29. Paleta, O.; Okrouhlõk, J.; Kubelka, V. Collect. Czech. Chem.
Ï
Commun., 1974, 39, 1336; Svoboda, J.; Paleta, O.; Liska, F.;
Ï
Dedek, V. Collect. Czech. Chem. Commun., 1981, 46, 1389.
30. Paleta, O.; Pelter, A.; Kebrle, J. Tetrahedron Lett. 1994, 35,
9259.
11. Fang, X.-P.; Anderson, J. E.; Chang, C.-J.; McLaughlin, J. L.
Tetrahedron, 1991, 47, 9751; Ruprecht, J. K.; Hui, Y. H.;
McLaughlin, J. L. J. Nat. Prod., 1990, 53, 237
31. Pearson, R. G., Ed.; Hard and Soft Acids and Bases; Dowden,
Hutchinson & Ross: Stroudsburg, 1973. Ho, T. L. Chem. Rev.,
1975, 75, 1. Ho, T. L. Hard and Soft Acids and Bases in Organic
Chemistry; Academic Press: New York, 1977.
12. Tuchinda, P.; Udchachon, J.; Reutrakul, V.; Santisuk, T.;
Taylor, W. C.; Farnsworth, N. R.; Pezzuto, J. M.; Kinghorn,
A. D. Phytochem. 1991, 30, 2685.

O. Paleta et al. / Tetrahedron 56 (2000) 3197±3207
3207
ÂÏ Â Â
32. Kvõcala, J.; Plocar, J.; Vlasakova, R.; Paleta, O.; Pelter, A.
Synlett. 1997, 986.
39. Tarrant, P.; Johncock, P.; Savory, J. J. Org. Chem. 1963, 28,
839.
33. Paleta, O.; Duda, Z.; Hajduch J.; unpublished results.
34. Bertucco, A.; Brennan, J.; Fachini, M.; Kluge, S.; Murphy, P. J.
Tetrahedron 1994, 50, 27.
40. Normant, J. F.; Foulon, J. P.; Masure, D.; Sauvetre, R.;
Villieras, J. Synthesis 1975, 122.
41. Nguyen, T.; Wakselman, C. J. Org. Chem. 1989, 54, 5640.
42. Furniss, B. S.; Hammford, A. J.; Smith, P. W. G.; Tatchell,
A. R. Vogel's Textbook of Practical Organic Chemistry (5th ed.);
J. Wiley: New York, 1991 Ch. 4.
35. Journal, F. F.; Maestro, M. C.; Martin, M. R.; Martin, M. V.;
Sanchez, F. J. Chem. Res. Miniprint 1980, 6, 2662±2682.
36. Arahori, H.; Sato, N. Jpn. Kokai Tokkyo Koho JP 63,170, 370±
371 (1988); Chem. Abs. 1989, 110, 8030. Ohnishi, H.; Iihama, T.;
Ishimitsu, K.; Yamada, T. PCT Int. Appl. WO 92 00,964 (1992);
Chem. Abs. 1992, 117, 7806.
43. House, H. O.; Chu, Ch.; Wilkins, J. M.; Umen, M. J. J. Org.
Chem. 1975, 40, 1460.
Ï
Ï
44. Sendrik, V. P.; Paleta, O.; Dedek, V. Collect. Czech. Chem.
Commun. 1977, 42, 2530.
Â
45. Paleta O.; Duda Z.; Holy A.; in preparation.
37. Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumana-
van, S. Acc. Chem. Res. 1996, 29, 552.
38. Sterlin, S. R.; Yatsenko, R. D.; Knunyants, I. L. Khim. Nauka
Promy., 1958, 3, 540; Chem. Abs., 1959, 53, 4959.