Fluorinated butanolides and butenolides. Part 5. Synthesis and nucleophilic reactions of 3-chloro-2-fluoro-2-buten-4-olide as tetronic acid analogue. Conjugate addition of hard nucleophiles and vinylic halogen displacement with soft phosphorus nucleophiles

Article abstract of DOI:10.1016/S0022-1139(99)00235-3

3-Chloro-2-fluorobut-2-en-4-olide (13) and 2-fluorobut-2-en-4-olide (14) were prepared by a six step synthesis starting from 1,2-dibromo-1,2-dichloro-1,2-difluoroethane (5). UV-initiated addition of 5 to ethylene afforded 1,4-dibromo-1,2-dichloro-1,2-difluorobutane (6a) that was easily dehydrochlorinated to 4-bromo-3,4-dichloro-3,4-difluorobut-1-ene (7) and subsequently by chlorine addition to 1-bromo-1,2,3,4-tetrachloro-1,2-difluorobutane (10). Fuming sulfuric acid affected CH₂-Br bond in 6a to afford 4-bromo-3,4-dichloro-3,4-difluorobutan-1-ol (8), while with 10 bearing stable terminal CH₂-Cl group the reaction took place at the trihalomethyl group to give 2,3,4-trichloro-2-fluorobutanoic acid (11a). Its sodium salt (11b) cyclized in solution or thermally in the solid state to 2,3-dichloro-2-fluorobutan-4-olide (12) that by dehydrochlorination with tertiary amine gave new butenolide 13 or by didechlorination with zinc 2-fluorobut-2-en-4-olide (14). Hard nucleophiles as methanol and piperidine afforded products of conjugate addition, while soft phosphorus nucleophiles, triethyl phosphite or tributylphosphane, affected vinylic C-Cl and C-F bonds to give products of nucleophilic vinylic substitution.

Full text of DOI:10.1016/S0022-1139(99)00235-3

Journal of Fluorine Chemistry 102 (2000) 147±157
Fluorinated butanolides and butenolides. Part 5. Synthesis and
nucleophilic reactions of 3-chloro-2-¯uoro-2-buten-4-olide as tetronic
acid analogue. Conjugate addition of hard nucleophiles and vinylic
halogen displacement with soft phosphorus nucleophiles$
*
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ÏÂ
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Oldrich Paleta , Andrei Volkov, Jirõ Het¯ejs
Â
Department of Organic Chemistry, Prague Institute of Chemical Technology, Technicka 5, 16628 Prague 6, Czech Republic
Received 22 June 1999; received in revised form 19 July 1999; accepted 30 August 1999
Dedicated to Professor Paul Tarrant on the occasion of his 85th birthday
Abstract
3-Chloro-2-¯uorobut-2-en-4-olide (13) and 2-¯uorobut-2-en-4-olide (14) were prepared by a six step synthesis starting from 1,2-
dibromo-1,2-dichloro-1,2-di¯uoroethane (5). UV-initiated addition of 5 to ethylene afforded 1,4-dibromo-1,2-dichloro-1,2-di¯uorobutane
(6a) that was easily dehydrochlorinated to 4-bromo-3,4-dichloro-3,4-di¯uorobut-1-ene (7) and subsequently by chlorine addition to
1-bromo-1,2,3,4-tetrachloro-1,2-di¯uorobutane (10). Fuming sulfuric acid affected CH2±Br bond in 6a to afford 4-bromo-3,4-dichloro-3,
4-di¯uorobutan-1-ol (8), while with 10 bearing stable terminal CH2±Cl group the reaction took place at the trihalomethyl group to give
2,3,4-trichloro-2-¯uorobutanoic acid (11a). Its sodium salt (11b) cyclized in solution or thermally in the solid state to 2,3-dichloro-
2-¯uorobutan-4-olide (12) that by dehydrochlorination with tertiary amine gave new butenolide 13 or by didechlorination with zinc 2-
¯uorobut-2-en-4-olide (14). Hard nucleophiles as methanol and piperidine afforded products of conjugate addition, while soft phosphorus
nucleophiles, triethyl phosphite or tributylphosphane, affected vinylic C±Cl and C±F bonds to give products of nucleophilic vinylic
substitution. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Tetronic acid; Radical addition; Hydrolysis of trihalogenomethyl group; Lactonization; Dehydrochlorination; Dehalogenation; 3-Chloro-2-
¯uorobut-2-en-4-olide; 2-Fluorobut-2-en-4-olide; Hard and soft nucleophiles; Conjugate addition; Vinylic nucleophilic displacement
1. Introduction
Several halogenated but-2-en-4-olides with ¯uorine or
chlorine atoms attached to the double bond have been
reported: 2-¯uorotetronic acid (Scheme 1, 2) was prepared
from tetronic acid [10]. 4-Tri¯uoromethyl derivative of 2
was prepared using aldehydes and 2-bromo-2-¯uoroacetate
in building block syntheses [11,12]. Di¯uorobutenolide 4
(Scheme 1) can be understood as an tetronic acid analogue
as C±F bond usually mimics C±OH grouping from the
biochemical activity point of view [7,8]. On the other hand,
the introduction of two halogeno-substituents in the C2 and
C3 positions creates a new reaction system, in which 3-
halogeno-substituents can undergo vinylic displacement to
There is a number of natural bioactive compounds pos-
sessing in their structure but-2-en-4-olide moiety [4,5] that
exhibit various bioactivity. Among many of them, an
increased interest have been paid recently to tetronic acid
(1) and their analogues and derivatives that have displayed
interesting pharmaceutical properties [6]. Introduction of a
halogen into bioactive molecule can change substantially its
properties. The introduction of ¯uorine atoms and ¯uori-
nated groups, which are generally known as strong modi®ers
of bioactivity, in organic molecule can dramatically change
its bioactivity as shown by many examples of pharmaceu-
ticals [7,8]. A similar effect can be expected for butanolides
and butenolides as documented by the interest to synthesize
¯uoroanalogues of podophyllotoxin [2,9].
$ Part 1, Ref. [1]. Part 2, Ref. [2]. Part 3, Ref. [3]. Part 4, Ref. [4].
* Corresponding author. Fax: ‡4202-2431-1082.
E-mail address: oldrich.paleta@vscht.cz (O. Paleta).
Scheme 1. Tetronic acid (1) and its analogues.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 2 3 5 - 3

148
O. Paleta et al. / Journal of Fluorine Chemistry 102 (2000) 147±157
obtain new analogues and derivatives of tetronic acid. Such
displacement reactions have been reported for 2,3-dichlor-
obut-2-en-4-olide 3 [13,14] and di¯uorobutenolide 4 in our
papers [1,3,4]. No nucleophilic reactions of ¯uorine-con-
taining but-2-en-4-olides have been reported so far with the
exceptions of our recent reports [1±4].
We wish to report now a building-block synthesis of 3-
chloro-2-¯uoro-2-buten-4-olide (13) as a tetronic acid (1)
analogue and a potential synthetic intermediate for further
transformations to obtain potentially bioactive compounds
with 3-¯uorofuran-2(5H)-on-4-yl moiety. Parallelly, 2-
¯uoro-2-buten-4-olide (14) has been prepared from the
common precursor 12; the reactivity and transformations
of 14 to acyclic podophyllotoxin analogues we have
reported recently [2].
symmetric isomer CFCl2±CCl3 (CFC-112b). Re®ning of the
raw CFC-112a was performed by the application of our
former method [15±17], i.e., by re¯uxing the industrial
CFC-112 with 60% fuming sulfuric acid that converted
CFC-112b to volatile chlorodi¯uoroacetic chloride. Pure
CFC-112a was transformed in two steps to dibromoderiva-
tive 5 that has been the real building block in butenolide
synthesis (Scheme 1). The four-carbon chain of the bute-
nolides 13 and 14 was built up by the radical addition of 5 to
ethylene. Several initiation systems have been employed in
additions of ¯uorinated bromoalkanes to non-¯uorinated
ole®ns, i.e., thermal decomposition of dibenzoyl peroxide
[18], copper chloride±ethanolamine redox system [19,20],
iron tetracarbonyle±ethanolamine system [21] and photo-
chemical initiation [22]. In contrast to the previous per-
oxide-initiated pressure reaction of 5 [18], we employed a
non-pressure photochemical initiation under which ethylene
was introduced in the photoreactor. 1,1,2-Trichloro-1,2,2-
tri¯uoroethane (CFC-113) was used as an inner ®lter to
prevent the products of a subsequent photolysis. The relative
yield of the main product 6a was dependent on the reaction
conditions (time, concentration) and achieved about 85%
under optimized conditions (Table 1). The reaction of
2. Results and discussion
2.1. Synthesis of butenolides 13 and 14
We started the synthesis of 13 and 14 from industrial
CFC-112a (Scheme 2) that contained about 15% of its non-
Scheme 2. Synthesis of butenolides 13 and 14 from industrial CFC-112.

O. Paleta et al. / Journal of Fluorine Chemistry 102 (2000) 147±157
149
Table 1
Photo-induced addition of 5 to ethylene: the composition of the reaction mixture
Run
5
CFC-113 (ml)
Time (min)
Reaction mixture composition (% rel.a)
(g)
(mol)
5
6a
6b
CH2BrCH2Br
1
2
32
30
30
64
64
64
96
96
96
96
0.109
0.102
0.102
0.218
0.218
0.218
0.328
0.328
0.328
0.328
75
75
75
50
50
50
35
35
35
35
150
120
90
8
8
51
57
26.5
21
14.5
14
3
12
55
12
11
4
170
140
120
165
125
110
100
10.5
12.5
13.5
8
59
19
11.5
10
5
59.5
62
18
6
15.5
21
9
7
58
13
8
10.5
15.5
19.5
61
14.5
12.5
8.5
15
9
61.5
61
10.5
11
10
a GCb.
halogenobutane 6a (Scheme 2) with fuming sulfuric acid
containing different concentration of sulfur trioxide led to
preferential hydrolysis of the terminal CH2±Br bond and the
formation of halogenobutan-1-ol 8 instead of hydrolysis of
bromochloro¯uoromethyl group as could be expected
according to literature [17,23±25]. Halogenobutan-1-ol 8
was characterized in the form of its ester with 3,5-dinitro-
benzoic acid (9). To direct the acid hydrolysis to trihalo-
genomethyl group, the terminal CH2±Br group was
converted to a more resistant CH2±Cl group in two steps
(Scheme 2). Halogenobutane 6a was dehydrochlorinated by
modi®ed previous procedure [18] using methanolic potas-
sium hydroxide in the presence of a phase-transfer catalyst
to afford the corresponding halogenated but-1-ene 7. The
addition of equimolar amount of chlorine to the 7 was
carried out very carefully in CFC-113 by periodical outside
irradiation with UV light and at low temperature to prevent
the formation of higher chlorinated compounds with 85±
90% yields of heptahalogenated butane 10. The result of
acid hydrolysis of butane 10 to the corresponding 2,3,4-
trichloro-2-¯uorobutanoic acid (or halogenide) (11a) by
oleum (Scheme 2) was strongly dependent on the sulfur
trioxide concentration: while low percent oleum was inef®-
cient, concentrated oleum led to a destruction of the starting
10, which is a sharp contrast to behavior of perhalogenated
¯uoroalkanes [17,23±25] (wide supra). A 30±40% concen-
tration of fuming sulfuric acid afforded acid halogenide 11
that was isolated in the form of free acid 11a in moderate
yields. Lactonization of the g-halogenoacid 11a (Scheme 2)
in basic water±methanol media was not successful. The
formation of lactone 12 from anhydrous salt 11b took place
spontaneously at room temperature with almost complete
conversion, but dif®culties with the separation of the pro-
duct cut the isolated yield of 12 to 20±30%. The most
preparatively effective method appeared pyrolysis of the dry
salt 11b under reduced pressure (60±80% isolated yields of
12). Dehydrochlorination of 12 to the targeted chloro¯uor-
obutenolide 13 (Scheme 2) requires attack of the b-bond C±
H (relatively to the ester group), which was not suf®ciently
reactive in 2-chloro-2-¯uorobutan-4-olide [26] to undergo
elimination. In the case of the precursor 12, dehydrochlor-
ination was accomplished comparatively easily using
triethylamine in diethyl ether at room temperature to afford
the butenolide 13 in acceptable yield. The same precursor 12
has been employed to obtain 2-¯uorobut-2-en-4-olide (14).
Didechlorination of 12 to the product 14 was carried with
zinc in ice acetic acid as the best solvent [27]. The reaction
was highly selective at room temperature and a complete
conversion of 12 was achieved in a short time. This synth-
esis of the new synthon 14 is an alternative to another one
that we have reported recently [2]. We have also described
some chemical properties of 14 in the reactions with various
nucleophiles [2].
2.2. Reactivity of butenolide 13
The molecule of 3-chloro-2-¯uorobut-2-en-4-olide (13)
possesses several reaction sites (Scheme 3): 1,2- and 1,4-
nucleophilic additions can be expected for a cyclic a,b-
unsaturated system containing vinylic ¯uorine, e.g., in
compound 14 [2]; halogen atoms attached to the double
bond can potentially be subjected to vinylic nucleophilic
displacement [1±4]; C4±H bond can be attacked by strong
Brùnsted bases.
We have found recently [1±4] that the reactivity of
¯uorinated but-2-en-4-olides towards nucleophiles is
strongly dependent both on the butenolide structure and a
nucleophile character. 2-Fluorobut-2-en-4-olide (14)
reacted with alkoxides and primary or secondary amines
Scheme 3. Potential reaction sites in butenolide 13.

150
O. Paleta et al. / Journal of Fluorine Chemistry 102 (2000) 147±157
[2], which are classi®ed as hard O- and N-nucleophiles [28±
30], respectively, by carbonyl-group attack combined with
ring opening [2]. Similarly, organylmagnesium compounds
reacted with 14 by hard center attack, i.e., by 1,2-addition
followed by ring opening and subsequent carnonyl group
addition [2]. In contrast, soft delocalized carbanions reacted
with 14 by 1,4-addition [2]. No preferential C4±H attack of
14 with this soft organolithiums or polymerization have
been observed [2]. In different way reacted 2,3-dichlorobut-
2-en-4-olide (3), in which nucleophilic displacement of b-
vinylic chlorine with thiolate ion took place [31]. Similarly,
in 4-methoxyderivative of dichlorobutenolide 3 b-vinylic
chlorine was easily substituted with aliphatic and alicyclic
amines [13,14]. Another chemical properties have been
observed for 4,4-dialkyl-2,3-di¯uorobut-2-en-4-olides (4):
oxyanions as hard O-nucleophiles [1,4], soft N-nucleophiles
(sodium salts of nucleoside bases) [3] and soft organylme-
tals reacted by vinylic displacement of b-¯uorine [4].
Organyllithiums and magnesium halides as well as amines
and their alkali salts reacted by hard attack at the carbonyl
group: amines reacted with ring opening [3], hard organyl
metals reacted with 1,2-addition followed by a novel rear-
rangement [1,4].
Scheme 5. Trapping of the intermediate enolate 18.
addition to afford the addition product 17, however, tars
were formed mainly. This behavior is in contrast with the
reactivity of the above mentioned butenolides, including 3
[14] and 4 [1,4] that afforded products of vinylic b-halogen
displacement.
It can be deduced from the above experiments that the
formation of tar-like products in reactions of 13 with strong
Brùnsted bases is probably caused by an initial C4±H bond
attack followed by subsequent reactions of the intermediate
carbanion with supposed structure 18 (Scheme 5). This C±H
bond in 13 is probably more acidic than that in dichlor-
obutenolide 3 and ¯uorobutenolide 14. Non-basic methanol,
but being a hard Lewis base [28±30], did not attack the C4±
H bond. We were successful in trapping lithium enolate 18
generated by lithium diisopropylamide from butenolide 13
by silylation. (Trimethyl-silyloxy)furan 19 appeared to be
an unstable compound that was converted to the starting
butenolide 13 in the presence of acetic acid and at room
temperatures. Its 19F NMR spectrum is characterized by a
doublet signal at 191.9 ppm.
2.3. Reactions of butenolide 13 with hard nucleophiles
Only small yield of unstable methyl ester 15, formed by
carbonyl group attack and subsequent ring opening, was
identi®ed in the reaction of butenolide 13 with sodium
methoxide in methanol (Scheme 4), which is a similar
reactivity as observed for ¯uorobutenolide 14 [2]. The
conversion of the starting 13 was complete and the major
products were tars. On heating, the product 15 was trans-
formed back to the starting butenolide 13. Surprisingly,
butenolide 13 reacted slowly with re¯uxing methanol to
give the product of conjugate addition 16 (Scheme 4) in low
yield, but no tar formation was observed. Similarly, bute-
nolide 13 reacted with piperidine in the sense of conjugate
2.4. Reactions of butenolide 13 with soft nucleophiles
As basic nucleophiles caused tar formation from 13, we
included in testing the nucleophilic reactivity of 13 non-
basic phosphorus nucleophiles triethyl phosphite and tribu-
tyl phosphane. It has been known that trialkyl phosphites
attack vinylic carbon±halogen bond in the sense of Arbuzov
rearrangement to afford the corresponding phosphonates,
e.g., a series of results was obtained with ¯uorinated cyclo-
butenes: for the displacement of vinylic halogen, the order
F > Cl > Br > I was found [32]. As a consequence of this
relation, in the case of 1-halogenopenta¯uorocyclobutene,
the preferential attack of C2±F bond with the formation of
(2-halogeno-3,3,4,4-tetra¯uoro-cyclobutenyl) trimethoxy
¯uorophosphorane was observed [33]. This primary product
is slowly transformed to an Arbuzov-type phosphonate on
standing. The same exclusive reactivity of the vinylic C±F
bond have been observed in the reaction of 1-chloro-
2,3,3,4,4,5,5-hepta¯uoro-cyclopentene with trialkyl phos-
phites to afford the corresponding phosphonates [33].
Similarly, the terminal C±F bond in per¯uoroalk-1-enes
Scheme 4. Reactions of butenolide 13 with hard nucleophiles.

O. Paleta et al. / Journal of Fluorine Chemistry 102 (2000) 147±157
151
In reactions of 13 with phosphorus nucleophiles the main
products were obtained in rich mixtures with byproducts
and not completely separated (e.g., 20 and 21), or were
unstable and not separated from the starting reagent (e.g.,
22). Their structures were elucidated only on the basis of 19
F
NMR and MS spectra and, therefore, shall be understood as
probable.
3. Experimental
3.1. General comments
Scheme 6. Reactions of butenolide 13 with soft phosphorus nucleophilic
reagents.
The temperature data were not corrected. Distillations of
high boiling compounds were carried out on a Vacuubrand
RC5 high vacuum oil pump. GC analyses were performed
on a Micromat HRGC 412 (GCa, Nordion Analytical; 25 m
glass capilary column, SE-30) and Chrom 5 (GCb, Labor-
was attacked by tris(trimethylsilyl) phosphites to undergo
Arbuzov rearrangement under the formation of (per¯uor-
oalken-1-yl) phosphonates [34]. The b-bond C±Cl was also
attacked with trialkyl phosphites in alkyl vinyl ketones [35]
and 2,3,4-trichlorobut-2-en-4-olide [36±38]. In the light of
the observations listed above [32±38], it had seemed rea-
listic to suppose a nucleophilic attack of vinylic C±Cl and/or
C±F bonds in butenolide 13. As the reaction of 13 with
triethyl phosphite was very slow at room temperatures
(Scheme 6), we carried out the phosphonation at 808C
and obtained a mixture of products 20 and 21 together with
a mixture of minor products. Under these conditions, the b-
bond C±Cl was attacked ®rst in 13, i.e., the ®rst nucleophilic
attack took place at the soft electrophilic carbon under the
formation of the Arbuzov phosphonate 20. It can also be
supposed that owing to high reactivity of vinylic C±F bonds,
the a-bond C±F in butenolide 13 was attacked subsequently
to give the end ¯uorophosphorane derivative 21.
Vinylic carbon±halogen bond is also attacked by trialk-
ylphosphanes. Terminal C±F bonds in per¯uoroole®ns were
attacked by tributylphosphane to afford the corresponding
(per¯uoroalk-1-en-1-yl)¯uorophosphoranes [39,40], while
cyclic per¯uoroole®ns afforded stable ¯uorinated cyclic
ylides by the reaction with triarylphosphanes [41,42]. Also,
b-bond C±Cl was attacked with trialkyl phosphites in alkyl
vinyl ketones to give the corresponding phosphonium chlor-
ide [43]. A similar reaction could be expected for the
chloro¯uorobutenolide 13. We carried out the reaction of
13 with tributylphosphane at low to room temperatures. The
reagent attacked soft electrophilic carbon with the complete
selectivity to afford phosphonium salt 22, no regioisomeric
products have been detected in the reaction mixture as well
as tars.
 ÏÂ
atornõ prõstroje, Prague; FID, 380 Â 0.3 cm packed column,
silicone elastomer E-301 on Chromaton N-AW-DMCS
(Lachema, Brno), nitrogen) instruments. NMR spectra were
recorded on a Bruker 400 AM (FT, 19F at 376.5 MHz),
Varian Gemini 300 HC (FT, 1H at 300 MHz, 13C at
75.46 MHz) and a Bruker WP 80 SY (FT, 19F at
75.4 MHz) instruments: TMS and CFCl3 as the internal
standards, chemical shifts in ppm (s singlet, bs broad singlet,
d doublet, t triplet, q quadruplet, qi quintuplet, m multiplet),
coupling constants J in Hz, solvents CDCl3, acetone-d6 and
DMSO-d6. IR spectra were recorded on FT±IR spectrometer
Nicolet 740. MS spectra were scanned on a Hewlett±Pack-
ard MSD 5971A instrument (1989, EI 70 eV).
Chemicals used were as follows: 1,1,2-trichloro-1,2,2-
tri¯uoroethane (CFC-113, re®ned) and 1,2-dichlorotetra-
¯uoroethane (CFC-112, industrial intermediate, puri®ed
by fraction distillation; both CFC, Spolek pro chemickou
Â
 Â
Â
a hutnõ vyrobu, Ustõ nad Labem). Triethylamine and piper-
idine (Fluka) were dried over KOH and distilled before use;
tributylphosphane (85%, Fluka), triethyl phosphite (Fluka)
was distilled. Methanol, diethyl ether, tetrahydrofuran and
dimethylsulfoxide were dried and puri®ed according to
standard procedures [44].
3.2. 1,2-Dibromo-1,2-dichloro-1,2-difluoroethane (5)
3.2.1. Refining of industrial CFC-112
A mixture of industrial 1,1,2,2-tetrachlorodi¯uoro-
ethane (CFC-112, 16% content of isomeric 1,1,1,2-tetra-
chlorodi¯uoroethane; 700 g), oleum (100 ml; concentration
of SO3 60%) and mercuric oxide (1.5 g) was re¯uxed
for 14 h and the volatile 2-chlorodi¯uoroacetyl ¯uoride
was condensed in an ice-cooled trap. CFC layer was then
washed with water, diluted solution of sodium hydrogen
carbonate and dried over calcium chloride. Crude CFC-112
was distilled to give isomerically pure (above 99.5% as
checked by 19F NMR) 1,1,2,2-tetrachlorodi¯uoroethane
(547 g).
The reactions of chloro¯uorobutenolide 13 with low-
basic and soft phosphorus nucleophilic reagents have sup-
ported our above deductions (see Section 2.3) that strong
Brùnsted bases very probably preferentially affected the
C4±H bond and caused tars formation in subsequent reac-
tions of the carbanion 18.

152
O. Paleta et al. / Journal of Fluorine Chemistry 102 (2000) 147±157
3.2.2. 1,2-Dichloro-1,2-difluoroethene
CFCl, J ˆ 260 and 27 Hz) ppm. 19F NMR (CDCl3) d:
114.2 to 111.9 (m, 2F, dec. 2 Â d, CFCl (A)); 112.4
(d, 1F, J ˆ 18 Hz, CFCl (B)); 112.2 (d, 1F, J ˆ 19 Hz,
CFCl (B)); 65.6 (d, 2F, J ˆ 19 Hz, CFClBr (A)); 65.5 (d,
2F, J ˆ 18 Hz, CFClBr (B)) ppm.
According to previously described procedure [45], the
reaction was carried out with CFC-112 (510 g, 2.5 mol),
zinc powder (250 g, 3.82 mol), a part of which (25 g) was
activated with acetic acid, and ethanol (450 ml). Crude
ole®n was treated with phosphorus pentoxide and fraction-
ally distilled (packed column) to give the product (287 g,
86%, isomeric purity (19F NMR) 99.5%), b.p. 20±21.58C.
1,6-Dibromo-3,4-dichloro-3,4-di¯uorohexane (6b, two
diastereoisomers A and B, ca. 1:1): Analysis: found: C,
20.28%; H, 2.20%; F, 11.44%. C6H8Br2Cl2F2 requires: C,
20.63%; H, 2.29%; F, 10.89%. M, 348.8. 1H NMR (CDCl3)
d: 2.69±3.06 (m, 2H, CH2 (A)); 3.54 (ddd, 1H, J ˆ 11.5,
10.0 and 5.2 Hz, CH2 (B)); 3.66 (ddd, 1H, J ˆ 11.0, 10.0
and 5.3 Hz, CH2 (B)) ppm. 13C NMR (CDCl3) d: 24.0±24.1
(m, 2 Â CH2); 40.5 (CH2Br, signal of higher order, shift/
intensity: 40.689/1, 40.603/8, 40.473/6, 40.423/6, 40.293/8,
40.208/1); 41.1 (CH2Br, signal of higher order, shift/inten-
sity: 41.259/1, 41.222/6, 41.116/2, 41.041/2, 40.935/3,
40.898/1), 113.6 (dd, CFCl, J ˆ 257 and 29 Hz); 113.7
(dd, CFCl, J ˆ 255 and 32 Hz) ppm. 19F NMR (CDCl3)
d: 119.5 (d, 1F, J ˆ 28 Hz, dec. s, CFCl (A)); 116.3 (d,
1F, J ˆ 29 Hz, dec. s, CFCl (B)) ppm.
3.2.3. Addition of bromine to
1,2-dichloro-1,2-difluoroethene
A two-necked ¯ask equipped with a re¯ux condenser
connected to atmosphere through a hydraulic seal with
sulfuric acid and dropping funnel, was charged with the
ole®n (150 g, 1.13 mol) and 1,1,2-trichlorotri¯uoroethane
(CFC-113, 40 ml). Bromine (180 g, 1.13 mol) was added
dropwise during 3 h with stirring and the mixture was stirred
for additional 3 h at room temperature. CFC was then
distilled off and the residue distilled under reduced pressure
to give 5 (284 g, 87%, purity (GCa) 98.5%), b.p. 54±568C/
45 mm Hg.
3.4. 4-Bromo-3,4-dichloro-3,4-difluorobut-1-ene (7)
3.3. Reaction of 1,2-dibromo-1,2-dichloro-1,2-
difluoroethane (5) with ethene (products 6a and 6b)
A mixture of the adduct 6a (50 g, 155 mmol), potassium
hydroxide (13 g, 232 mmol), tetrabutylammonium bromide
(1 g), methanol (65 ml) and water (75 ml) was heated on a
bath at 708C while intensive stirring (magnetic spinbar) for
8 h when the conversion of 6a was ca. 97% (GCa). The
crude product as lower oily layer was separated (35.7 g,
95%) and collected from a series of runs. The collected
crude 7 (150 g) was dried over calcium chloride and then
magnesium sulfate and subjected to distillation under
reduced pressure that afforded product 7 (138 g, 84%, purity
(GCa) 98%), b.p. 78±798C/110 mm Hg. Analysis:
found : C, 20.29%; H, 1.22%; F, 16.26%. C4H3BrCl2F2
(two diastereoisomers A and B, ca. 1:1) requires: C,
20.17%; H, 1.25%; F, 15.84%. M, 239.9. 1H NMR
(CDCl3) d: 5.68 (dd, 1H, J ˆ 10.8 and 1.2 Hz, HCH);
5.90 (dd, 1H, J ˆ 16.9 and 1.8 Hz, HCH); 6.22 (ddd, 1H,
J ˆ 10.8, 16.8 and 27.6 Hz, CH) ppm. 13C NMR (CDCl3) d:
108.9 (dd, CFClBr, J ˆ 316 and 35 Hz); 109.0 (dd, CFClBr,
J ˆ 315 and 36 Hz); 110.4 (dd, CFCl, J ˆ 258 and 28 Hz);
110.8 (dd, CFCl, J ˆ 258 and 27 Hz); 122.9 (d, CH2,
J ˆ 9 Hz); 123.0 (d, CH2, J ˆ 9 Hz); 130.9 (d, CH,
J ˆ 22 Hz); 131.0 (d, CH, J ˆ 22 Hz) ppm. 19F NMR
(CDCl3) d: 119.3 (bs, 1F, dec. bd, J ˆ 15 Hz, CFCl
(A)); 118.9 (bs, 1F, dec. d, 19 Hz, CFCl (B)); 67.3
(d, 1F, dec. d, 20 Hz, CFClBr (A)); 67.1 (bd, 1F, dec.
bd, J ˆ 18 Hz, CFClBr (B)) ppm.
Reactions were carried out in an immersion-well photo-
reactor (75 ml) cooled from outside to 108C to 08C; a
medium-pressure UV lamp (Tesla, RVK 125) in a water-
cooled double jacket (quartz and Simax1 glass, gas inlet)
was used as light source; a dry-ice cooled spiral re¯ux
condenser connected with a dry-ice cooled trap which was
connected to atmosphere through a hydraulic seal with
sulfuric acid. The reactor was charged with 5 and CFC-
113 (Table 1) and the whole apparatus was ¯ushed with
argon for 2 h while cooling to 308C to 208C. Gaseous
ethylene was then introduced into the photoreactor on
irradiation at such ¯ow-rate that a small excess bubbled
through the seal. The conversion of 5 was monitored by GC.
CFC-113 was then recovered by distillation and the residue
was collected. The collected residues (530 g of the total
779 g of runs 1±10, Table 1) were fractionally distilled
(heated jacket, column 30 cm/1.5 cm, Berle saddles) under
vacuum: product 6a was taken at 83±85 8C/12 mm Hg
(226 g, purity (GCb) 98%); product 6b was obtained at
135±140 8C/7 mm Hg (63 g, purity (GCa) 95.5%). 1,4-
Dibromo-1,2-dichloro-1,2-di¯uorobutane (6a, two diaster-
eoisomers A and B, ca. 1:1): Analysis: found: C, 15.35%; H,
1.15%; F, 12.34%. C4H4Br2Cl2F2 requires: C, 14.95%; H,
1.25%; F, 11.84%. M, 320.8. 1H NMR (CDCl3) d: 2.79±2.96
(m, 2H, CH2CFCl (A)); 2.98±3.10 (m, 2H, CH2CFCl (B));
3.56 (ddd, 1H, J ˆ 11.5, 10.0 and 5.1 Hz, CH2Br (A)); 3.67
(ddd±dt, 1H, J ˆ 10.6 and 5.3 Hz, CH2Br (B)) ppm. 13C
NMR (CDCl3) d: 23.8 (2 Â CH2Br); 41.2 (d, CH2,
J ˆ 21 Hz); 41.3 (d, CH2, J ˆ 21 Hz); 109.2 (dd, CFClBr,
J ˆ 316 and 33 Hz); 109.4 (dd, CFClBr, J ˆ 315 and
33 Hz); 113.7 (dd, CFCl, J ˆ 260 and 28 Hz); 113.8 (dd,
3.5. 4-Bromo-3,4-dichloro-3,4-difluorobutan-1-ol (8)
The reaction was carried out in a round-bottomed ¯ask
(magnetic spinbar) equipped with a re¯ux condenser con-
nected to atmosphere through a hydraulic seal with sulfuric
acid. A mixture of the adduct 6a (5 g, 16 mmol), oleum

O. Paleta et al. / Journal of Fluorine Chemistry 102 (2000) 147±157
153
(12 ml; concentration of SO3 60%), mercuric oxide (0.2 g)
and silver acetate (0.1 g) was heated on a bath (508C) for
30 min with stirring. The mixture was then dropwise added
to a solution of sodium pyrosul®te (5 g) in water (30 ml).
The water mixture was then extracted with diethyl ether
(7 Â 20 ml), the combined extracts were washed with a
small amount of the pyrosulfate solution (2 ml), sodium
hydrogencarbonate solution (2 ml) and water (2 ml) and
dried over magnesium sulfate. Ether was then removed
(rotary evaporator) and crude alkanol 8 (2.63 g, purity
(GCb) ca. 80%) was directly used for the preparation of
96%), b.p. 90±928C/5 mm Hg. Compound 10 consisted of
four diastereoisomers: two major 1:1 and two minor 1:1;
major:minor ˆ 3:1. Analysis: found: C, 15.77%; H, 1.17%;
Br, 25.34%; Cl, 46.16%; F, 12.19%. C4H3BrCl4F2 requires:
C, 15.43%; H, 0.96%; Br, 25.34%; Cl, 45.76%; F, 12.21%.
M, 310.8. Minor diastereoisomers (A and B): 1H NMR
(CDCl3) d: 3.80 (dddd, 1H, J ˆ 12.0, 9.2, 1.3 and 0.6 Hz,
CH2Cl); 4.19±4.09 (m, 1H, CH2Cl); 4.83 (dddd, 1H,
J ˆ 19.9, 9.2, 3.9 and 2.9 Hz, CHCl) ppm. 13C NMR
(CDCl3) d: only 62.3 (d, CHCl, J ˆ 30 Hz); 60.8 (d, CHCl,
J ˆ 30 Hz), 45.6 (m, 2  CH2) ppm. 19F NMR (CDCl3) d:
107.4 (1F, overlap with major diastereoisomer, CFCl (A));
105.8 (bd, 1F, J ˆ 17 Hz, CFCl (B)); 59.2 (d, 1F,
J ˆ 17 Hz, CFClBr (A)); 58.7 (d, 1F, J ˆ 18 Hz, CFClBr
1
dinitrobenzoate 9. H NMR (CDCl3) d: 2.2 (m, 1H, CH2);
3.0 (m, 1H, CH2); 4.11 (t, 1H, J ˆ 4.6 Hz, CH2O); 4.17 (m,
1H, CH2O); 6.22 (bs, 1H, OH).
1
(B)) ppm. Major diastereoisomers (A and B): H NMR
3.6. (4-Bromo-3,4-dichloro-3,4-difluorobutan-1-yl) 3,5-
dinitrobenzoate (9)
(CDCl3) d : 3.67 (ddd, 1H, J ˆ 12.4, 9.9 and 1.2 Hz,
CH2Cl); 4.19±4.09 (m, 1H, CH2Cl); 4.95 (dddd, 1H,
J ˆ 14.2, 9.9, 7.3 and 2.5 Hz, CHCl) ppm. 19C NMR
(CDCl3) d: 45.0 (m, 2  CH2); 64.0 (dd, CHCl, J ˆ 23
and 2 Hz); 65.0 (dd, CHCl, J ˆ 23 and 2 Hz); 108.3 (dd,
2  CFClBr, J ˆ 37 and 315 Hz); 112.0 (dd, CFCl, J ˆ 264
and 29 Hz); 112.8 (dd, CFCl, J ˆ 264 and 28 Hz) ppm. 19F
(CDCl3) d: 107.4 (bd, 1F, J ˆ 16 Hz, CFCl (A)); 106.2
(bs, 1F, CFCl (B)); 61.1 (d, 1F, J ˆ 21 Hz, CFClBr (A));
60.5 (d, 1F, J ˆ 21 Hz, CFClBr (B)) ppm.
A mixture of crude alkanol 8 (1 g, ca. 3 mmol), 3,5-
dinitrobenzoyl chloride (2 g, 9 mmol) and pyridine (3 ml)
was heated on a bath (1008C) for 10 min. The reaction
mixture was then poured in ice-water (20 ml) and concen-
trated HCl (5 ml) was added. Precipitate was ®ltered off and
the solution was evaporated to dryness (rotary evaporator).
Yellow brown mass was twice recrystallized (benzene/
hexane ˆ 1:1) to obtain white crystals of benzoate 9 (two
diastereoisomers A and B, ca. 1:1, 0.58 g, 41%), m.p. 76±
778C. Analysis: found: C, 29.67%; H, 1.59%; F, 8.50%; N,
6.13%. C11H7BrCl2F2N2O6 requires: C, 29.23%; H, 1.56%;
3.8. 2,3,4-Trichloro-2-fluorobutanoic acid (11a)
A ¯ask equipped with a re¯ux condenser connected with
a dry-ice cooled trap which was connected to atmosphere
through a hydraulic seal with sulfuric acid was charged with
halogenobutane 10 (5 g, 16 mmol), oleum (5 g; concentra-
tion of SO3 35%), mercuric oxide (0.3 g) and silver acetate
(0.03 g). The ¯ask with the reactants was immersed in a
pre-heated bath (95±1008C) for 30±40 min with stirring
(magnetic spinbar). Cool reaction mixture was then
dropwise added to water under cooling with ice. Turbidity
was ®ltered off and the solution was extracted with diethyl
ether (10 Â 10 ml), combined extracts were dried over
magnesium sulfate. Ether was removed under reduced
pressure (rotary evaporator) and yellowish crystals were
washed on ®lter (sintered glass) with CFC-113 (1 ml) to
give the acid 11a (1.24 g, 38.5%). For analytical purposes,
product 11a was recrystallized (hexane/benzene) to give
white crystals, m.p. 122±1248C. Analysis: found: C,
23.07%; H, 1.95%; Cl, 50.21%; F, 9.02%. C4H4Cl3FO2
requires: C, 22.94%; H, 1.93%; Cl, 50.79%; F, 9.07%.
1
F, 8.41%; N, 6.20%. M, 452.0. H NMR (CDCl3) d: 2.81±
2.98 (m, 1H, CH2); 3.04±3.15 (m, 1H, CH2); 4.86 (dt, 1H,
J ˆ 6.6 and 11.6 Hz, CH2O (A)); 4.89 (dt, 1H, J ˆ 6.1 and
11.8 Hz, CH2O (B)); 9.19 (d, 2H, J ˆ 2.1 Hz, Ar); 9.26 (t,
1H, J ˆ 2.1 Hz, Ar) ppm. 19F NMR (CDCl3) d : 113.6 (bs,
1F, dec. bs, CFCl (A)); 113.4 (bs, 1F, dec. bs, CFCl (B));
67.1 (d, 1F, dec. d, J ˆ 19 Hz, CFClBr (A)); 66.9 (bd,
1F, dec. bd, J ˆ 17 Hz, CFClBr (B)) ppm.
3.7. 1-Bromo-1,2,3,4-tetrachloro-1,2-difluorobutane (10)
A three-necked ¯ask (250 ml, Simax1 glass) equipped
with a water-cooled re¯ux condenser connected with a dry-
ice cooled trap which was connected to atmosphere through
a hydraulic seal with sulfuric acid was charged with halo-
genoole®n 7 (84 g, 0.35 mol) and CFC-113 (75 ml) and
placed on a bath ( 208C to 308C) in housing with
aluminum re¯ective coating. Chlorine was introduced in
the mixture under from-outside-irradiation with medium-
pressure UV lamp (Tesla, RVK 80) with stirring (magnetic
spinbar) for 4 h when the conversion of 7 was complete (as
checked by GCb). Reaction mixture was treated with a
water solution of sodium pyrosul®te, with a water solution
of sodium carbonate and dried over magnesium sulfate.
After removing CFC-113 (recovery by distillation), the
residue was fractionally distilled on a column (see product
6) to give halogenobutane 10 (89.7 g, 86%, purity (GCb)
1
M, 209.4. H NMR (DMSO-d6) d: 3.79 (dd, 1H, J ˆ 9.6
and 2.6 Hz, CH2Cl); 4.39 (dd, 1H, J ˆ 12.4 and 2.6 Hz,
CH2Cl); 4.62 (dd, 1H, JFH ˆ 21.2 Hz, JHH ˆ 9.8 and
2.6 Hz, CHCl); 5.50 (s, OH) ppm. 13C NMR (DMSO-d6)
d: 43.6 (s); 62.4 (d, JCF ˆ 22.2 Hz); 100.8 (d,
JCF ˆ 264.1 Hz); 163.7 (d, JCF ˆ 27 Hz) ppm. 19F NMR
(DMSO-d6) d: 132.2 (d, 1F, JFH ˆ 21.3 Hz) ppm. IR (KBr
tablet) (cm 1): 888 (w), 901 (w), 1158 (m), 1436 (w), 1760
(s), 2628 (w), 2867 (m), 3026 (m).

154
O. Paleta et al. / Journal of Fluorine Chemistry 102 (2000) 147±157
3.9. Sodium 2,3,4-trichloro-2-fluorobutanoate (11b)
JCF ˆ 28 Hz) ppm. 19F NMR (CDCl3) d: 127.8 ppm (d,
1F, JFH ˆ 11.5 Hz) ppm. MS (Mr ˆ 172), m/z/% rel. int.: EI:
(CCl4) cm 1: 915 (w), 1014 (m) 1071 (m), 1158 (m), 1267
(w), 1831 (s), 3029 (w).
‡
A solution of acid 11a (1.0 g, 4.7 mmol) in water (20 ml)
was titrated with a 2 M-solution of sodium carbonate
(phenolphthaleine as indicator) and the solution was then
heated (708C) with charcoal (0.5 g). After ®ltration, water
was removed under reduced pressure, the toluene (10 ml)
was added to the residue and solvents were removed
under reduced pressure (rotary evaporator). Residual wet
salt was dried at 70±758C in vacuo (0.8 mm Hg) for
12 h to obtain dry product 11b (0.99 g, 91%). Analysis:
found: C, 20.43%; H, 1.21%; F, 7.82%. C4H3Cl3FNaO2
172 (M ), 165, 147, 137, 114, 93, 79, 67, 57, 45, 31. IR
3.11. 3-Chloro-2-fluorobut-2-en-4-olide (13)
Butanolide 12 (0.50 g, 2.9 mmol) was placed in a ¯ask
equipped with a re¯ux condenser with a drying tube (NaOH
pellets); to the ¯ask, a solution of triethylamine (0.31 g,
3.1 mmol) in acetonitrile (1 g, 24 mmol) was dropwise
added under cooling on an ice bath while stirring (magnetic
spinbar). The mixture was stirred at room temperature for
12±16 h when the conversion of the starting butenolide 12
was usually complete (checked by 19F NMR). Volatile
components of the reaction mixture were then removed
on rotary evaporator and the waxy solid was extracted with
diethyl ether (5 Â 1 ml). The ethereal extract was evapo-
rated (rotary evaporator) to give crude butenolide 13 that
was puri®ed by distillation on a Hickmann-type microdis-
tillation apparatus to afford butenolide 13 in the yield of
210 mg (52%), b.p. 96±1008C/8 mm Hg (1.06 Pa), m.p. 25±
318C. Analysis: found: C, 34.94%; H, 1.35%; Cl, 25.17%; F,
13.25%. C4H2ClFO2 requires: C, 35.30%; H, 1.48%; Cl,
25.72%; F, 13.96%. M, 136.0. 1H NMR (CDCl3) d:
4.82 ppm (d, 2H, JFH ˆ 5.9 Hz) ppm. 13C NMR (CDCl3)
d: 68.1 (s); 129.2 (d, JCF ˆ 8.1 Hz); 142.3 (d,
JCF ˆ 278.5 Hz); 162.8 (d, JCF ˆ 28.4 Hz) ppm. 19F
NMR (CDCl3) d: 146.2 ppm (t, 1F, JFH ˆ 5.6 Hz) ppm.
IR (CCl4) cm 1: 941 (w), 1093 (m), 1329 (w), 1705 (m),
1797 (s), 3027 (w). MS (Mr ˆ 136), m/z/% rel. int.: EI: 136
1
requires: C, 20.88%; H, 1.32%; F, 8.26%. M, 229.9. H
NMR (D2O) d: 3.85 (dd, 1H, J ˆ 9.5 and 2.5 Hz, CH2Cl);
4.38 (dd, 1H, J ˆ 12.3 and 2.5 Hz, CH2Cl); 4.65 (dd, 1H,
JFH ˆ 21.2 Hz, JHH ˆ 9.7 and 2.4 Hz, CHCl) ppm. 13C
NMR (D2O) d: 45.5 (s); 63.8 (d, JCF ˆ 23.3 Hz); 102.3
(d, JCF ˆ 267 Hz); 165.8 (d, JCF ˆ 31.1 Hz) ppm. 19F NMR
(D2O) d: 133.0 (d, 1F, JFH ˆ 21 Hz) ppm. IR (KBr tablet)
(cm 1): 905 (m), 1170 (m), 1261 (m), 1765 (s), 2867 (m),
3022 (m).
3.10. 2,3-Dichloro-2-fluorobutan-4-olide (12)
3.10.1. Method A
Dry salt 11b (1.0 g, 4.4 mmol) was dissolved in dry
DMSO and heated on a bath (408C) under argon for 8 h
with stirring (magnetic spinbar). The mixture was then
diluted with water (15 ml) and the solution obtained was
extracted with diethyl ether (15 Â 7 ml). Combined ethereal
extracts were washed with water (5 ml), dried over magne-
sium sulfate and ether was removed under reduced pressure
(rotary evaporator). Distillation of residual oil in vacuo
afforded butanolide 12 (0.31 g, 41%, purity (19F NMR)
93%), b.p. 103±1108C/25 mm Hg, m.p. of the redistilled
fraction was 28±348C. Analysis: found: Cl, 41.04%; F,
11.13%. C4H3Cl2FO2 requires: Cl, 40.99%; F, 10.98%.
M, 172.9.
‡
(M ), 107, 101, 91, 79, 78, 57, 44, 37, 31.
3.12. 2-Fluorobut-2-en-4-olide (14)
Ice acetic acid (1 ml) and zinc powder (2.08 g,
31.8 mmol) were placed in a ¯ask equipped with a re¯ux
condenser with a drying tube (MgSO4); to the ¯ask, a
solution of butanolide 12 (1.835 g, 10.6 mmol) in ice acetic
acid (0.5 ml) was added dropwise while stirring intensively
(magnetic spinbar). The mixture was stirred at room tem-
perature for 2±4 h, when the conversion of the starting
butanolide 12 was usually complete (checked by 19F
NMR), and stands overnight. The mixture was extracted
with diethyl ether (2 Â 5 ml), the combined extracts were
mixed with ®nely ground magnesium sulfate (ca. 2 g) and
®ltered. The ®ltrate was neutralized with a concentrated
solution of sodium carbonate and dried over magnesium
sulfate. The ether was removed under reduced pressure. The
residue, crude 14, was puri®ed by distillation on a Hick-
mann-type microdistillation apparatus to afford butenolide
14 in the yield of 0.76 g (71%), b.p. 103±1058C/198 mm Hg
(2.64 kPa). Analysis: found: C, 47.11%; H, 2.35%.
3.10.2. Method B
The ¯ask of a distillation apparatus (¯ushed with argon)
was charged with powdered dry salt 11b (2.0 g, 8.7 mmol)
and the ¯ask was immersed in a metal bath (Wood's metal)
pre-heated to 1308C under reduced pressure (40 mm Hg)
and the bath was slowly heated to ca. 2008C. Crude buta-
nolide 12, that distilled slowly in the range of 110±1208C/
40 mm Hg (1.34 g, 89%, purity (GCb) 88%), was redistilled
to afford more pure 12 (95%, GCa), b.p. 101±1058C/0.8 mm
Hg, m.p. 22±278C. Analysis: found: C, 27.14%; H, 1.63%;
Cl, 40.14%; F, 11.13%. C4H3Cl2FO2 requires: C, 27.78%;
H, 1.75%; Cl, 40.99%; F, 10.98%; M, 172.9. 1H NMR
(CDCl3) d: 4.18 (dd, 1H, J ˆ 9.2 and 9.3 Hz, CH2); 4.66
(dd, 1H, J ˆ 9.3, 7.3 and 0.85 Hz, CH2); 4.78 ppm (dd, 1H,
JHH ˆ 9.2 and 7.3 Hz, JFH ˆ 11.5 Hz, CHCl) ppm. 13C
NMR (CDCl3) d: 57.6 ppm (d, JCF ˆ 25.4 Hz); 69.2 ppm
(d, JCF ˆ 6.2 Hz); 101.1 ppm (d, JCF ˆ 267.1 Hz); 164.4 (d,
1
C4H2FO2 requires: C, 47.52%; H, 2.14%. M, 101.0. H
NMR (CDCl3) d: 4.86 (dd, 2H, J ˆ 2.0 and 6.2 Hz, CH2),

O. Paleta et al. / Journal of Fluorine Chemistry 102 (2000) 147±157
155
6.81 (q, 1H, J ˆ 2.1 Hz, CH=) ppm. 19F NMR (CDCl3) d:
3.13.3. Reaction with piperidine:
3-chloro-2-fluoro-3-(piperidin-1-yl)butan-4-olide (17)
141.9 (dt, J ˆ 3.1 and 6.1 Hz) ppm.
To a solution of butenolide 13 (100 mg, 0.74 mmol) in
anhydrous methanol (2 ml) in a double-neck ¯ask under
inert atmosphere, a solution of piperidine (125 mg,
1.47 mmol) in diethyl ether (2 ml) was added dropwise
from 608C (dry-ice cooled bath). The mixture was
stirred from 608C to 308C for 3 h, then at 208C to
58C for another 3 h and subsequently overnight at
58C to achieve the complete conversion of 13 (checked
by TLC and 19
3.13. Reactions of butenolide 13 with hard nucleophiles
3.13.1. Reactions with sodium methoxide: methyl
3-chloro-2-fluoro-4-hydroxybut-2-enoate (15)
3.13.1.1. Method A. A mixture of butenolide 13 (50 mg,
0.37 mmol) and methanol (1 ml) was stirred under dry
atmosphere at 608C for 30 min. Then, finely ground
sodium carbonate was added in one portion (75 mg,
1.4 mmol), the mixture was stirred for another 3 h at
608C and then allowed to warm to room temperature
while stirring. Dark mixture afforded only tars after
evaporation of methanol. A similar result was obtained
when sodium hydrogen carbonate was used as the base.
F NMR). Volatile components of the reaction
mixture were removed on rotary evaporator and the brown
residue was chromatographed on silica gel (see compound
15) to obtain not completely pure 17 (ca. 85%, GC±MS),
calculated yield ca. 19%. 1H NMR (CDCl3) d: 1.60±
1.80 ppm (m, 6H, J ˆ 6.7, 5.8, 5.5 and 5.0 Hz,
CH2CH2CH2); 3.58 ppm (t, 4H, J ˆ 5.6 Hz, CH2NCH2);
4,30 ppm (d, 2H, JFH ˆ 5.2 Hz, CH2O); 5.12 (d, 1H,
JFH ˆ 44.2 Hz, CHF) ppm. 19F NMR (CDCl3) d:
120.1 ppm (dt, 1F, JFH ˆ 44.1 and 5.1 Hz) ppm. MS
3.13.1.2. Method B. In a double-neck flask, sodium hydride
(30 mg, 1.2 mmol, three times washed with petroleum
ether and dried in vacuum) was dissolved in methanol
(1 ml). To this mixture, a solution of butenolide 13
(150 mg, 1.1 mmol) in methanol (1 ml) was added under
cooling the reaction flask on a water±ice bath (8±108C) and
the mixture was stirred at room temperature for 2 h when the
conversion was almost complete (monitored by 19F NMR).
The mixture was then neutralized with trifluoroacetic acid
and methanol was removed by rotary evaporator. The tar-
like dark residue was purified by column chromatography
(silica gel, 4 and 10 g, 40±100 mm, d ˆ 2 cm, chloroform,
check by TL) to give the product 15 in 18 mg yield (16%) as
a mixture of (Z)- and (E)- isomers (ca. 70%:30% rel.). When
the crude product 15 was distilled in vacuum, its complete
transformation to the starting butenolide 13 occurred.
Analysis: found: Cl, 20.72%. C5H6ClFO3 requires: Cl,
21.03%. M, 168.6. 1H NMR (CDCl3) d: 3.85 ppm (bs,
1H, OH); 4.79 ppm (s, 3H, OCH3); 4.95 ppm (dd, 2H,
JFH ˆ 8.4 and 3.8 Hz, CH2) ppm. 19F NMR (CDCl3) d:
126.8 to 129.7 (2  dd, JFH ˆ 8.5 and 3.7 Hz, (Z)/
(E) ˆ 70/30) ppm.
‡
(Mr ˆ 221), m/z/% rel. int.: EI: 222/8 (M ‡ 1), 202/5
(M F), 192/7, 186/15 (M Cl), 156/2, 136/2 (M C5H11N),
112/100, 107/6, 84/23, 70/7, 69/54, 56/15, 55/11, 42/16,
41/42.
3.13.4. 4-Chloro-3-fluoro-2-(trimethylsilyloxy)furan (19)
A mixture of butenolide 13 (100 mg, 0.73 mmol), tri-
methylchlorosilane (100 mg, 1 mmol) a dry tetrahydrofuran
(3 ml) in a ¯ask under argon atmosphere was cooled to
1058C to
1158C. A solution of LDA (130 mg,
0.73 mmol, 1.5 M solution in n-hexane) in tetrahydrofuran
(3 ml) was slowly added to the ¯ask while stirring. After
15 min of the addition, a sample of the reaction mixture
was rapidly withdrawn by a pre-cooled syringe, put in
cooled NMR test tube and the 19F NMR spectrum
was taken while cooling. The reaction temperature was
stepwise increased and the NMR analysis carried out.
The content of the unstable compound 19 at various
temperatures is shown in Table 2. After 45 min
reaction at 758C, the mixture was neutralized with
acetic acid, the solution was rapidly concentrated at
room temperature on rotary evaporator and the residue
subjected to column chromatography (silica gel 10 g,
dichloromethane/petroleum ether 5/2) to afford the
starting butenolide 13 (65 mg) as the only identi®able
3.13.2. Reaction with methanol:
3-chloro-2-fluoro-3-methoxybutan-4-olide (16)
A mixture of butenolide 13 (50 mg, 0.37 mmol) and
anhydrous methanol (2 ml) was re¯uxed under dry atmo-
sphere for 24 h when the conversion of 13 was ca. 40% (19F
NMR). Methanol was removed on rotary evaporator and
the dark residue was chromatographed on silica gel (see
compound 15) to obtain not completely pure 16 (ca. 70%,
GC±MS), calculated yield ca. 15%. 19F NMR (CDCl3) d:
116.4 (ddd, JFH ˆ 38.2, 3.0 and 2.8 Hz) ppm. MS
Table 2
Temperature dependence of the content of 19 in the reaction mixture
Reaction
Temperature
Content
‡
time (min)
(8C)
of 19 (%)
(Mr ˆ 168), m/z/% rel. int.: EI: 168/13 (M ), 153/15
(M CH3), 135/84 (M CH3O), 133/24, 109/54, 107/33,
101/100 (M CH3OHCl), 91/7, 89/13, 87/11, 81/19, 79/
35, 73/40, 71/17, 61/27, 59/35, 57/25, 53/14, 45/54, 44/
19, 31/62.
15
30
115
78
ꢀ0
32
51
5
45
75
180
‡17

156
O. Paleta et al. / Journal of Fluorine Chemistry 102 (2000) 147±157
compound. 19F NMR (CDCl3) d: 191.9 (d, JFH ˆ 3.6 Hz)
Ministry of Education of the Czech Republic (Project
LB98233). The authors thank heartily to Dr. V. Kubelka
for kind assistance in assignment of some MS spectra.
ppm.
3.14. Reactions of butenolide 13 with soft phosphorus
nucleophiles
References
3.14.1. Reaction with triethyl phosphite
(products 20 and 21)
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Â
A ¯ask containing a mixture of butenolide 13 (50 mg,
0.367 mmol) and triethyl phosphite (200 mg, 1.2 mmol)
was connected to a source of constant vacuum of
100 mm Hg (13.3 kPa) to remove volatile reaction products.
The mixture was heated at 808C for 24 h and at the end the
composition of the mixture was the following (GC±MS): 13
(20%), 20 (diethyl 4-[3-¯uoro-2(5H)-furanonyl]-phospho-
nate, 16%), 21 (diethyl 4-[3-¯uoro-2(5H)-furanonyl]-2-
(triethoxy¯uorophosphoranyl)-phosphonate, 25%), (prob-
ably 3-chloro-3-ethoxy-2-¯uorobutan-4-olide, 11%) and
unidenti®ed compounds. The mixture was concentrated
on rotary evaporator and chromatographed on silica gel
(see compound 17) to obtain not completely pure mixture of
compounds 20 and 21 that was analyzed by 19F NMR and
GC±MS. 20: 19F NMR (CDCl3) d: 143.6 ppm (dt,
ÂÏ Â
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Â
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Â
1
JFH ˆ 5.1 Hz, JFP ˆ 2 Hz; decoupling H: d, JFP ˆ 2 Hz)
Â
 ÂÏ
[13] M. Semonsky, V. Zikan, B. Kakac, V. Jelõnek, Collect. Czech. Chem.
‡
ppm. MS (Mr ˆ 237), m/z/% rel. int.: EI: 237/0.3 (M ), 223/
Commun. 35 (1970) 96.
 ÂÏ
[14] V. Zikan, L. Vrba, B. Kakac, M. Semonsky, Collect. Czech. Chem.
Â
2 (M C2H4), 211/17, 193/6, 191/7, 183/100, 165/35, 153/
18, 128/6, 125/8, 112/10, 109/14, 101/11, 91/7, 82/10, 81/
22, 76/3, 65/19, 56/9, 47/18, 45/22, 31/10. 21: MS
Commun. 37 (1972) 1091.
Ï
[15] A. Posta, O. Paleta, I. Hemer, Collect. Czech. Chem. Commun. 32
(1967) 2301.
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Ï Â
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‡
(Mr ˆ 384), m/z/% rel. int.: EI: 384 (M ), 369/10, 356/43
Ï
(M C2H4), 328/21 (M 2C2H4), 300/26 (M 3C2H4), 282/
10, 272/38, 256/15, 255/16, 244/100, 227/51, 215/10, 199/
30, 187/23, 169/21, 164/12, 135/35, 107/18, 89/9, 81/19, 65/
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(1968) 2970.
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A
 Ï
[22] Z. Chvatal, V. Dedek, J. Fluorine Chem. 29 (1985) 149.
solution of tributylphosphane (85%, 100 mg,
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Ï Ï
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0.421 mmol) in dry diethyl ether (2 ml) was dropwise added
through septum to a stirred mixture of butenolide 13 (50 mg,
0.367 mmol) and diethyl ether (4 ml) at 758C under argon.
The mixture was stirred for 30 min at 758C, then let to
warm to room temperature and stirred overnight. The con-
tent of the product 22 (tributyl 4-[3-¯uoro-2(5H)-furano-
nyl]phosphonium chloride ca. 19%), that decomposed at
daily light, was checked by 19F NMR. The mixture was
concentrated on rotary evaporator and the crude product
containing tributylphosphane analyzed. 19F NMR (CDCl3)
d: 146.5 ppm (dt, JFH ˆ 5.6 Hz, JFP ˆ 2.5 Hz; decoupling
1H: d, JFP ˆ 2.5 Hz) ppm. MS (Mr ˆ 182), m/z/% rel. int.:
(1970) 1302.
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Á
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È
[34] H. Wessolowski, G.L. Gard, G.-V. Roschenthaler, J. Fluorine Chem.
‡
EI: 327/0.2 (M ), 281/0.6, 225/0.4, 202/10, 173/26, 147/10,
131/16, 118/18, 104/29, 76/100, 62/66, 55/21, 39/32.
80 (1996) 149.
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Acknowledgements
The research was supported by the Grant Agency of the
Czech Republic (grant 203/96/1057) and the grant of the
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Naumov, Izv. Akad. Nauk SSSR Ser. Khim. 36 (1987) 2373.

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1427.