Synthesis of 5-alkyl-3,4-difluorofuran-2(5H)-ones by lactonisation. Effects of substituents on cyclisation ability of fluorinated 4-hydroxyalkanoates. DFT calculations of the cyclisation energies

Article abstract of DOI:10.1016/j.jfluchem.2014.03.009

5-Alkyl-3,4-difluorofuran-2(5H)-ones were synthesised starting with radical addition of ethers to methyl 2,3,3-trifluoroprop-2-enoate, followed by alkyloxy bond cleavage, acid-catalyzed lactonisation and dehydrofluorination. For a study of substituent effects on lactonisation, methyl 4-bromo-2-chloro-2- fluorodecanoate and 2-chloro-2-fluoro-4,4-dimethoxybutanoate based on radical additions of methyl 2-bromo-2-chloro-2-fluoroacetate to oct-1-ene or vinyl acetate were prepared. DFT calculations of the transition state energies of the exo-trig cyclisations confirmed the observation that the ring closure became more feasible with increasing number of alkyls at C4 of the fluorinated 4-hydroxyesters.

Full text of DOI:10.1016/j.jfluchem.2014.03.009

Journal of Fluorine Chemistry 162 (2014) 45–59
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of 5-alkyl-3,4-difluorofuran-2(5H)-ones by lactonisation.
Effects of substituents on cyclisation ability of fluorinated
4-hydroxyalkanoates. DFT calculations of the cyclisation energies
a
a
a
a,
Jan Hajduch a,b, Zdenek Duda , Jirı Beran , Jaroslav Kvıcala , Oldrich Paleta
*
ˇ
ˇ´
´ˇ
ˇ
a
´
Department of Organic Chemistry, Institute of Chemical Technology Prague, Technicka 5, 166 28 Prague 6, Czech Republic
b Institute of Organic Chemistry and Biochemistry, Academy of Sciences, 16610 Prague 6, Czech Republic
A R T I C L E I N F O
A B S T R A C T
Article history:
5-Alkyl-3,4-difluorofuran-2(5H)-ones were synthesised starting with radical addition of ethers to
methyl 2,3,3-trifluoroprop-2-enoate, followed by alkyloxy bond cleavage, acid-catalyzed lactonisation
and dehydrofluorination. For a study of substituent effects on lactonisation, methyl 4-bromo-2-chloro-
2-fluorodecanoate and 2-chloro-2-fluoro-4,4-dimethoxybutanoate based on radical additions of methyl
2-bromo-2-chloro-2-fluoroacetate to oct-1-ene or vinyl acetate were prepared. DFT calculations of the
transition state energies of the exo-trig cyclisations confirmed the observation that the ring closure
became more feasible with increasing number of alkyls at C4 of the fluorinated 4-hydroxyesters.
ß 2014 Elsevier B.V. All rights reserved.
Received 22 January 2014
Received in revised form 19 March 2014
Accepted 22 March 2014
Available online 1 April 2014
Keywords:
Methyl 2,3,3-trifluoroacrylate
Regioselective radical addition
Photo-induced addition
Dehydrofluorination
5-Alkyl-3,4-difluorofuran-2(5H)-ones
5-Alkyl-3-fluorofuran-2(5H)-ones
Exo-trig lactonisations
DFT lactonisation energy
1. Introduction
fluorinated L-ascorbic acids for biomedical studies has been
reported [9]. From this point of view, 5,5-dialkyl-3,4-difluoro-
furan-2(5H)-ones (3) can be understood as analogues of 1 or 2.
Similarly, 5-alkyl-3,4-difluorofuran-2(5H)-ones (4) are analogues
of 1 and 2 and, in addition, they are potential novel synthetic
intermediates. These compounds had not been synthesised so far
and research of their synthesis has been the aim of this publication.
2-Fluoro- or 2,3-difluoro-a,b-unsaturated oxo compounds and
esters belong to useful synthetic intermediates, which enable to
synthesise various types of fluorine-containing compounds, e.g.
[1]. 3-Fluoro- or 3,4-difluorofuran-2(5H)-ones (formally 2-fluoro-
or 2,3-difluorobut-2-enolides) as
a type of a,b-unsaturated
systems can be utilised in an analogous way by nucleophilic
additions or vinylic substitution of fluorine: Podophyllotoxin
analogs were synthesised starting with 2-fluorobut-2-enolide
[2], the fluorobutenolide cycle was modified by nucleophilic
rearrangement [3] or nucleoside analogues possessing fluorobu-
tenolide ring were prepared [4].
Fluorine atom as a substituent usually mimics hydroxy group
[5] in bioactive compounds and frequently introduces new
bioactivity, e.g. [6]. Tetronic (1) and ascorbic (2) acids belong to
numerous bioactive natural butenolide derivatives [7]. Their
analogues and derivatives have displayed interesting pharmaceu-
tical properties [8]. The preparation of 2-fluorotetronic and
2. Results and discussion
2.1. Syntheses of 2,3-difluorobut-2-enolides
On the basis of our recent positive experience [10], we started
the syntheses of the target products 4 (Fig. 1) with the radical
addition of primary alkanols to trifluoroacrylate (6). The reaction is
depicted in Scheme 1 and the results are summarised in Table 1. In
the course of the radical additions of alkanols, the
relatively to the hydroxyl group were cleaved specifically and the
intermediate radicals added specifically to the -carbon of the
a-bonds C–H
b
trifluoroacrylate. However, the radical additions (products 7–11)
were accompanied with nucleophilic additions (adducts 12–15),
which were dominant for ethanol (13, 60% rel.) and exclusive for
methanol (12, 100% rel.). The portions of the nucleophilic additions
*
Corresponding author. Tel.: +420 22044 4284; fax: +420 22044 4288.
E-mail address: Oldrich.Paleta@vscht.cz (O. Paleta).
http://dx.doi.org/10.1016/j.jfluchem.2014.03.009
0022-1139/ß 2014 Elsevier B.V. All rights reserved.

46
J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
HO
OH
Table 1
OH
HO
Products of the addition of alkan-1-ols to trifluoroacrylate (6) under radical
initiation.
O
O
O
HO
O
1
R
Radical addition
% rel.
Nucleophilic addition
% rel.
2
ascorbic acid
tetronic acid
H
7
0a,b
40a,b
12
13
14
15
0a, 100b
60a,b
42a, 55b
19a, 29b
Me
Et
8
F
F
F
F
F
9
58a, 45b
81a, 71b
R
Hept
11
O
O
R
O
O
3
R
O
O
R
a
UV.
b
5
4
DBP/AIBN.
Fig. 1. Fluorinated analogues of tetronic and ascorbic acids.
The resulting 4-hydroxyalkanoates 7–11 (Scheme 1) were
obtained in moderate to good isolated yields (55–83%) (Table 3).
Methyl 2,3,3-trifluoro-4-hydroxyalkanoates 8–11 appeared to
be relatively stable compounds that could be distilled or purified
by column chromatography on silica gel. This behaviour is in sharp
contrast with their 4-alkylated analogues, which cyclised sponta-
neously in solution when formed [10]. In light of the Baldwin
predictions [15] the cyclisation of the 4-hydroxyesters should be
easy. However, no cyclisation occurred by a long term treatment of
8–11 with conc. hydrochloric acid in methanol. A successful
cyclisation was achieved using p-toluenesulfonic acid in boiling
toluene. Difficult cyclisation was observed formerly for 5,5-
difluoro-4-hydroxypentanoate [16] probably due to a lowered
nucleophilicity of the hydroxylic oxygen (Table 4).
The formation of the main cyclisation products 27–30,
butanolides (dihydrofuranones) was accompanied by small
amounts of the corresponding but-2-enolides (2(5H)-furanones)
31–34, probably formed by thermal dehydrofluorination from the
precursors 27–30. The target difluorobutenolides 31–34 were
obtained by dehydrofluorination of trifluorobutanolides 27–30
using triethylamine at r.t. (Table 5, [17]).
were decreasing with the chain length (Table 1). This result is in a
contrast with the radical additions of alkanols to tetrafluoroethene
[11], hexafluoropropene [12] or 3,3-difluoroacrylate [13], where
no products of nucleophilic additions were observed. The mixtures
of the pairs of products 7–11 and the corresponding 12–15 were
inseparable and therefore not employed in syntheses.
To avoid nucleophilic additions, aliphatic ethers were employed
instead of alkanols (Scheme 1). The additions occurred at the
a-
positions relatively to the oxygen bridge (products 16–21). In
unsymmetrical ethers, higher alkyls were more reactive than the
methyl group (products 22–23, Table 2). The intermediate
alkoxymethyl radicals 22a–23a leading to the minor products
22–23 were very likely formed by the 1,3-hydrogen shift (Scheme
2) [14]. The monoadditions were accompanied by the additions of
both
a-bonds C–H to the acrylate (products 24–26, Table 2). To
suppress the double additions, the molar ratio ether/trifluoroa-
crylate should be 20/1 and higher. The additions of ether radicals
were also completely regioselective to the
b-carbon of the
trifluoro-acrylate. Completely unsuccessful were attempts to carry
out additions of ethers containing phenyl ring, e.g. anisole,
phenetole or benzyl methyl ether, where, very likely, aromatic
cycle caused quenching of the primary radicals. Completely
unreactive was also methyl neopentyl ether due to steric reasons.
The cleavage of the ether linkage in 4-alkoxy-2,3,3-trifluor-
oalkanoates 16–21 was carried out using boron tribromide at r.t.
We attempted to synthesise difluorofuranones possessing
functionalised alkyl at the 5-C. The results are summarised in
Scheme 3. Radical addition of 2,2-dimethyl-1,3-dioxolane to
trifluoroacrylate afforded the expected 1:1 adduct 35 in good
yield (UV 65%, DBP/AIBN 75%). Its hydrolysis by HCl in refluxing
methanol gave 4,5-dihydroxypentanoate 36 (yield 46%), but no
butanolide.
R1
CF2 CHF-CO2Me
initiation
R2 = H
R1 CH2
R1 CH2
O
CF2-CHF-CO2Me
12-15
+
O
CF2=CF-COOMe
+
R2
7-11
OH
6
7, 12, R1 = H
8, 13, R1 = Me
9, 14, R1 = Et
10,
R1 = Pr
11, 15, R1 = Hept
R2 = alkyl
initiation
TsOH
BBr3
R1
CF2 CHF-CO2Me
O-R2
16-21
R2 = Me, Et, Pr, Bu, Hept
F
F
F
F
F
+
+
1
R1
R1
-CH -O-CH -CF -CHF-CO Me
R
O
O
2
2
2
2
O
O
R1 = Pr, Hept
22,23
27-30
31-34
+
NEt3
MeO2CCHFCF2 CF2CHFCO2Me
27, 31, R1 = Me 29, 33, R1 = Pr
28, 32, R1 = Et 30, 34, R1 = Hept
R1
O
R1
24-26
16, R1 = Me, R2 = Et; 17 (Me, t-Bu); 18 (Et, Pr);
19 (Pr, Me); 20 (Pr, Bu); 21 (Hept, Me)
R1 = Me (24), Et (25), Pr (26)
Scheme 1. Overview of syntheses of 5-alkyl-3,4-difluorofuran-2(5H)-ones from aliphatic components.

J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
47
Table 2
Addition of dialkyl ethers to trifluoroacrylate (6) under UV or radical initiation (Scheme 1).
Entry
R1
R2
Initiation
T (8C)
Time (h)
Main product
R1
By-product
%
% rel.
1
2
3
Me
Me
Et
Et
UV
20
70
70
20
70
90
90
8
16
10
14
12
10
12
16
17
18
19
19
20
21
Me
Me
Et
51
56
62
57
65
58
49
24
–
42
–
t-Bu
Pr
DBP/AIBN
DBP/AIBN
UV
25
22
22
26
23
24
11
17
29
14
4a
4b
5
Pr
Me
Pr
DBP/AIBN
DBP/AIBN
DBP/AIBN
Pr
Pr
Bu
Pr
6
Hept
Me
Hept
2.2. Effects of substituents on cyclisation
H
H
H
.
initiation
CH
3(CH2)n
CH3(CH2)n
C
H
O
CH2
CH2
O
CH
Difficult cyclisation of 2,3,3-trifluoro-4-hydroxyesters 7–11
could be caused by a lowered nucleophilicity of the hydroxy
oxygen due to the neighbour C-F bonds. To verify this effect we
attempted to prepare 5-alkyl-3-fluorofuran-2(5H)-one (5, Scheme
4) or 5-alkyl-3-chloro-3-fluorofuran-2(5H)-one (53, Scheme 5)
possessing the 3-CH2 moiety. The attempted synthesis of 5 started
with regiospecific radical addition of methyl bromochlorofluor-
oacetate to oct-1-ene to afford 4-bromo-2-chloro-2-fluorodecano-
ate (47, 51%, Scheme 4). Its transformation to 2-chloro-2-fluoro-4-
hexyl-butanolide (49) was carried out in two ways: (1) the adduct
47 was refluxed in aqueous methanol and hydrochloric acid to be
completely converted to 49 in 80 h (yield 70%); (2) the adduct 47
was hydrolysed to sodium salt 48, which on heating in DMSO [17]
afforded 49 (raw yield 82%). Dehydrochlorination of 49 by a series
of agents (triethylamine, DABCO, DBU, potassium fluoride,
potassium hydroxide, sodium carbonate, tert-butoxide) in various
solvents (diethyl ether, tetrahydrofuran, DMF, DMSO, acetonitrile
or toluene) was not successful, usually a rich mixtures of products
were obtained.
In attempted synthesis of butanolide 53, regiospecific radical
addition of methyl bromochlorofluoroacetate to vinyl acetate was
used to afford 4-acetoxy-4-bromo-2-chloro-2-fluorobutanoate
(50, yield 70%, Scheme 5). The yield of the 1:1 adduct was
sensitive to the reaction temperature, at 100 8C telomers were
obtained only. The adduct 50 was first transformed to the
corresponding dimethyl acetal 51 and subsequently to the free
acid 52. We attempted to transform the all three compounds 50–
52 to 2-chloro-2-fluoro-4-methoxybutanolide (53) using hydro-
chloric, polyphosphoric or p-toluenesulfonic acid in various
solvents unsuccessfully: or the substrates were unreactive, or
mixtures of products or polymers were obtained. This result is in a
sharp contrast with easy lactonisations of acetalised 4-oxobu-
tanoate moieties (also as a part of cyclic or saccharide structures)
under an acid catalysis [18].
major
1,3-H-shift
H
.
CH3(CH2)n
minor
C
H
O
CH2
22a-23a
Scheme 2. Rearrangement of intermediate ether radicals.
Lactonisation of dihydroxypentanoate 36 proceeded as in
Scheme 1 under the catalysis of p-toluenesulfonic acid in refluxing
toluene (Scheme 3) to give a mixture of the products 37–40: both
hydroxy groups participated in the lactonisation to afford 5-(37,
39) and 6-membered lactones (38, 40), the latter being highly
prevailing. The saturated lactones 37–38 were transformed to the
corresponding unsaturated ones 39–40 (Scheme 3) by triethyla-
mine as above.
The transformation of tetrahydrofuran to 5-(halogenoalkyl)fur-
anones 44 and 45 (Scheme 3) was successful: the only radical
adduct 41 was specifically cleaved by boron tribromide to 7-
bromo-4-hydroxyheptanoate (42). The lactonisation of 42 to 43
and subsequent dehydrofluorination of 43 to difluorofuranones 44
and 45 were realised in usual way (Scheme 3).
Table 3
Cleavage of the C–O linkage in 4-alkoxyalkanoates (16–21) using BBr3.
4-Alkoxyester
R1
Time (h)
Product
R2
R1
%
16
Me
Me
Et
Et
3
8
5
3
7
3
8
8
Me
Me
Et
83
55
70
74
61
68
17
18
19
20
21
t-Bu
Pr
An overview on lactonisation reactions is given in Table 6. The
lactonisations in entries 1 and 2a are nucleophilic substitution of
chlorine by carboxylate oxygen, which is easier at the primary
carbon in 54 than in 47. A dramatic difference in lactonisation
ability is met for the comparable structures 56 and 7–11 (entries 3
9
Pr
Me
Bu
10
10
11
Pr
Pr
Pr
Hept
Me
Hept
Table 4
Table 5
Lactonisation of 4-hydroxyesters 8–11.
Dehydrofluorination of butanolides using NEt3.
4-Hydroxy-
ester
Time (d)
Products
Butanolide
Time (h)
Butenolide
a
%
Butanolide
Butenolide
27
28
29
30
43
Me
1
1
1
1
1
31
32
33
34
44
92
96
89
93
88
%rel.
94
%rel.
Et
8
9
Me
10
8
27
28
29
30
31
32
33
34
6
5
9
8
Pr
Et
95
91
92
Hept
Br(CH2)3
10
11
Pr
8
Hept
2
a
Total isolated yield.

48
J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
F
F
F
F
F
HO
F
21% + 60% rel.
+
6
O
O
O
+
HO
O
initiation
O
O
O
37
38
NEt3
CF2 CHF-CO2Me
CF2 CHF-CO2Me
33% rel. 67% rel.
conc.HCl
OH
HO
O
TsOH
F
36
F
F
35
8% + 11% rel.
HO
F
+
HO
O
O
O
O
39
40
O
O
+
6
initiation
F
F
CF2 CHF-CO2Me
F
CF2 CHF-CO2Me
88%
Br
42
Br
BBr3
OH
F
TsOH
41
O
O
43
75%
72-75%
NEt3
F
F
F
NaI
Br
I
O
O
O
O
44
45
88%
95%
Scheme 3. Overview of syntheses of 5-alkyl-3,4-difluorofuran-2(5H)-ones using starting cyclic ethers.
and 4): while 4,4-dialkylated alkanoates 56 cyclise spontaneously,
the monoalkylated analogues 7–11 require several-days refluxing
under acid catalysis. In contrast, the compounds 50–52 as close
analogues of 42 and functional derivatives of 2-chloro-2-fluoro-4-
oxobutanoic acid at the same time did not afford the corresponding
4-methoxybutanolides.
the respective representatives of the non-cyclizing and easily
cyclizing hydroxy ester. As the experimental cyclisations were
performed under strongly acidic catalysis (TsOH) in non-polar
toluene, the role of the solvent was neglected and the computa-
tions were performed for gas-phase approximation. Lactoniation of
hydroxy esters is a type of transesterification [19].
We started the study with conformational search of fluorobu-
tanoate 7 (Table 6). We concentrated on the potential key step, i.e.
nucleophilic addition to protonated species 7H+, and hence first
decided to find its most stable conformation. Due to multiple
substituent fluorine atoms, around 60 conformers were taken into
account. In contrast to the expected anti conformer 7AH+, the
3. DFT calculations on lactonisation
For fluorinated hydroxycarboxylic acid with varied substitution
on the C4 of the carbon chain, striking differences in the ability to
cyclise prompted us to start a theoretical study of the lactonisation.
We chose methyl 2,3,3-trifluoro-4-hydroxybutanoate (7) and
methyl 2,3,3-trifluoro-4-hydroxy-4-methylpentanoate (56a) as
BrCClF COOMe
+
F
AcO
DBP, 80°C
46
BrCClF COOMe
+
C6H13
DBP, 90 °C
46
Cl
+
[H ]
AcO
O
Cl
F
OMe
Br
50
[H+]
C6H13
O
HCl(g) CH OH
OMe
Br
Cl
Cl
O
F
F
47
Cl
O
F
+
[H ]
CH3O
O
Cl
F
O
CH O
O
R
CH3O
OMe
53
C6H13
O
+
51
DMSO
49
[H ]
ONa
Br
Cl
F
F
48
+
[H ]
CH3O
O
R = C6H13
O
R
O
CH3O
OH
52
5
Scheme 5. Attempts to synthesise 2-chloro-2-fluoro-4-methoxybutan-4-olide (53).
Scheme 4. Synthesis of 2-chloro-2-fluoro-4-hexyl butan-4-olide (49).

J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
49
Table 6
Overview on the lactonisation of 4-hydroxy- or/and 4-halogenoalkanoates to form butan-4-olides (furan-2(5H)-ones).
Entry
1
Starting compound
Reaction conditions
Product(s)
Character of cyclisationa
Moderately easy
Refs.
[17]
200 8C ! 89%
Cl
Cl
Cl
Cl
F
F
DMSO, 40 8C, 8 h ! 41%
O
O
F
Cl
O
ONa
54
55
Cl
2a
2b
Y = Na
Moderately easy difficult
Cl
F
DMSO, 80 8C, 3 h ! 82%
Y = CH3
O
R
HCl, H2O, CH3OH, reflux, 80 h ! 70%
O
R
O
OY
Cl
47-48
49
R = C6H13
R = C6H13
3
Spontaneously formed during photoaddition
Spontaneous
[10]
F
F
F
F
F
F
at 20 8C and work up
R2
R1
56
R2
R1
O
OMe
O
+
OH
O
57
R1, R2 = Me, Et
R1-R2 = (CH2)5
4
TsOH, toluene, reflux, 2–10 d ! 88–96%
Difficult
F
F
F
F
F
F
F
F
O
R
R1
R1
27-30
O
O
O
O
OH OMe
31-34
7-11
5-8% rel.
R = Me, Et, Pr,
Hept
5
6
TsOH, toluene, reflux, 10 h ! defined mixture
Non-regioselective
F
F
F
F
F
F
F
F
HO
F
+
O
HO
O
O
O
O
38
HO
37
OH OMe
36
Cl
21% rel.
60% rel.
HCl, H2O, CH3OH, r.t., 12 h ! mixture
Unidentified mixture of products
Unfavourable
F
AcO
O
OMe
Br
50
7
8
Various acids [H+], H2O, CH3OH, reflux
Unidentified mixture of products
Unidentified mixture of products
Unfavourable
Unfavourable
Cl
F
CH3O
CH3O
O
OMe
51
Cl
Various acids [H+], various solvents, reflux
F
CH3O
CH3O
O
OH
52
a
All cyclisations are of exo-trig character [15].
gauche conformer 7BH+ with the O–H–OH coordination proved to
be most stable (Fig. 2). Further we found that the next structure on
the potential lactonisation pathway, protonated monoalkylated
orthoester 7CH+, is not a minimum on the potential energy surface
(PES). Identical result was obtained when implicit solvent using
SCRF methodology was included.
Recent computational publications addressing acidic hydrolysis
of simple esters as ethyl acetate catalyzed with water-solvated
proton [20] or sulfuric acid [21] encountered analogous problems.
Instead of the traditional pathway including cationic intermedi-
ates, a ‘‘contact ion-pair’’ mechanism with neutral intermediates
and transition states transferring protons between substrate and a
catalyst was found to be energetically more favourable.
We found this approach to be perfectly applicable for our study.
In the calculations, we employed two acids, hydrogen fluoride and
methanesulfonic acid as a close substitute for 4-toluenesulfonic
acid.
The computed lactonisation pathway catalysed with the former
acid is depicted in Scheme 6. The reaction starts with coordination
of HF to hydroxyester 7 or 56A leading to the cluster 58A or 59A.
The respective relative Gibbs free energies found are 0.0 kJ/mol
(axial, anti), 27.3 kJ/mol (equatorial, anti), 30.3 kJ/mol (axial, syn)
and 52.8 kJ/mol (equatorial, syn). For these four conformations, the
whole reaction pathway according to Scheme 6 was computed.
Due to clarity, only the pathway starting from the most stable
conformer and giving transition states of lowest energies is

50
J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
H
O
‡
H
O
H
O
F
F
H
F
H
F
O
O
HF
H
F
F
F
HO
R
H
O
O
O
F
F
O
H
O
F
O
R
R
F
R
F
R
F
F
F
R
R
R
58A,59A
58B,59B
58C,59C
R = H (7,58),Me (56A,59)
‡
H
H
O
O
F
H
O
F
F
F
F
F
O
F
- HF
H
H
F
O
F
O
O
O
O
F
F
R
O
O
R
R
R
F
F
-MeOH
F
F
R
R
R
R
58F,59F
58E,59E
58D,59D
Scheme 6. ‘‘Contact ion-pair’’ mechanism of lactonisation catalyzed with HF.
depicted in Fig. 3. The simulated reaction continues from cluster
58A or 59A through cyclic transition state 58B or 59B, in which
simultaneously one hydrogen atom is transferred from HF to the
carbonyl group, while second hydrogen atom is moving from the
hydroxyl group to the fluorine atom of HF. The movement of both
hydrogens is accompanied by the attack of the hydroxy group to
the carbonyl forming ortholacton/HF cluster 58C or 59C. The
simulated reaction continues by recoordination of HF to the hydroxy
group of ortholacton and the methoxy group yielding cluster 58D or
59D. The removal of methanol from the ortholacton is analogously
accompanied by two hydrogen transfers from and to the fluorine
atom of HFtrough transition state58E or 59E and the whole reaction
pathway finishes with the formation of lactone and methanol
coordinated to HF (58F, 59F). Fig. 3 shows the potential energy
surfaces of the simulated lactonisation of both substrates 7, 56A.
A comparison of both potential energy surfaces indicates that
the energy of the first transition state plays negligible role in the
preference for the cyclisation of the more substituted hydroxyester
57A. Hence, it is the second part of the lactonisation process, i.e. the
energy of the transition state of the decomposition of ortholactone
cluster 59E and even more the stability of the product cluster 59F,
which seems to play the major role in the preferred lactonisation.
An analogous result was obtained when methanesulfonic acid was
included in the calculations similarly to sulfuric acid [21] (see the
Supporting information).
To summarise the calculations, in can be stated that
computational analysis confirmed experimentally observed
preference for the cyclisation of the more substituted hydro-
xyester 56A (Scheme 6).
All computations were performed using the Gaussian 09W
program [22] using the M06 functional [23] and SV(P) basis set
[24]. For visualisations, GaussView program [25] was employed.
Vibrational analysis was performed for all structures to obtain
their standard Gibbs energies and characterise them as minima or
transition states.
Fig. 2. Expected (7AH+) and found (7BH+) minimal energy conformations of
protonated ester 7.
4. Conclusions
The syntheses of 4-alkyl-2,3-difluorobut-2-enolides (5-alkyl-
3,4-difluorofuran-2(5H)-ones) were developed starting with radi-
cal additions of ethers to methyl trifluoroacrylate. 2-Chloro-2-
fluoro-4-hexylbutanolide was prepared using bromochlorofluor-
oacetate and oct-1-ene. DFT calculations of the transition state
energies of the exo-trig cyclisations of halogenated 4-hydroxyalk-
anoates were carried out and confirmed the observation that the
cyclisations become more feasible with increasing number of
alkyls at C4.
5. Experimental
5.1. General
Unless noted otherwise, all starting materials were obtained
from commercial suppliers and were used without further
purification. Asymmetric ethers were prepared by the Williamson
synthesis. Methyl 2,3,3-trifluoroacrylate (MTFA) was prepared
according to Ref. [10].
Fig. 3. Simulated HF-catalysed lactonisation of hydroxyesters 7 (cluster 58, blue full
line) and 56A (cluster 59, red dotted line). (For interpretation of the references to
colour in this figure legend, the reader is referred to the web version of this article).

J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
51
NMR spectra were recorded on a Varian 300 HC (1H, 300.1 MHz;
13C, 75.5 MHz; 19F, 276.5 MHz) instrument in CDCl3. Chemical
Diastereoisomer B: 1H NMR (CDCl3):
d
1.28 (d, 3H,
3JHH = 6.6 Hz), 3.06 (s, OH), 3.81 (s, 3H), 4.02–4.22 (m, 1H),
2
3
3
shifts
d
(ppm) are relative to tetramethylsilane (1H, 0.0 ppm),
5.22 (ddd, 1H, CHF, JHF = 46 Hz, JHF = 20 Hz, JHF = 1 Hz) ppm.
13C NMR (CDCl3): 15.1 (d, CH3,3JCF = 3 Hz), 54.0 (s, OCH3), 66.6
CDCl3 (13C, 77.0 ppm) or CFCl3 (19F, 0.0 ppm). For recording of 13
C
d
NMR spectra the pulse sequences APT or DEPT were used. Coupling
constants J are given in Hz. Mass spectra were recorded using a
combination of Hewlett Packard GC HP 5890 series II gas
(dd, CH,2JCF = 32, 2JCF = 25 Hz), 86.1 (dt, CF2,1JCF = 198,
1
2
2JCF = 30 Hz), 85.5 (ddd, CF2, JCF = 192 Hz, JCF = 37 Hz), 119.3
(dt, CHF, 1JCF = 254 Hz, 2JCF = 26 Hz), 166.6 (ddd, C55O,
chromatograph and
a
Hewlett Packard MS HP 5971 mass
2JCF = 24 Hz, 3JCF = 4 Hz), 166.2 (ddd, C55O,2JCF = 24 Hz,
3
spectrometer (70 eV, EI). The capillary column for GC was DB5-
MS. Purities of some compounds were measured using a Micromat
HRGC 412 (HNU-Nordion, capillary column NB-30). Infrared
spectra were recorded on a NICOLET 740 spectrophotometer.
3JCF = 10 Hz, JCF = 2 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ120.3 (dm,
2
2
1F, JFF = 266 Hz), 128.3 (dm, 1F, JFF = 266 Hz), ꢀ204.0 (dm, 1F,
2JHF = 45 Hz) ppm.
Methyl 3-ethoxy-2,3,3-trifluoropropanoate (13). 1H NMR
3
(300.1 MHz, CDCl3):
d
1.28 (t, 3H, JHH = 7.2 Hz), 3.85 (s, 3H),
3
2
5.2. Radical addition of alcohols to MTFA (6)
4.00 (q, 2H, JHH = 7.2 Hz), 4.96 (dt, 1H, CHF, JHF = 46.3 Hz,
3JHF = 5.5 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ81.3 (ddd, 1F,
5.2.1. General procedures
2JFF = 144.8 Hz, 3JFF = 11 Hz, 3JHF = 4.9 Hz), ꢀ83.1 (ddd, 1F,
3
3
Typical procedure A: MTFA (6, ca. 500 mg, 3.6 mmol) and alcohol
(ca. 68 mmol) were added to an UV cuvette (5 mL). After bubbling
nitrogen into the cooled (ꢀ50 8C) solution for 15 min, it was
irradiated until full conversion of MTFA was observed (monitored
by GC). The excess alcohol was evaporated or distilled off and
CH2Cl2 (15 mL) was added to the residue. The mixture was washed
twice with saturated water solution of NaHCO3 (10 mL). The
organic layer was dried over MgSO4, filtered and CH2Cl2 was
evaporated. The crude product was purified by column chroma-
tography (silica gel 20 g, CH2Cl2).
Typical rocedure B: Nitrogen was bubbled into a mixture of MTFA
(ca. 500 mg, 3.6 mmol) and alcohol (ca. 68 mmol) cooled to ꢀ20 8C
for ca. 15 min. Dibenzoyl peroxide (DBP) and AIBN (2 mol%/2 mol%
ratio)wereadded and themixturewasheated at 65 8Cuntilcomplete
conversionofMTFAwasobserved (monitoredby GC). Thefinal work-
up of the reaction mixture was the same as in procedure A.
2JFF = 144.7 Hz, JFF = 14.8 Hz, JHF = 6.0 Hz), ꢀ202.6 (ddd, 1F,
2JHF = 52.7 Hz, JFF = 19.3 Hz, JFF = 17 Hz) ppm. GC–EIMS: m/z
(rel. int.): 185 (19) [M ꢀ 1]+, 155 (6.1), 149 (10.5), 133 (9.4), 123
(19), 115 (9), 105 (14), 93 (100), 75 (31), 57 (58).
3
3
5.2.4. Reaction of MTFA with propanol: Products 9 and 14
Procedure A: MTFA (480 mg, 3.43 mmol), propan-1-ol (4.10 g,
68.3 mmol), 13 h, product as a mixture of 9 and 14 (518 mg,
2.59 mmol, 75.6%), ratio 9/14 = 58/42.
Procedure B: MTFA (512 mg, 3.66 mmol), propan-1-ol (4.04 g,
67.3 mmol), 12 h, product as a mixture of 9 a 14 (626 mg,
3.13 mmol, 85.6%), ratio 9/14 = 45/55. C7H11F3O3 (200.16) (9 + 14):
calcd C 42.00, H 5.54; found C 42.10, H 5.48.
Methyl 2,3,3-trifluoro-4-hydroxyhexanoate (9). Diastereoisomer
A: 1H NMR (CDCl3):
d
1.01 (t, 3JHH = 7.4 Hz), 1.46–1.92 (m, 2H), 2.84
2
(s, OH), 3.82 (s, 3H), 3.79–3.94 (m, 1H), 5.17 (ddd, JHF = 45.6 Hz,
3
3JHF = 20.3 Hz, JHF = 3.3 Hz) ppm. 13C NMR (CDCl3):
d 9.6 (s, CH3),
2
5.2.2. Reaction of MTFA with methanol: Product 12
21.95 (s, CH2), 52.97 (s, OCH3), 71.13 (dd, JCF = 28.7 Hz,
2JCF = 29.8 Hz, CHOH), 84.81 (ddd, ds2, 1JCF = 191.8 Hz,
Procedure A: MTFA (488 mg, 3.49 mmol), methanol (2.20 g,
68.8 mmol), 6 h, no reaction occurred (monitored by 19F NMR).
Procedure B: MTFA (501 mg, 3.58 mmol) and methanol (2.02 g,
63.1 mmol), 10 h, gave product 12 (527 mg, 3.06 mmol, 85.5%). For
analysis see [26].
1
1
2JCF = 30.4 Hz, CHF), 118.56 (ddt, JCF = 265.6 Hz, JCF = 269.1 Hz,
2
2JCF = 25.8, CF2), 165.32 (d, JCF = 23.4 Hz, C55O) ppm. 19F NMR
(CDCl3):
d
ꢀ115.65
(ddt,
1F,
2JFF = 267.2 Hz,
3JHF = 4.6 Hz,3JFF = 3JHF = 12.2 Hz), ꢀ125.28 (ddt, 1F, 2JFF = 266.1 Hz,
Methyl 2,3,3-trifluoro-3-methoxypropanoate (12): 1H NMR
3JHF = 18.6 Hz,3JFF = 3JHF = 7.7 Hz), ꢀ207.15 (ddd, 1F, 2JHF = 46.5 Hz,
3
(CDCl3):
2JHF = 46.7 Hz, JHF = 4.4 Hz) ppm. 13C NMR (CDCl3):
CH3O, 3JCF = 6.6 Hz), 52.96 (s, CH3O), 85.59 (ddd, CHF,
d
3.61 (s, 3H, CH3O), 3.83 (s, 3H, CH3O), 4.96 (dt, 1H,
3JFF = 12.3 Hz, JFF = 8.5 Hz) ppm.
3
3
d
50.82 (t,
Diastereoisomer B: 1H NMR (CDCl3):
d
1.02 (t, JHH = 7.1 Hz),
1.46–1.92 (m, 2H), 3.06 (s, OH), 3.83 (s, 3H), 3.79–3.94 (m, 1H), 5.16
2
2
2
3
3
1JCF = 198.1 Hz, JCF = 37.8 Hz, JCF = 34.9 Hz), 119.54 (dt, CF2,
(ddd, JHF = 46.7 Hz, JHF = 12.1 Hz, JHF = 7.1 Hz) ppm. 13C NMR
(CDCl3): 9.6 (s, CH3); 21.78 (s, CH2), 52.89 (s, OCH3), 71.33 (dd,
2JCF = 24.6 Hz, JCF = 28.7 Hz, CHOH), 85.54 (dt, JCF = 195.2 Hz,
2
2
1JCF = 268.0 Hz, JCF = 23.5 Hz), 163.86 (d, C55O, JCF = 24 Hz) ppm.
d
19F NMR (CDCl3)
d
ꢀ84.1 (dd, 1F, JFF = 134.6 Hz, JFF = 3.9 Hz),
2
3
2
1
2 3
2
1
ꢀ86.2 (dd, 1F, JFF = 143.6 Hz, JFF = 5.9 Hz), ꢀ202.8 (d, 1F,
2JCF = 37.2 Hz, JCF = 29.2 Hz, CHF), 118.72 (dt, JCF = 239.9 Hz,
2JHF = 46.6 Hz) ppm.
2JCF = 22.9 Hz, CF2), 165.59 (dt, JCF = 21.1 Hz, JCF = 3.4 Hz,
2
2
C55O) ppm. 19F NMR (CDCl3):
d
ꢀ120.45 (dt, 1F, JFF = 267.3 Hz,
2
5.2.3. Reaction of MTFA with ethanol: Products 8 and 13
Procedure A: MTFA (491 mg, 3.51 mmol), ethanol (2.20 g,
68.8 mmol), 12 h, product as a mixture of 8 and 13 (503 mg,
2.70 mmol, 77.1%), ratio 8/13 = 37/67.
Procedure B: MTFA (496 mg, 3.54 mmol), ethanol (2.02 g,
63.1 mmol), 9 h, product as a mixture of 8 and 13 (469 mg,
2.52 mmol, 71.2%), ratio 8/13 = 41/59. C6H9F3O3 (186.13) (8 + 13):
calcd C 38.72, H 4.87; found C 38.89, H 4.90.
3JHF = 3JFF = 15.9 Hz),
ꢀ126.22
(ddt,
1F,
2JFF = 268.2 Hz,
3JHF = 20.6 Hz, 3JHF = 3JFF = 2.5 Hz), ꢀ203.91 (ddd, 1F, 2JHF = 45.7 Hz,
3JFF = 9.6 Hz, JFF = 4.0 Hz) ppm.
3
Methyl 2,3,3-trifluoro-3-propoxypropanoate (14). 1H NMR
3
(CDCl3):
d
0.92 (t, 3H, JHH = 7.1 Hz), 1.60–1.71 (m, 2H), 3.85 (s,
3
2
3H), 3.89 (t, 2H, JHH = 6.6 Hz), 4.97 (dt, 1H, CHF, JHF = 46.7 Hz,
3JHF = 4.9 Hz) ppm. 13C NMR (CDCl3):
10.01 (s, CH3), 22.31 (s,
d
3
CH2), 53.01 (s, OCH3), 65.99 (t, CH2O, JCF = 5.4 Hz), 85.82 (ddd,
1
Methyl 2,3,3-trifluoro-4-hydroxypentanoate (8). Diastereoisomer
CHF, JCF = 198.3 Hz, 2JCF = 38.6 Hz, 2JCF = 35.2 Hz), 119.38 (dt, CF2,
A: 1H NMR (CDCl3):
d
1.28 (d, 3H, 3JHH = 6.6 Hz), 3.06 (s, OH), 3.79 (s,
1JCF = 268.0 Hz, JCF = 23.5 Hz), 164.10 (d, C55O, JCF = 23.8) ppm.
2
2
2
3H), 4.02–4.22 (m, 1H), 5.06 (ddd, 1H, CHF, JHF = 48 Hz,
19F NMR (CDCl3):
d
ꢀ80.54 (ddd, 1F, 2JFF = 144.1 Hz, 3JFF = 12.2 Hz,
3
2
3
3JHF = 13 Hz, JHF = 1 Hz) ppm. 13C NMR (CDCl3):
d
15.4 (d, CH3,
3JHF = 4.9 Hz), ꢀ82.67 (ddd, 1F, JFF = 144.0 Hz, JFF = 14.6 Hz,
3JCF = 2 Hz), 53.6 (s, OCH3), 66.8 (dd, CH, 2JCF = 30 Hz, 2JCF = 25 Hz),
3JHF = 4.9 Hz), ꢀ202.16 (ddd, 1F, JHF = 47.6 Hz, JFF = 14.5 Hz,
3JFF = 12.2 Hz) ppm. GC–EIMS: m/z (rel. int.): 180 (0.5) [M ꢀ 20]+,
171 (6.4), 142 (1.8), 141 (33), 139 (4.6), 123 (10), 113 (9.2), 109
(1.4), 93 (2.3), 92 (27), 91 (7.3), 82 (13), 79 (1.4), 69 (3.2), 63 (5.5),
59 (47).
2
3
1
2
86.1 (dt, CF2, JCF = 198 Hz, JCF = 30 Hz), 119.2 (ddd, CHF,
1
2
1JCF = 252 Hz, JCF = 255 Hz, JCF = 22 Hz) ppm. 19F NMR (CDCl3):
2
2
d
ꢀ116.2 (dm, 1F, JFF = 266 Hz), ꢀ127.0 (dm, 1F, JFF = 266 Hz),
2
ꢀ207.2 (dm, 1F, JHF = 47 Hz) ppm.

52
J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
5.2.5. Reaction of MTFA with octan-1-ol: products 11 and 15
Procedure A: MTFA (488 mg, 3.49 mmol) and octan-1-ol (8.61 g,
66.3 mmol), 14 h; as product, a mixture of 11 and 15 (655 mg,
2.43 mmol, 69.6%), ratio 11/15 = 81/19.
Procedure B: MTFA (505 mg, 3.61 mmol) and octan-1-ol (9.12 g,
70.2 mmol), 11 h, as product, a mixture of 11 and 15 (724 mg,
2.68 mmol, 74.4%), ratio 11/15 = 71/29. C12H21F3O3 (270.29): calcd
C 53.33, H 7.83; found C 53.28, H 7.77.
7.62 mmol, 51.1%) and bis-adduct 24 (971 mg, 36.9%). Crystal-
lisation (hexane) afforded 22 mg of pure colourless crystals of bis-
adduct 24 (mp 80–82 8C) as the meso-form.
Methyl 4-ethoxy-2,3,3-trifluoropentanoate (16): Diastereoisomer
3
A: 1H NMR (CDCl3):
d
1.19 (t, 3H, JHH = 7.1 Hz), 1.29 (d, 3H,
3JHH = 6.1 Hz), 3.40–3.68 (m, 2H), 3.58–3.88 (m, 2H), 3.84 (s, 3H),
5.10 (ddd, 1H, 2JHF = 46.7 Hz, 3JHF = 12.1 Hz, 3JHF = 5.5 Hz) ppm. 13
NMR (CDCl3): 11.58 (dm, CH3), 15.1 (s, CH3), 2.7 (s, CH3), 65.6 (s,
CH2), 72.8 (dd, CH, JCF = 23.5 Hz, JCF = 29.8 Hz), 85.4 (ddd, CHF,
C
d
2
2
Methyl 2,3,3-trifluoro-4-hydroxyundecanoate (11). Diastereo-
3
2
2
isomer A: 1H NMR (CDCl3):
d
0.88 (t, 3H, JHH = 6.6 Hz), 1.18–
1JCF = 193.5 Hz, JCF = 29.2 Hz, JCF = 32.7 Hz), 118.2 (ddd, CF2,
1
2
1.86 (m, 12H), 2.28 (s, OH), 3.85 (s, 3H), 3.86–4.12 (m, 1H), 5.05–
5.45 (m, 1H) ppm. 13C NMR (CDCl3):
14.0 (s, CH3), 22.6–31.7 (m,
1JCF = 257 Hz, JCF = 249.6 Hz, JCF = 24.1 Hz), 165.0 (dd, C55O,
3
d
2JCF = 24.1 Hz, JCF = 6.9 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ113.7
6C, (CH2)6), 53.1 (s, CH3), 69.7–70.6 (m, CH), 85.7 (dt, CHF,
(ddt, 1F, 2JFF = 270.9 Hz, 3JFF = 12.2 Hz, 3JHF = 12.6 Hz, 3JHF = 5.1 Hz),
2
2
3
3
1JCF = 195.8 Hz, JCF = 30.3 Hz), 115.1–122.2 (m, CF2), 165.6 (d,
ꢀ125.0 (ddt, 1F, JFF = 269.8 Hz, JFF = 7.1 Hz, JFH = 6.7 Hz,
2
C55O, JCF = 21.7 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ115.7 (ddt, 1F,
3JFH = 17.3 Hz), ꢀ206.5 (ddd, 1F, JHF = 46.8 Hz, JFF = 12.6 Hz,
2 3
2JFF = 265.8 Hz, JHF = 12.0 Hz, JFF = 3JHF = 4.7), ꢀ125.4 (ddt, 1F,
3JFF = 7 Hz) ppm.
3
3
2JFF = 266.5 Hz, JHF = 18.5 Hz, JFF = 3JHF = 8.3 Hz), ꢀ207.10 (ddd,
Diastereoisomer B: 1H NMR (CDCl3):
d
1.16 (t, 3H, 3JHH = 7.1 Hz),
3
3
2
3
3
3
1F, JHF = 46.6 Hz, JFF = 12.4 Hz, JFF = 8.7 Hz) ppm.
1.29 (d, 3H, JHH = 6.1 Hz), 3.40–3.68 (m, 2H), 3.58–3.88 (m, 2H),
Diastereoisomer B: 1H NMR (CDCl3):
1.18–1.86 (m, 12H), 2.08 (s, OH), 3.87 (s, 3H), 3.86–4.12 (m, 1H),
5.05–5.45 (m, 1H) ppm. 13C NMR (CDCl3):
14.0 (s, CH3), 22.6–31.7
d
0.89 (t, 3H, 3JHH = 6.0 Hz),
3.87 (s, 3H), 5.24 (ddd, 1H, CHF, JHF = 45.6 Hz, JHF = 20.9 Hz,
3JHF = 2.7 Hz) ppm. 13C NMR (CDCl3):
11.8 (dm, CH3), 15.2 (s,
CH3), 52.8 (s, CH3), 65.6 (s, CH2), 72.7 (dd, CH, JCF = 25.2 Hz,
2
3
d
2
d
1
2
(m, 6C, (CH2)6), 53.0 (s, CH3), 69.7–70.6 (m, CH), 85.1 (ddd, CHF,
1JCF = 192.4 Hz, 2JCF = 36.7 Hz, 2JCF = 29.8 Hz), 115.1–122.2 (m, CF2),
2JCF = 30.9 Hz), 84.8 (ddd, CHF, JCF = 190.6 Hz, JCF = 28.1 Hz,
2JCF = 37.2 Hz), 118.5 (ddd, CF2, JCF = 255.2 Hz, JCF = 251.9 Hz,
1
1
2
165.2 (d, C55O, JCF = 25.2 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ120.3
2JCF = 23.5 Hz), 165.1 (d, C55O,2JCF = 24.7 Hz) ppm. 19F NMR
2
3
3
2
3
(ddd, 1F, JFF = 267.5 Hz, JHF = 16.6 Hz, JFF = 13.6 Hz), ꢀ126.2
(CDCl3):
d
ꢀ119.0 (dddd, 1F, JFF = 270.3 Hz, JFF = 12.4 Hz,
(ddd, 1F, JFF = 268.2 Hz, JFF = 3JHF = 6.7 Hz, JHF = 4.2 Hz), ꢀ203.8
3JHF = 19.7 Hz,
3JHF = 5.6 Hz) ppm;
ꢀ126.3
(dddd,
1F,
2
3
3
3
3
3
(dddd,
1F,
2JHF = 44.2,
3JFF = 16.7 Hz,
3JHF = 6.1 Hz,
2JFF = 268.9 Hz, JFF = 6.3 Hz, JFH = 4.6 Hz, JFH = 18.5 Hz), ꢀ203.8
4JHF = 2.4 Hz) ppm.
(dddd,
1F,
2JFH = 44.7 Hz,
3JFF = 13.2 Hz,
3JFF = 6.1 Hz,
Methyl 2,3,3-trifluoro-3-octyloxypropanoate (15). 1H NMR (MHz,
4JFF = 4.2 Hz) ppm. C8H13F3O3 (214.18): calcd C 44.86, H 6.12;
3
CDCl3):
d
0.86 (t, 3H, JHH = 6.1); 1.49–1.71 (m, 12H), 3.85 (s, 3H),
found C 44.93, H 6.23.
3.92 (t, 2H, 3JHH = 6.6 Hz), 4.96 (dt, 1H, 2JHF = 46.8 Hz,
3JHF = 5.8 Hz) ppm. 13C NMR (CDCl3):
14.0 (s, CH3); 25.5–31.7
(m, (CH2)6), 52.3 (s, CH3), 64.5 (t, CH2O, JCF = 5.7 Hz), 85.8 (ddd,
Dimethyl 4,40-oxybis(2,3,3-trifluoropentanoate) (24, meso-form).
d
1H NMR (CDCl3):
1H, JHF = 12.7 Hz, JHH = 6.5 Hz, JHF = 1.1 Hz), 5.43 (ddd, 1H,
2JHF = 45.6 Hz, 3JHF = 14.3 Hz, 3JHF = 7.2 Hz) ppm. 13C NMR (CDCl3):
d
1.33 (d, 3H, 3JHH = 6.6 Hz), 3.84 (s, 3H), 4.29 (dtq,
3
3
3
4
CHF,1JCF = 198.4 Hz, JCF = 38.4 Hz, JCF = 35.2 Hz), 119.4 (dt, CF2,
1JCF = 268.0 Hz, 2JCF = 23.8 Hz) ppm. 19F NMR (CDCl3):
2
2
2
d
ꢀ80.6 (ddd,
d
12.6 (d, CH3), 54.2 (s, OCH3), 73.4 (dd, CH, JCF = 24.4 Hz,
2
3
3
1
2
1F, JFF = 144.0 Hz, JFF = 11, JHF = 4.9 Hz), ꢀ82.7 (ddd, 1F,
2JCF = 30.9 Hz), 87.3 (dt, CHF, JCF = 192.6 Hz, JCF = 29.8 Hz), 120.3
3
3
1
1
2
2JFF = 144.1 Hz, JFF = 14.7 Hz, JHF = 6.1 Hz), ꢀ202.1 (ddd, 1F,
(ddd, CF2, JCF = 235.9 Hz, JCF = 244.7 Hz, JCF = 22.9 Hz), 166.4
(ddd, C55O, 2JCF = 23.8 Hz, 3JCF = 4.8 Hz, 3JCF = 3.2 Hz) ppm. 19F NMR
3
3
2JHF = 46.4 Hz, JFF = 14.7 Hz, JFF = 11 Hz) ppm. GC–EIMS: m/z
(rel. int.): 271 (10) [M + 1]+, 241 (19), 240 (11), 129 (9.2), 113
(19), 111 (17), 110 (14), 84 (18), 82 (19), 81 (14), 71 (76), 69 (40), 68
(22), 57 (100).
2
(CDCl3):
d
ꢀ114.3 (dm, 1F. JFF = 268.2 Hz), ꢀ133.6 (dddd, 1F,
2JFF = 268.1 Hz, JFF = 3JFH = 7.3 Hz, JFH = 16.6 Hz), ꢀ207.1 (dt, 1F,
CHF, 2JFH = 45.6 Hz, 3JFF = 10.1 Hz) ppm. GC–MS (EI): 355
(M+ + 1.2.4), 314 (0.5), 213 (0.5), 169 (100), 183 (0.4), 149
(15.3), 121 (0.8), 95 (2.4), 71 (4.0), 59 (2.3), 43 (4.0). C12H16F6O5
(354.24): calcd C 40.69, H 4.55; found: C 40.85, H 4.61.
3
3
5.3. Radical addition of ethers to MTFA
5.3.1. General procedure
Typical procedure A: MTFA (ca. 14 mmol) and ether (ca.
270 mmol) were placed into a UV reactor and the mixture was
purged with nitrogen at ꢀ50 8C for 15 min. and then irradiated.
After full conversion of MTFA (monitored by GC) the excess of the
ether was evaporated or distilled off and CH2Cl2 (15 mL) was added
to the residue. The mixture was extracted twice with saturated
water solution of NaHCO3 (10 mL). The organic layer was dried
over MgSO4, filtrated and CH2Cl2 was evaporated. The crude
product was distilled under vacuum or purified by column
chromatography.
Typical procedure B: MTFA (ca. 15 mmol) and ether (ca.
290 mmol) were placed into a three-necked flask and the mixture
was purged with nitrogen at ꢀ20 8C for 15 min. Then DBP (2 mol%)
and AIBN (2 mol%) were added to the solution. The resulting
mixture was heated under reflux until complete conversion of
MTFA occurred (monitored by GC). The final work up of reaction
mixture was the same as in procedure A.
5.3.3. Reaction of MTFA with tert.butyl ethyl ether: Product 17
Procedure B: MTFA (2.10 g, 15.0 mmol) and tert-butyl ethyl
ether (30.0 g, 294 mmol) gave 2.23 g (9.22 mmol, 61.4%) of product
17.
Methyl 4-tert-butoxy-2,3,3-trifluoropentanoate (17): Diastereo-
isomer A: 1H NMR (CDCl3): 1.19 (s, 9H), 1.27 (d, 3H, 3JHH = 6.6 Hz),
d
3.83 (s, 3H), 3.95–4.13 (m, 1H), 5.01–5.31 (m, 1H) ppm. 13C NMR
(CDCl3): 15.5 (s, CH3), 28.4 (s, CH3), 52.7 (s, OCH3), 66.2 (dd, CH,
d
2
1
2 ꢁ JCF = 26.3 Hz), 75.5 (s, O–C), 84.9 (dt, CHF, JCF = 192.4 Hz,
2JCF = 29.7 Hz), 118.6 (dt, CF2, 1JCF = 245.1 Hz, 2JCF = 25.8 Hz), 165.2
2
(d, C55O, JCF = 24.7 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ114.2 (ddd, 1F,
CF2, 2JFF = 265.8 Hz, 3JHF = 20.2 Hz, 3JFF = 10.0 Hz), ꢀ121.3 (ddd, 1F,
2
3
3
CF2, JFF = 265.6 Hz, JHF = 22.6 Hz, JFF = 11.2 Hz); ꢀ205.6 (dt, 1F,
CHF, JHF = 46.1 Hz, JFF = 3JHF = 10.6 Hz) ppm.
Diastereoisomer B: 1H NMR (CDCl3):
1.19 (s, 9H), 1.27 (d, 3H,
3JHH = 6.6 Hz), 3.84 (s, 3H), 3.95–4.13 (m, 1H), 5.01–5.31 (m, 1H)
ppm. 13C NMR (CDCl3): 16.6 (d, CH3, 3JCF = 8.8 Hz), 28.3 (s, CH3),
2
3
d
d
2
2
52.7 (s, OCH3), 67.3 (dd, CH, JCF = 24.6 Hz, JCF = 30.0 Hz), 75.4 (s,
O–C), 84.9 (ddd, CHF, 2JCF = 29.2 Hz, 2JCF = 97.9 Hz, 1JCF = 191.6 Hz),
118.5 (dt, CF2, JCF = 258.6 Hz, JCF = 24.1 Hz), 165.0 (d, C55O,
2JCF = 24.1 Hz) ppm. 19F NMR (CDCl3):
ꢀ119.1 (dddd, 1F, CF2,
5.3.2. Reaction of MTFA with diethyl ether: Products 16 and 24
Procedure A: MTFA (2.08 g, 14.4 mmol) and diethyl ether
(21.1 g, 285 mmol) gave a mixture of mono-adduct 16 (1.63 g,
1
2
d

J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
53
2JFF = 269.9 Hz, 3JFF = 3JHF = 18.3 Hz, 3JHF = 4.3 Hz); ꢀ121.3 (ddd, 1F,
CF2, 2JFF = 265.6 Hz, 3JHF = 22.6 Hz, 3JFF = 11.2 Hz); ꢀ123.5 (ddd, 1F,
Diastereoisomer B: 1H NMR (CDCl3):
1.50–1.72 (m, 4H), 3.47 (s, 3H), 3.72–3.85 (m, 1H), 3.60 (s, 3H), 5.08
(ddd, 1H, 2JHF = 46.7 Hz, 3JHF = 10.4 Hz, 3JHF = 9.3 Hz) ppm. 13C NMR
d
0.96 (t, 3H, 3JHH = 7.1 Hz),
3
3
2JFF = 270 Hz, JHF = 17.1 Hz, JFF = 7.8 Hz); ꢀ203.0 (ddd, 1F, CHF,
2JHF = 45.7 Hz,
3JHF = 13.5 Hz,
3JFF = 8.3 Hz) ppm. C10H17F3O3
(CDCl3):
d 13.93 (s, CH3), 18.76 (s, CH2), 29.73 (s, CH2CH), 52.76 (s,
2
2
(242.24): calcd C 49.58, H 7.08; found C 49.69, H 7.26.
OCH3), 59.83 (s, OCH3), 79.23 (dd, CH, JCF = 24.1 Hz, JCF = 4 Hz),
1
2
2
85.51 (ddd, CHF, JCF = 193.6 Hz, JCF = 30.3 Hz, JCF = 21.2 Hz),
1
1
2
5.3.4. Reaction of MTFA with dipropyl ether: Products 18 and 25
Procedure B: MTFA (2.17 g, 15.5 mmol) and dipropylether
(30.1 g, 295 mmol) gave product 18 (2.32 g, 9.59 mmol, 61.8%)
and product 25 (586 mg, 1.53 mmol, 19.8%).
118.93 (ddd, CF2, JCF = 256.2 Hz, JCF = 256 Hz, JCF = 24.1 Hz),
164.51–165.3 (m, C55O) ppm. 19F NMR (CDCl3):
ꢀ116.49 (dddd,
d
2
3
3
3
1F, JFF = 271.6 Hz, JFH = 18.3 Hz, JFF = 12.2 Hz, JFH = 4.6 Hz),
2
3
3
ꢀ121.17 (dddd, 1F, JFF = 271.6 Hz, JFH = 18.3 Hz, JFF = 7.6 Hz,
3JFH = 3.1 Hz), ꢀ202.43 (dddd, 1F, CHF, 2JFH = 45.8 Hz, 3JFF = 13.7 Hz,
3JFF = 7.6 Hz, 4JFH = 3.1 Hz) ppm. GC–EIMS: m/z (rel. int.): 215 (0.05)
[M]+, 208 (0.05), 185 (3), 157 (0.5), 149 (2), 129 (1.5), 107 (3.5), 87
(72), 77 (4), 59 (19), 45 (100).
Methyl 4-propoxy-2,3,3-trifluorohexanoate (18). Diastereoisomer
3
A: 1H NMR (CDCl3):
d
0.89 (2x t, 3H, JHH = 4.4 Hz), 1.02 (t, 3H,
3JHH = 6.6 Hz), 1.45–1.80 (m, 4H), 3.40–3.62 (m, 3H), 3.83 (s, 3H),
4.92–5.29 (m, 1H) ppm. 13C NMR (CDCl3):
10.04 (bs, CH3), 10.38
d
(s, CH3), 20.93 (s, CH2), 23.09 (s, CH2), 52.80 (s, OCH3), 74.04 (s,
Methyl 4-butoxy-2,3,3-trifluorobutanoate (22). 1H NMR
2
3
OCH2), 78.95 (d, OCH, JCF = 26.3 Hz), 85.32 (ddd, CHF,
(300.1 MHz, CDCl3):
d
1.96 (t, 3H, JHF = 6.6 Hz), 1.32–1.48 (m,
2
2
3
1JCF = 191.7 Hz, JCF = 31.5 Hz, JCF = 5.7 Hz), 119.05 (dd, CF2,
4H), 3.48–3.60 (m, 2H), 3.48 (t, 2H, JHH = 7 Hz), 3.85 (s, 3H), 5.14
(ddd, 1H, 2JHF = 46.2 Hz, 3JHF = 12.6 Hz, 3JHF = 7.7 Hz) ppm. 13C NMR
1JCF = 282.3 Hz,
1JCF = 257.1 Hz),
165.04
(d,
C55O,
2JCF = 24.7 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ111.8 (ddd, 1F,
(CDCl3): d 13.57 (s, CH3), 18.95 (s, CH2), 31.39 (s, CH2), 68.16 (t,
2JFF = 270 Hz, JFF = 6.1 Hz), ꢀ120.6 (ddt, 1F, JFF = 270.3), ꢀ205.5
OCH2CF2, JCF = 29.8 Hz), 72.26 (s, CH2O), 84.8 (ddd, CHF,
3
2
2
2
2
2
(dt, 1F, CHF, JHF = 46.3 Hz) ppm.
1JCF = 193.6 Hz, JCF = 32.1 Hz, JCF = 29.2 Hz), 117.85 (dt, CF2,
3
2
Diastereoisomer B:
d
0.89 (2x t, 3H, JHH = 4.4 Hz), 1.02 (t, 3H,
1JCF = 250.2 Hz, JCF = 25.2 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ114.76
3JHH = 6.6 Hz), 1.45–1.80 (m, 4H), 3.40–3.62 (m, 3H), 3.85 (s, 3H),
(dtt, 1F, 2JFF = 270.1 Hz, 3JFH = 13.7 Hz, 3JFF = 3JFH = 7.6 Hz), ꢀ117.16
4.92–5.29 (m, 1H) ppm. 13C NMR (CDCl3):
d 10.04 (bs, CH3), 10.46
(dtt, 1F, 2JFF = 270.1 Hz, 3JFF = 3JHF = 13.7 Hz, 3JHF = 10.7 Hz), ꢀ205.3
3
2
4
(s, CH3), 21.50 (d, CH2CH, JCF = 3.0 Hz), 23.19 (s, CH2), 52.85 (s,
OCH3), 74.12 (s, OCH2), 78.98 (dd, OCH, 2JCF = 50.5 Hz,
(dtt, 1F, CHF, JHF = 47.6 Hz, 3JFF = 10.7 Hz, JHF = 3.1 Hz) ppm. GC–
EIMS: m/z (rel. int.): 215 (0.25) [M]+, 208 (2), 185 (0.5), 171 (0.5),
155 (44), 133 (6), 120 (2.5), 87 (13), 77 (7), 57 (100), 41 (40).
2JCF = 24.7 Hz), 85.28 (ddd, CHF, JCF = 193.5 Hz, JCF = 56.7 Hz,
1
2
2JCF = 30.9 Hz), 119.10 (ddd, CF2, JCF = 250.8 Hz, JCF = 226.7 Hz,
1
1
2JCF = 6.4 Hz), 164.90 (dt, C55O, JCF = 24.0 Hz, JCF = 4.5 Hz) ppm.
5.3.6. Reaction of MTFA with dibutyl ether: Products 20 and 26
Procedure B: MTFA (2.01 g, 14.4 mmol) and dibutyl ether
(36.3 g, 279.2 mmol) gave product 20 (2.25 g, 8.33 mmol, 57.9%)
and product 26 (718 mg, 1.75 mmol, 24.4%).
2
3
19F NMR (CDCl3):
d
ꢀ117.1 (ddt, 1F, JFF = 271.5 Hz, JFF = 7 Hz),
2
3
2 3
ꢀ121.6 (dddd, 1F, JFF = 271.5 Hz, JFF = 15 Hz), ꢀ202.4 (dddd, 1F,
2
CHF, JHF = 45.1 Hz) ppm. C10H17F3O3 (242.24): calcd C 49.58; H,
7.08; found C 49.79, H, 7.05.
Methyl 4-butoxy-2,3,3-trifluoroheptanoate (20). Diastereoisomer
Dimethyl 4,40-oxybis(2,3,3-trifluorohexanoate) (25). Mixture of
A: 1H NMR (CDCl3):
d 0.84–1.0 (m, 6H), 1.25–1.75 (m, 8H), 3.44–
diastereoisomers: 1H NMR (300.1 MHz, CDCl3):
d
0.80–1.00 (m, 6H),
1.41–1.79 (m, 4H), 3.37–3.66 (m, 2H), 5.01–5.38 (m, 2H) ppm. 19
NMR (CDCl3):
3.68 (m, 3H), 3.84 (s, 3H), 5.11 (dt, 1H, JHF = 46.2 Hz,
3JFF = 10.4 Hz) ppm. 13C NMR (CDCl3):
13.76 (s, CH3), 14.01 (s,
2
F
d
d
ꢀ111.1–(ꢀ119.4) (m, 2F), ꢀ120.1–(ꢀ121.9) (m,
CH3), 18.87 (s, CH2), 19.15 (s, CH2), 30.64 (s, CH2), 32.08 (s, CH2),
52.38 (s, OCH3), 72.04 (s, OCH2), 77.08–78.04 (m, CH), 85.22 (dd,
CHF, 1JCF = 191.8 Hz, 2JCF = 30.3 Hz), 118.98 (dt, CF2, 1JCF = 250.8 Hz,
1JCF = 258.2 Hz, 2JCF = 23.5 Hz), 164.72 (d, C55O, 2JCF = 23.5 Hz) ppm.
2F), -201.8-(-206.5) (2F) ppm. GC–EIMS: m/z (rel. int.): 381 (10)
[M ꢀ 1]+, 324 (9.2), 323 (75), 303 (14), 283 (39), 244 (9.4), 183 (95),
163 (38), 143 (24), 111 (11), 103 (13), 93 (38), 91 (21), 59 (100).
C16H24F6O5 (410.35): calcd C 43.99, H 5.27; found C 43.87, H 5.30.
19F NMR (CDCl3): diastereoisomer A:
d
ꢀ112.78 (ddd, 1F,
3
3
2JFF = 269.5 Hz, JHF = 20.4 Hz, JHF = 10.6 Hz), ꢀ120.48 (ddd, 1F,
5.3.5. Reaction of MTFA with butyl methyl ether: Products 19 and 22
Procedure A: MTFA (2.13 g, 15.2 mmol) and butyl methyl ether
(29.1 g, 330.7 mmol) gave mixture of products 19 (89% rel.) and 22
(11% rel.), (2.43 g, 10.7 mmol, 70%).
Procedure B: MTFA (2.21 g, 15.8 mmol) and butyl methyl ether
(27.8 g, 316.0 mmol) gave mixture of products 19 (83% rel.) and 22
(17% rel.), (2.71 g, 11.9 mmol, 75%).
C9H15F3O3 (228.21) (19 + 22): calcd C 47.37, H 6.63; found C
47.07, H 6.67.
Methyl 2,3,3-trifluoro-4-methoxyheptanoate (19). Diastereo-
isomer A: 1H NMR (CDCl3):
2JFF = 269.4 Hz, 3JHF = 23.5 Hz, 3JHF = 10.2 Hz), ꢀ205.51 (dt, 1F, CHF,
3
2JHF = 46.3 Hz, JFF = 10.8 Hz) ppm.
Diastereoisomer B: 1H NMR (CDCl3):
d
0.84–1.0 (m, 6H), 1.25–
1.75 (m, 8H), 3.44–3.68 (m, 3H), 3.86 (s, 3H), 5.15 (ddd, 1H,
2JHF = 46.2 Hz, 3JFF = 19.8 Hz, 3JFF = 3.3 Hz) ppm. 13C NMR (CDCl3):
d
13.76 (s, CH3), 14.01 (s, CH3), 18.83 (s, CH2), 19.09 (s, CH2), 30.06 (s,
CH2), 31.98 (s, CH2), 52.38 (s, OCH3), 71.94 (s, OCH2), 77.08–78.04
(m, CH), 85.13 (ddd, CHF, 1JCF = 191.8 Hz, 2JCF = 60.7 Hz,
1
2
2JCF = 30.9 Hz), 118.91 (dt, CF2, JCF = 253.6 Hz, JCF = 28.1 Hz),
164.63 (d, C55O, JCF = 23.5 Hz) ppm. 19F NMR (CDCl3):
(dddd, 1F, JFF = 271.4 Hz, JHF = 3JFF = 13.5 Hz, JHF = 4.6 Hz),
d
ꢀ117
2
3
2
3
3
d
0.95 (t, 3H, JHH = 7.2 Hz), 1.50–
2
3
3
1.72 (m, 4H), 3.43 (s, 3H), 3.72–3.85 (m, 1H), 3.65 (s, 3H), 5.14 (ddd,
1H, CHF, 2JHF = 46.2 Hz, 3JHF = 19.8 Hz, 3JHF = 3.3 Hz) ppm. 13C NMR
ꢀ121.46 (dddd, 1F, JFF = 269.2 Hz, JHF = 18.3 Hz, JHF = 2.3 Hz,
3JFF = 2.2 Hz), ꢀ202.32 (ddt, 1F, CHF, JHF = 45.8 Hz, JFF = 7.7 Hz,
4JHF = 5.7 Hz) ppm. C12H21F3O3 (270.29): calcd C 53.33, H 7.83;
found C 53.06, H 7.55.
2 3
(CDCl3):
d 13.93 (s, CH3), 18.76 (s, CH2), 30.16 (s, CH2CH), 52.76 (s,
OCH3), 59.77 (s, OCH3), 78.86 (dd, CH, 2JCF = 23.5 Hz, 2JCF = 2.3 Hz),
1
2
2
85.06 (ddd, CHF, JCF = 191.8 Hz, JCF = 30.3 Hz, JCF = 26.3 Hz),
Dimethyl 4,40-oxybis(2,3,3-trifluoroheptanoate) (26). Mixture of
1
2
118.8 (dt, CF2, JCF = 256 Hz, JCF = 24.1 Hz), 164.5–165.3 (m,
diastereoisomers: 1H NMR (300.1 MHz, CDCl3):
d
0.79–0.98 (m, 6H,
CH3), 1.24–1.79 (m, 8H, CH2CH2), 3.74–3.83 (m, 6H, OCH3), 3.85–
4.07 (m, 2H, CH), 4.88–5.36 (m, 2H, CHF) ppm. 19F NMR (CDCl3):
C55O) ppm. 19F NMR (CDCl3):
d
ꢀ112.13 (ddt, 1F, JFF = 271.6 Hz,
2
3JFH = 10.7 Hz,
3JFF = 3JFH = 7.6 Hz),
ꢀ121.33
(ddt,
1F,
d
2JFF = 271.6 Hz, JFH = 15.3 Hz, JFF = 3JFH = 9.2 Hz), ꢀ205.18 (ddd,
1F, CHF, 2JFH = 45.8 Hz, 3JFF = 11.2 Hz, 3JFF = 9.2 Hz) ppm. GC–EIMS:
m/z (rel. int.): 215 (0.05) [M]+, 208 (0.05), 185 (8), 157 (1.5), 149
(5.5), 129 (3.5), 107 (5), 87 (73), 77 (5), 59 (24), 45 (100).
ꢀ111.97–(ꢀ121.68) (m, 4F, CF2), ꢀ202.25–(ꢀ205.26) (m, 2F, CHF)
ppm. GC–EIMS: m/z (rel. int.): 410 (0.1) [M]+, 409 (32) [M ꢀ 1]+,
337 (15), 318 (4.3), 317 (17), 297 (100), 265 (17), 295 (21), 229
(23.4), 225 (49), 197 (98), 177 (19), 157 (64), 177 (19), 157 (64),
3
3

54
J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
129 (34), 97 (25), 93 (21), 59 (79), 28 (40). C16H24F6O5 (410.35):
calcd C 46.83, H 5.90; found C 47.35, H 6.08.
3JFH = 22 Hz), ꢀ127.4 (dddd, 1F, 3JFF = 5.1 Hz, 3JFH = 22 Hz,
2
3JFH = 5.1 Hz), ꢀ203.9 (ddd, 1F, JHF = 45.7 Hz) ppm.
5.3.7. Reaction of MTFA with 1-methoxyoctane: Products 21 and 23
Procedure B: Reaction of MTFA (2.15 g, 15.4 mmol) and 1-
methoxyoctane (46.6 g, 303.0 mmol) gave an inseparable mixture
of products 21 (86% rel.) and 23 (14% rel.) (2.82 g, 9.59 mmol,
62.3%). C13H23F3O3 (284.32) (mixture of 21 and 23): calcd C 54.93,
H 8.10; found C 54.37, H 8.10.
5.3.9. Reaction of MTFA with tetrahydrofurane: Product 41
Procedure A: Reaction of MTFA (1.94 g, 13.9 mmol) and THF
(22.3 g, 309.7 mmol) gave product 41 (2.12 g, 10.0 mmol, 71.8%).
Procedure B: Reaction of MTFA (2.02 g, 14.4 mmol) and THF
(20.2 g, 280.6 mmol) gave product 41 (2.23 g, 10.5 mmol, 75.3%).
Methyl 2,3,3-trifluoro-3-(tetrahydrofuran-2-yl)-propanoate (41).
Methyl 4-methoxy-2,3,3-trifluoroundecanoate (21). Diastereo-
Diastereoisomer A: 1H NMR (CDCl3): diastereoisomer A:
(m, 4H), 3.70–3.82 (m, 2H), 3.74 (s, 3H), 4.11–4.34 (m, 1H), 4.92–
5.25 (m, 1H) ppm. 13C NMR (CDCl3):
24.3 (s, CH2), 24.6 (s, CH2),
52.5 (s, OCH3), 69.5 (s, CH2O), 75.5 (dd, OCH, JCF = 33.1 Hz,
d 1.73–2.13
3
isomer A: 1H NMR (CDCl3):
d
0.82 (t, 3H, JHH = 7.0), 1.15–1.65
(m, 12H), 3.36 (s, 3H), 3.41–3.52 (m, 1H), 3.67–3.88 (m, 1H), 3.77 (s,
d
2
3
2
3H), 5.01 (dt, 1H, JHF = 46.4 Hz, JHF = 10.9 Hz) ppm. 13C NMR
1
2
(CDCl3): 14.0 (s, CH3), 22.6–31.7 (m, 6C, (CH2)6), 52.8 (s, OCH3),
d
2JCF = 23.5 Hz), 85.7 (ddd, CHF, JCF = 195.8 Hz, JCF = 30.9 Hz,
2
1
1
59.8 (s, OCH3), 79.3 (t, CH, JCF = 23.5 Hz), 85.5 (dt, CHF,
2JCF = 28.1 Hz), 118.3 (ddt, CF2, JCF = 255.9 Hz, JCF = 250.7 Hz,
2JCF = 21.7 Hz), 164.3–164.8 (m, C55O) ppm. 19F NMR (CDCl3):
1JCF = 193.5 Hz, JCF = 30.9 Hz), 118.9 (dt, CF2, JCF = 253.6 Hz,
d
2
1
2JCF = 24.6 Hz), 164.9 (d, C55O, 2JCF = 24 Hz) ppm. 19F NMR (CDCl3):
ꢀ115.3 (dt, 1F, JFF = 265.6 Hz, JFF = 13.6 Hz), ꢀ125.1 (ddt, 1F,
2
3
3
3
d
ꢀ112.1
(ddt,
1F,
2JFF = 270.1 Hz,
3JFH = 10.7 Hz,
2JFF = 265.6 Hz, JHF = 23 Hz, JFF = 6.3 Hz), ꢀ207.4 (ddd, 1F, CF,
3JFF = 3JFH = 7.6 Hz), ꢀ121.3 (ddt, 1F, 2JFF = 271.6 Hz, 3JFH = 15.3 Hz,
3JFF = 3JFH = 9.2 Hz), ꢀ205.2 (ddd, 1F, CHF, 2JFH = 47.3 Hz,
3JFF = 10.7 Hz) ppm. GC–EIMS: m/z (rel. int.): 285 (0.1) [M + 1]+,
264 (0.3), 205 (1), 185 (7.3), 173 (6.2), 143 (70.6), 141 (7.3), 111
2JHF = 46.5 Hz, JFF = 12.7 Hz, JFF = 7.9 Hz) ppm.
3
3
Diastereoisomer B: 1H NMR (CDCl3):
3.82 (m, 2H), 3.73 (s, 3H), 4.11–4.34 (m, 1H), 4.92–5.25 (m, 1H)
ppm. 13C NMR (CDCl3):
24.3 (s, CH3), 24.6 (s, CH3), 52.5 (s, OCH3),
d 1.73–2.13 (m, 4H), 3.70–
d
2
2
(21), 91 (5.7), 69 (100), 55 (41), 41 (42).
69.5 (s, CH2O), 74.3 (dd, OCH, JCF = 33.7 Hz, JCF = 23.5 Hz), 84.9
3
1
Diastereoisomer B: 1H NMR (CDCl3):
d
0.82 (t, 3H, JHH = 7 Hz),
(ddd, CHF, JCF = 191.2 Hz, 2JCF = 37.8 Hz, 2JCF = 27.5 Hz), 118.4 (dt,
1
2
1.15–1.65 (m, 12H), 3.40 (s, 3H), 3.41–3.52 (m, 1H), 3.67–3.88 (m,
CF2, JCF = 253 Hz, JCF = 25.7 Hz), 164.3–164.8 (m, C55O) ppm. 19F
2
3
2
3
1H), 3.79 (s, 3H), 5.07 (ddd, 1H, JHF = 46 Hz, JHF = 18.9 Hz,
3JHF = 3.1 Hz) ppm. 13C NMR (CDCl3):
14.0 (s, CH3), 22.6–31.7
(m, 6 C, (CH2)6), 52.8 (s, OCH3), 59.8 (s, OCH3), 79.3 (dd, CH,
NMR (CDCl3):
d
ꢀ120 (ddd, 1F, JFF = 266.8 Hz, JFF = 13.7 Hz,
2 3
d
3JFH = 21.2 Hz), ꢀ126.6 (ddd, 1F, JFF = 266.8 Hz, JHF = 22.9 Hz,
3JFF = 5.4 Hz), ꢀ205.0 (dddd, 1F, CF, JHF = 40 Hz, JFF = 13.7 Hz,
2
3
2
1
4
2JCF = 31.5 Hz, JCF = 24.1 Hz), 85.1 (ddd, CHF, JCF = 191.8 Hz,
3JFF = 5.7 Hz, JHF = 2.6 Hz) ppm.
2
1
2JCF = 36.1 Hz, JCF = 29.8 Hz), 117.9 (dt, CF2, JCF = 250.8 Hz,
2JCF = 25.2 Hz), 164.8 (dd, C55O, JCF = 23 Hz, JCF = 6 Hz) ppm. 19F
5.4. Cleavage of the ether bond
2
3
2
3
NMR (CDCl3):
d
ꢀ116.4 (dddd, 1F, JFF = 271.6 Hz, JFH = 18.3 Hz,
3JFF = 13.7 Hz, JFH = 4.6 Hz), ꢀ121.1 (dddd, 1F, JFF = 271.6 Hz,
5.4.1. General procedure
3
2
3
3
3JFH = 16.8 Hz, JFF = 7.6 Hz, JFH = 3.1 Hz), ꢀ202.4 (ddd, 1F, CHF,
2JFH = 45.8 Hz, 3JFF = 13.7 Hz, 3JFF = 7.6 Hz) ppm. GC–EIMS: m/z (rel.
int.): 285 (0.1) [M + 1]+, 232 (0.3), 205 (1.7), 185 (15), 165 (2.3), 143
(68), 141 (7.3), 111 (19), 91 (5.7), 69 (100), 55 (37), 41 (35).
A mixture of alkanoate (ca. 8 mmol) and dichloromethane
(30 mL) was cooled to ꢀ50 8C and BBr3 (ca. 10 mmol) was added
dropwise. The reaction mixture was warmed to r.t. during 2 h
while stirring until complete conversion of the starting alkenoate
(monitored by 19F NMR). The mixture was then very slowly poured
into an ice-cold 20% solution of NaHCO3 while vigorously stirring
for additional 30 min. The organic layer was separated and washed
twice with water (10 mL), dried over MgSO4, filtered and the
solvent was evaporated. The residue was purified by column
chromatography (20 g silica gel, CH2Cl2) or by vacuum distillation
(25).
Methyl 4-octyloxy-2,3,3-trifluorobutanoate (23). 1H NMR
3
(300.1 MHz, CDCl3):
12H), 3.41–3.52 (m, 1H), 3.79 (s), 5.07 (ddd, 1H, JHF = 46.9 Hz,
3JHF = 13.2 Hz, 3JHF = 8.1 Hz) ppm. 13C NMR (CDCl3):
14.0 (s, CH3),
d
0.82 (t, 3H, JHH = 5 Hz), 1.15–1.65 (m,
2
d
22.6–31.7 (m, 6C, (CH2)6), 59.8 (s, OCH3), 68.2 (t, OCH2CF2,
1
2JCF = 29.7 Hz), 72.6 (s, CH2O), 84.8 (ddd, CHF, JCF = 193.5 Hz,
2JCF = 32.1 Hz, 2JCF = 29.7 Hz), 164.4–164.8 (m, C55O) ppm. 19F NMR
2
3
(CDCl3):
d
ꢀ114.8 (dtt, 1F, JFF = 270.8 Hz, JFH = 12.2 Hz,
3JFF = 3JFH = 9.2 Hz),
ꢀ117.4
(dtt,
1F,
2JFF = 270.1 Hz,
5.4.2. Methyl-2,3,3-trifluoro-4-hydroxypentanoate (8)
Reaction of alkoxyester 16 (10.5 g, 49 mmol) and BBr3 (16 g,
63.7 mmol) gave product 8 (7.61 g, 40.9 mmol, 83.4%) as a
colourless oil, bp 38–41 8C/0.8 mmHg.
3JFF = 3JHF = 21.4 Hz, 3JHF = 12.2 Hz), ꢀ205.3 (dt, 1F, CHF,
2JHF = 45.8 Hz, JFF = 9.2 Hz) ppm.
3
5.3.8. Reaction of MTFA with 2,2-dimethyl-1,3-dioxolane: Product 35
Procedure B: Reaction of MTFA (2.14 g, 15.3 mmol) and 2,2-
dimethyl-1,3-dioxolane (30.8 g, 302.0 mmol) gave product 35
(2.44 g, 10.1 mmol, 65.8%).
Reaction of alkoxyester 17 (1.89 g, 7.8 mmol) with BBr3 (2.54 g,
10.1 mmol) gave product 8 (0.8 g, 4.27 mmol, 54.8%).
5.4.3. Methyl-2,3,3-trifluoro-4-hydroxyhexanoate (9)
Reaction of alkoxyester 18 (2.02 g, 8.34 mmol) and BBr3 (2.72 g,
10.8 mmol) gave product 9 (1.17 g, 5.85 mmol, 70.2%) as a
colourless oil.
Methyl
3-(2,2-dimethyl-1,3-dioxolan-4-yl)-2,3,3-trifluoropro-
1.36 (s,3H),
panoate (35). Diastereoisomer A: 1H NMR (CDCl3):
d
3
1.43 (s, 3H), 3.86 (s, 3H), 4.16 (2x dd, 1H, JHH = 7.2 Hz,
2JHH = 8.9 Hz), 4.28 (2x dd, 1H, JHH = 8.8 Hz, JHH = 8.9 Hz), 4.52
3
2
(ddt, 1H, 3JHF = 21 Hz), 5.15 (ddd, 1H, 2JHF = 46.5 Hz, 3JHF = 14.2 Hz,
5.4.4. Methyl 2,3,3-trifluoro-4-hydroxyheptanoate (10)
Alkoxyester 19 (2 g, 7.4 mmol) and BBr3 (2.41 g, 9.62 mmol)
gave product 10 (1.17 g, 5.46 mmol, 73.8%) as a colourless oil.
Alkoxyester 20 (1.94 g, 7.18 mmol) and BBr3 (2.34 g,
9.33 mmol) gave product 10 (0.94 g, 4.41 mmol, 61.4%) as a
colourless oil.
3JHF = 4.7 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ115.4 (dt, 1F, 2JFF = 267 Hz,
3JFF = 13 Hz, 3JFH = 13 Hz), ꢀ125.8 (dddd, 1F, 3JFF = 6 Hz,
3JFH = 21.4 Hz, 3JFH = 5.2 Hz), ꢀ207.1 (ddd, 1F, 2JHF = 46.5 Hz) ppm.
Diastereoisomer B: 1H NMR (CDCl3):
d 1.38 (s, 3H), 1.47 (s, 3H),
3.89 (s, 3H), 4.16 (2x dd, 1H, 3JHH = 7.2 Hz, 2JHH = 8.9 Hz), 4.28 (2x
dd, 1H, 3JHH = 8.8 Hz, 2JHH = 8.9 Hz), 4.47 (ddt, 1H, 3JHF = 22 Hz), 5.2
(ddd, 1H, 2JHF = 45.7 Hz, 3JHF = 22.5 Hz, 3JHF = 2.1 Hz) ppm. 19F NMR
Diastereoisomer A: 1H NMR (CDCl3):
1.75 (m, 4H), 2.48 (bs, OH), 3.83–3.87 (m, 3H), 3.88–4.06 (m, 1H),
5.26 (ddt, 1H, 2JHF = 45.6 Hz, 3JHF = 19.8 Hz, 3JHF = 3.3 Hz) ppm. 13
d 0.94–0.97 (m, 6H), 1.28–
(CDCl3):
d
ꢀ122.1 (ddd, 1F, 2JFF = 266 Hz, 3JFF = 14.1 Hz,
C

J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
55
NMR (CDCl3):
d
13.62 (s, CH3), 18.44 (s, CH2), 30.77 (s, CH2), 53.07
3JHH = 2.9 Hz), 4.51 (dd, 1H, 2JHH = 14.9 Hz, 3JHH = 3 Hz), 4.65 (dddd,
1H, 3JHF = 3 Hz, 3JHF = 3JHH = 3JHH = 6.1 Hz), 5.19 (ddd, 1H,
2JHF = 45.8 Hz, 3JHF = 12.2 Hz, 3JHF = 8.1 Hz) ppm. 19F NMR (CDCl3):
2
(s, OCH3), 69.80 (t, CH, JCF = 20.8 Hz), 85.59 (dt, CHF,
1JCF = 195.8 Hz, JCF = 30.9 Hz), 118.57 (ddt, CF2, JCF = 251.4 Hz,
2
1
1JCF = 252 Hz, JCF = 22.3 Hz), 165.6 (d, C55O, JCF = 24.7 Hz) ppm.
d
ꢀ116.5 (dddd, 1F, JFF = 262.7 Hz, JHF = 3JHF = 3JFF = 10.1 Hz),
2
2
2
3
19F NMR (CDCl3): diastereoisomer A:
d
ꢀ115.59 (ddt, 1F,
ꢀ120.4 (ddt, 1F, 2JFF = 262.1 Hz, 3JHF = 10 Hz, 3JFF = 9.9 Hz,
3JHF = 13.8 Hz), ꢀ205.7 (ddd, 1F, 2JHF = 45 Hz, 3JFF = 10 Hz,
3JFF = 9.9 Hz) ppm.
2JFF = 270.4 Hz, JHF = 12.5 Hz, JFF = 3JHF = 5.2 Hz), ꢀ125.18 (ddt,
3
3
2
3
3
1F, JFF = 266.3 Hz, JHF = 18.4 Hz, JFF = 3JHF = 7.9 Hz), ꢀ206.98
2
3
3
(ddd, 1F, CHF, JHF = 46.7 Hz, JFF = 14.2 Hz, JFF = 4.7 Hz) ppm.
Diastereoisomer B: 1H NMR (CDCl3):
d 3.86 (s, 3H), 3.96 (s, OH),
Diastereoisomer B: 1H NMR (CDCl3):
d
0.94–0.97 (m, 6H), 1.28–
4.11 (s, OH), 4.38 (dd, 1H, 2JHH = 13.8 Hz, 3JHH = 5 Hz), 4.43 (dd, 1H,
3
3
1.75 (m, 4H), 2.67 (bs, OH), 3.83–3.87 (m, 3H), 3.88–4.06 (m, 1H),
5.16 (dm, 1H, JHF = 46.7 Hz) ppm. 13C NMR (CDCl3):
CH3), 30.77 (s, CH2), 52.98 (s, OCH3), 69.81 (t, CH, JCF = 28 Hz),
84.96 (ddd, CHF, JCF = 191.8 Hz, JCF = 37.2 Hz, JCF = 29.7 Hz),
2JHH = 14 Hz, JHH = 5.2 Hz), 4.77 (dddd, 1H, JHF = 22.2 Hz,
2
d 30.64 (s,
3JHF = 3JHH = 3JHH = 6 Hz), 5.27 (ddd, 1H, 2JHF = 45 Hz, 3JHF = 19.9 Hz,
2
3JHF = 4.1 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ118.9 (dddd, 1F,
1
2
2
2JFF = 262.4 Hz,
3JHF = 20.4 Hz,
2
3JFF = 11.9 Hz,
3JHF = 4.1 Hz),
1
2
3
3
118.72 (dt, CF2, JCF = 253.6 Hz, JCF = 25.7 Hz), 165.26 (d, C55O,
ꢀ121.8 (ddt, 1F, JFF = 261.8 Hz, JHF = 16.2 Hz, JFF = 7.9 Hz,
3JHF = 8 Hz), ꢀ203.7 (ddd, 1F, 2JHF = 43.9 Hz, 3JFF = 12 Hz,
3JFF = 7.7 Hz) ppm. C6H9F3O4 (202.13): calcd C 35.65, H 4.49; found
C 36.69, H 3.83.
2JCF = 26.3 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ120.45 (ddd, 1F,
2JFF = 267.4 Hz, JHF = 19.7 Hz, JFF = 13.8 Hz), ꢀ126.27 (dddd, 1F,
3
3
2JFF = 268.3 Hz, JHF = 19.9 Hz, JHF = 3.1 Hz, JFF = 6.9 Hz), ꢀ203.87
(dddd, 1F, CHF, 2JHF = 45.8 Hz, 3JFF = 13.7 Hz, 4JHF = 2 Hz,
3JFF = 5.9 Hz) ppm. C8H13F3O3 (214.18): calcd C 44.86, H 6.12;
found C 44.78, H 6.10.
3
3
3
5.5. Lactonisation of 4-hydroxyesters
5.5.1. General procedure
5.4.5. Methyl-2,3,3-trifluoro-4-hydroxyundecanoate (11)
Reaction of alkoxyester 21 (1.85 mg, 6.51 mmol) with BBr3
(2.12 g, 8.46 mmol) gave product 11 (1.20 g, 4.43 mmol, 68.1%) as a
colourless oil.
Hydroxyester and p-toluenesulfonic acid monohydrate
(5 mol%) in toluene were refluxed until complete conversion of
the hydroxyester (check by 19F NMR). Toluene was evaporated and
the residue was purified by column chromatography (silica gel 5 g,
CH2Cl2) or distilled. The resulting mixtures of dihydrofuranone and
furanone were analysed and used in the following dehydrofluor-
inating step without further purification.
5.4.6. Methyl-8-bromo-2,3,3-trifluoro-4-hydroxyhexanoate (42)
Reaction of alkoxyester 41 (11.3 g, 53.3 mmol) with BBr3
(17.3 g, 69.2 mmol) gave product 42 (11.8 g, 40.1 mmol, 75.2%) as a
colourless oil. Diastereoisomer A: 1H NMR (CDCl3):
4H), 2.83–3.99 (m, 2x OH), 3.44 (t, 3H, JHH = 6 Hz), 3.84 (s, 3H),
3.89–4.12 (m, 1H), 3.89–4.12 (m, 1H), 5.17 (ddd, 1H, 2JHF = 46.2 Hz,
3JHF = 12.6 Hz, 3JHF = 7.7 Hz) ppm. 13C NMR (CDCl3):
d
1.64-2.21 (m,
5.5.2. 3,4,4-Trifluoro-5-methyldihydrofuran-2-one (27)
A mixture of hydroxyester 8 (7.05 g, 37.9 mmol) and TsOH.H2O
(360 mg, 1.89 mmol) in toluene (40 mL) was refluxed for 10 days to
give a mixture of dihydrofuranone 27 and furanone 31 (5.37 g,
34.8 mmol, 92.0%) as a colourless oil. The ratio 27/31 was 94/6 and
the ratio of diastereoisomers of 27 (A/B) was 65/35, b.p. 36–42 8C/
0.8 mmHg.
3
d
27.5 and 28.5
(2 x s, (CH2)2), 33 (s, BrCH2), 53.2 (s, OCH3), 69.5 (dd, CH,
2
1
2JCF = 29.2 Hz, JCF = 25.2 Hz), 85.5 (dt, CHF, JCF = 196.4 Hz,
2JCF = 30.3 Hz), 118.4 (ddd, CF2, JCF = 255.9 Hz, JCF = 253.1 Hz,
2JCF = 23.5 Hz), 165.1 (d, C55O, JCF = 22.9 Hz) ppm. 19F NMR
1
1
2
Product 27. Diastereoisomer A: 1H NMR (CDCl3):
d
1.48 (dd, 3H,
2
3
4
(CDCl3):
d
ꢀ115.3 (ddt, 1F, JFF = 266.7 Hz, JHF = 12.6 Hz,
3JHH = 6.6 Hz, JFH = 1.7 Hz), 4.63–4.76 (m, 1H), 5.34 (ddd, 1H,
3JFF = 5 Hz), ꢀ125.1 (ddt, 1F, JFF = 266.7 Hz, JHF = 18.3 Hz,
2JFH = 48.4 Hz, 3JFH = 14.8 Hz, 3JFH = 7.7 Hz) ppm. 13C NMR (CDCl3):
2
3
3JFF = 3JHF = 8.2 Hz), ꢀ207 (ddd, 1F, JHF = 46.6 Hz, JFF = 12.2 Hz,
d 11.4 (d, CH3, JCF = 6.9 Hz), 75.3 (dd, CH, JCF = 29.8 Hz,
2
3
3
2
3JFF = 9 Hz) ppm.
2JCF = 25.8 Hz), 82.8 (ddd, CHF, JCF = 207.2 Hz, JCF = 33.2 Hz,
1
2
Diastereoisomer B: 1H NMR (CDCl3):
d
1.64–2.21 (m, 4H), 2.83–
2JCF = 18.9 Hz), 118.5 (dt, CF2, JCF = 257.6 Hz, JCF = 14.9 Hz),
1
2
3.99 (m, 2x OH), 3.45 (t, 3H, 3JHH = 6 Hz), 3.86 (s, 3H), 3.89–4.12 (m,
1H), 5.18 (ddd, 1H, 2JHF = 47.8 Hz, 3JHF = 20.7 Hz, 3JHF = 2.7 Hz) ppm.
164.7 (dd, C55O, JCF = 21.7 Hz, JCF = 14.9 Hz) ppm. 19F NMR
2
3
2
(CDCl3): diastereoisomer A:
3JFF = 3JFH = 7.2 Hz),
d
ꢀ122.0 (ddt, 1F, JFF = 235.8 Hz,
13C NMR (CDCl3):
d
27.5 and 28.5 (2 x s; (CH2)2), 32 (s, BrCH2), 53.1
ꢀ134.3
(ddt,
1F,
2JFF = 235.7 Hz,
(s, OCH3), 69.5 (dd, CH, 2JCF = 29.2 Hz, 2JCF = 25.2 Hz), 85 (ddd, CHF,
3JFF = 3JFH = 15.7 Hz, 3JFH = 5.8 Hz), ꢀ219.4 (dt, 1F, CHF,
1JCF = 192.3 Hz, JCF = 36.1 Hz, JCF = 29.2 Hz), 118.5 (dt, CF2,
2JFH = 48.4 Hz, JFF = 7 Hz) ppm. GC–EIMS: m/z (rel. int.): 134
2
2
3
2
2
1JCF = 254.2 Hz, JCF = 26.3 Hz), 165.6 (dt, C55O, JCF = 22.9 Hz,
(2.5) [M ꢀ 20]+, 119 (14), 105 (24), 91 (7.4), 88 (5.5), 77 (22), 71
3JCF = 3 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ119.9 (ddd, 1F,
(16), 64 (2.9), 63 (4.5), 51 (8.7), 44 (0.5), 43 (100).
3
3
2JFF = 268.6 Hz, JHF = 18.8 Hz, JFF = 15.4 Hz), ꢀ125.7 (ddd, 1F,
Diastereoisomer B: 1H NMR (CDCl3):
d
1.48 (d, 3H, 3JHH = 6.6 Hz);
3
3
2
3
2JFF = 268.7 Hz, JHF = 19.4 Hz, JFF = 3.8 Hz), ꢀ203.7 (dddd, 1F,
4.71–4.86 (m, 1H), 5.18 (dt, 1H, JFH = 48.9 Hz, JFH = 8.2 Hz) ppm.
2JHF = 45.8 Hz,
3JFF = 12.4 Hz,
3JFF = 6 Hz,
13C NMR (CDCl3):
d
14.3 (dd, CH3, 3JCF = 4.6 Hz, 3JCF = 4 Hz), 78.2 (t,
4JHF = 1.8 Hz) ppm. C8H12F3O3Br (293.08): calcd C 32.78, H 4.13;
CH, JCF = 28.1 Hz), 84 (ddd, CHF, JCF = 213 Hz, JCF = 27.5 Hz,
2
1
2
1
2
found C 32.94, H 4.19.
2JCF = 18.9 Hz), 118.7 (dt, CF2, JCF = 257.6 Hz, JCF = 14.9 Hz),
164.5 (dd, C55O, 2JCF = 21.7 Hz, 3JCF = 9.7 Hz) ppm. 19F NMR (CDCl3):
5.4.7. Methyl 2,3,3-trifluoro-4,5-dihydroxypentanoate (36)
d
ꢀ121.1 (dm, 1F, 2JFF = 244.8 Hz), ꢀ124.8 (dm, 1F, 2JFF = 235.8 Hz),
2
3
A mixture of alkoxyester 35 (2.15 g, 8.88 mmol), methanol
(20 mL) and conc. HCl (6 mL) was refluxed for 20 h until complete
conversion of 35 was observed (check by 19F-NMR). Methanol was
evaporated and the residue was dissolved in diethyl ether (30 mL).
The mixture was washed with NaHCO3 (20%, 10 mL). The water
layer was extracted with ethyl acetate (10 mL) and the organic
layer was dried over MgSO4, filtered and evaporated. Product 36
was isolated by column chromatography (diethyl ether), yield
ꢀ219.4 (dt, 1F, JFH = 53.1 Hz, JFF = 13.2 Hz) ppm. GC–EIMS: m/z
(rel. int.): 134 (7.5) [M ꢀ 20]+, 119 (22), 105 (14), 91 (4.7), 88 (15.5),
77 (1.7), 71 (1.5), 64 (13), 51 (19), 43 (100).
5.5.3. 5-Ethyl-3,4,4-trifluorodihydrofuran-2-one (28)
Refluxing a mixture of hydroxyester 9 (1.12 g, 5.60 mmol) and
TsOH.H2O (51 mg, 0.27 mmol) in toluene (20 mL) for 8 days gave a
mixture of dihydrofuranone 28 and furanone 32 (901 mg,
5.33 mmol, 95.9%) as a colourless oil. The ratio 28/32 was 95/5
and the ratio of diastereoisomers of 28 was 59/41.
835 mg (4.14 mmol, 46.5%). Diastereoisomer A: 1H NMR (CDCl3):
3.85 (s, 3H), 3.96 (s, OH), 4.09 (s, OH), 4.47 (dd, 1H, 2JHH = 15.1 Hz,
d

56
J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
2
3
Product 28. 1H NMR (CDCl3): 1H NMR (CDCl3):
d
1.11 (t, 3H,
4.41–4.59 (m, 1H), 5.33 (ddd, 1H, JFH = 48.4 Hz, JFH = 14.3 Hz,
3JFH = 7.7 Hz) ppm. 13C NMR (CDCl3):
13.9 (s, CH3), 22.5–31.5 (m,
(CH2)6), 78.8 (dd, CH, 2JCF = 29.7 Hz, 2JCF = 25.2 Hz), 84.1 (ddd, CHF,
3
3JHH = 7.1 Hz), 1.12 (t, 3H, JHH = 7.7 Hz), 4.53–4.65 (m, 1H), 5.13
d
(dt, 1H, 2JFH = 48.9 Hz, 3JFH = 8.8 Hz) ppm. 13C NMR (CDCl3):
(s, CH3), 22.28 (dd, 2x CH2, 3JCF = 4 Hz), 82.81 (t, CH, 2JCF = 27.5 Hz),
d 9.07
1JCF = 213.5 Hz, JCF = 26.9 Hz, JCF = 18.9 Hz), 118.9 (dt, CF2,
2
2
1
2
2
2
2
83.13 (ddd, CHF, JCF = 206.6 Hz, JCF = 33.7 Hz, JCF = 33.7 Hz),
1JCF = 257.6 Hz, JCF = 14.9 Hz), 164.6 (dd, C55O, JCF = 22.3 Hz,
1
2
118.49 (dt, CF2, JCF = 258.8 Hz, JCF = 16 Hz), 164.55 (ddd, C55O,
3JCF = 15.5 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ119.4 (ddt, 1F,
2JCF = 22.1 Hz, JCF = 4.8 Hz, JCF = 3.8 Hz) ppm. 19F NMR (CDCl3):
d
2JFF = 237.3 Hz, JFF = 3JFH = 8 Hz), ꢀ133.6 (ddt, 1F, JFF = 237.1 Hz,
3
3
3
2
ꢀ118.48 (dddd, 1F, JFF = 230.1 Hz, JFF = 3JFH = 7.5 Hz), 124.13
3JFF = 3JFH = 15.4 Hz, JFH = 6.1 Hz), ꢀ219.1 (dt, 1F, JFF = 48.3 Hz,
3JFF = 6.7 Hz) ppm. GC–EIMS: m/z (rel. int.): 218 (0.3) [M ꢀ 20]+,
209 (0.3), 195 (3.3), 176 (3), 169 (3), 149 (3.5), 148 (8.3), 135 (4.5),
111 (6), 97 (7.5), 84 (25), 83 (17), 69 (34), 56 (74), 43 (100).
2
3
3
2
(dddd, 1F, JFF = 247.9 Hz, JFF = 3JFH = 7.7 Hz), ꢀ218.62 (dt, 1F,
2
3
2
3
CHF, JHF = 48.5 Hz, JFF = 7 Hz) ppm. GC–EIMS: m/z (rel. int.): 169
(19) [M + 1]+, 149 (32), 139 (5.7), 129 (17), 119 (3.2), 111 (10), 103
(13), 95 (90), 91 (34), 82 (100), 77 (34), 73 (28), 64 (12), 57 (64), 51
(18), 47 (11), 41 (9.2), 29 (45).
Diastereoisomer B: 1H NMR (CDCl3):
1.88 (m, 12H), 4.56–4.70 (m, 1H), 5.14 (dt, 1H, JFH = 48 Hz,
d 0.82–0.98 (m, 3H), 1.19–
2
Diastereoisomer B: 1H NMR (CDCl3):
4.50 (m, 1H), 5.30 (ddd, 1H, JFH = 48.4 Hz, JFH = 14.3 Hz,
3JFH = 8.2 Hz) ppm. 13C NMR (CDCl3):
d
1.66–2.00 (m, 2H), 4.37–
3JFH = 8.2 Hz) ppm. 13C NMR (CDCl3):
d 13.9 (s, CH3), 22.5–31.5 (m,
(CH2)6), 81.7 (t, CH, 2JCF = 26.9 Hz), 83.1 (ddd, CHF, 1JCF = 206.6 Hz,
2
3
2
d
8.81 (s, CH3), 20.24 (d,
2JCF = 33.7 Hz, JCF = 18.9 Hz) ppm, other signals overlapped with
3
2
2
CH2, JCF = 6.3 Hz), 80.03 (dd, CH, JCF = 28.1 Hz, JCF = 24.6 Hz),
noise. GC–EIMS: m/z (rel. int.): 218 (0.5) [M ꢀ 20]+, 209 (0.5), 195
(2), 189 (2), 176 (4.5), 155 (3), 148 (11), 135 (6.5), 111 (11.5), 109
(7.5), 84 (31), 69 (39), 56 (80.5), 43 (100).
1
2
2
84.13 (ddd, CHF, JCF = 213.5 Hz, JCF = 26.9 Hz, JCF = 18.9 Hz),
1
2
118.79 (dt, CF2, JCF = 258.8 Hz, JCF = 14.9 Hz), 162.4 (d, C55O,
2JCF = 21.2 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ119.12 (ddt, 1F,
2JFF = 247.7 Hz, JFF = 3JFH = 13.7 Hz, JFH = 7.9 Hz), ꢀ133.45 (ddt,
1F, 2JFF = 238 Hz, 3JFF = 3JFH = 15.2 Hz, 3JFH = 6 Hz), ꢀ216.8 (ddd, 1F,
CHF, 2JFH = 48.9 Hz, 3JFF = 10.7 Hz, 3JFF = 6.9 Hz) ppm. GC–EIMS: m/z
(rel. int.): 169 (37) [M + 1]+, 149 (88), 139 (7.2), 129 (39), 119 (6.5),
109 (11), 103 (23), 95 (100), 91 (39), 82 (94), 77 (37), 64 (11), 57
(60), 53 (13), 41 (85), 29 (17).
5.5.6. 5-(3-Bromopropyl)-3,4,4-trifluorodihydrofuran-2-one (43)
Refluxing a mixture of hydroxyester 42 (10.05 g, 34.3 mmol)
and TsOH.H2O (322 mg, 1.69 mmol) in toluene (50 mL) for 4 days
gave a mixture dihydrofuranone 43 and furanone 44 (7.87 mg,
30.2 mmol, 88.1%) as a colourless oil in a ratio of 43/44 = 33/77
with the diasteromeric ratio of 43 A/B = 88/12, b.p. = 95–102 8C/
3
3
0.1 mmHg. Diastereoisomer A: 1H NMR (CDCl3):
4H), 3.47 (s, 2H, JHH = 5), 4.62–4.79 (m, 1H), 5.33 (ddd, 1H,
2JFH = 48.4 Hz, 3JFH = 14.3 Hz, 3JFH = 7.7 Hz) ppm. 13C NMR (CDCl3):
25.4 (s, CH2), 27.6 (d, CH2CH, 3JCF = 23.4 Hz), 32 (s, BrCH2), 78 (dd,
d 1.78–2.26 (m,
3
5.5.4. 3,4,4-Trifluoro-5-propyldihydrofuran-2-one (29)
Refluxing a mixture of hydroxyester 10 (1.14 g, 5.23 mmol) and
TsOH.H2O (49 mg, 0.26 mmol) in toluene (10 mL) for 8 days gave a
mixture of dihydrofuranone 29 and furanone 33 (851 mg,
4.68 mmol, 89.4%) as a colourless oil. The ratio 29/33 was 91/9
and the ratio of diastereoisomers of 29 was 61/39. Diastereoisomer
d
2
2
1
CH, JCF = 30.3 Hz, JCF = 24.7 Hz), 83.9 (ddd, CHF, JCF = 214.1 Hz,
2JCF = 27.5 Hz, JCF = 18.9 Hz), 118.3 (dt, CF2, JCF = 258.2 Hz,
2
1
2JCF = 24.1 Hz), 163.9–164.5 (m, C55O) ppm. 19F NMR (CDCl3):
d
1
2
A: 1H NMR (CDCl3):
4.69 (m, 1H), 5.36 (ddd, 1H, JFH = 48.4 Hz, JFH = 14.3 Hz,
3JFH = 7.7 Hz) ppm. 13C NMR (CDCl3):
d
0.94–0.8 (m, 3H), 1.38–2.02 (m, 4H), 4.44–
ꢀ119.9 (dm, 1F, JFF = 236 Hz), ꢀ133.2 (ddt, 1F, JFF = 236.1 Hz,
3JFF = 3JFH = 16.4 Hz, 3JFH = 5.5 Hz), ꢀ219.5 (d, 2JHF = 48.2) ppm. GC–
EIMS: m/z (rel. int.): 262 (12) [M + 1]+, 260 (12) [M ꢀ 1]+, 243 (2.4),
223 (2.4), 199 (5.2), 181 (76), 161 (35), 152 (5.2), 141 (27), 121 (20),
106 (26), 97 (58), 77 (73), 71 (35), 65 (17), 55 (33), 39 (100), 29 (31).
Diastereoisomer B: 1H NMR (CDCl3):
2H, JHH = 5), 4.49–4.62 (m, 1H), 5.16 (dt, 1H, JFH = 48.9 Hz,
2
3
d 13.25 (s, CH3), 17.72 (s,
3
2
CH2), 28.3 (d, CH2, JCF = 5.2 Hz), 78.4 (dd, CH, JCF = 28.6 Hz,
2JCF = 22.9 Hz), 84.15 (ddd, CHF, JCF = 212.4 Hz, JCF = 26.9 Hz,
1
2
2JCF = 18.9 Hz), 118.91 (dt, CF2, JCF = 257.6 Hz, JCF = 14.9 Hz),
d
1.78–2.26 (m, 4H), 3.47 (s,
1
2
2
3
3
2
164.83 (dd, C55O, JCF = 21.8 Hz, JCF = 16.1 Hz) ppm. 19F NMR
2
3
(CDCl3):
d
ꢀ119.42 (ddt, 1F, JFF = 237 Hz, JFF = 3JFH = 7.4 Hz),
3JFH = 8.8 Hz) ppm. 13C NMR (CDCl3):
d
25.3 (s, CH2), 27.6 (bs, CH2),
2
ꢀ133.54
(ddt,
1F,
2JFF = 237.4 Hz,
3JFF = 3JFH = 15.5 Hz,
32 (s, BrCH2, 80.8 (t, CH, JCF = 26.3 Hz), 82.9 (ddd, CHF,
3JFH = 6.3 Hz),
ꢀ218.95
(dt,
CHF,
1F,
2JFF = 48.4 Hz,
1JCF = 206.6 Hz, JCF = 34.3 Hz, JCF = 18.3 Hz), 118.3 (dt, CF2,
2
2
3JFF = 6.9 Hz) ppm. GC–EIMS: m/z (rel. int.): 162 (0.01) [M ꢀ 20]+,
154 (0.25), 139 (2.5), 117 (2.5), 111 (6.5), 103 (21), 91 (16), 82 (28),
77 (32), 60 (32), 56 (61), 41 (100).
1JCF = 258.2 Hz, JCF = 25.8 Hz), 163.9–164.5 (m, C55O) ppm. 19F
2
NMR (CDCl3):
d
ꢀ119.3 (dm, 1F, 1JFF = 261.6 Hz), ꢀ124.5 (dddd, 1F,
2JFF = 246.2 Hz,
3JFF = 3JFH = 9.7 Hz),
ꢀ218.2
(d,
1F,
Diastereoisomer B: 1H NMR (CDCl3):
2.02 (m, 4H), 4.44–4.69 (m, 1H), 5.18 (dt, 1H, JFH = 52.8 Hz,
d
0.94–0.98 (m, 3H), 1.38–
2JHF = 49.2 Hz) ppm.
2
3JFH = 10.4 Hz) ppm. 13C NMR (CDCl3):
d
13.12 (s, CH3), 17.97 (s,
5.5.7. Lactonisation of methyl 2,3,3-trifluoro-4,5-
CH2), 30.66 (t, CH2, 3JCF = 2.5 Hz), 81.45 (t, CH, 2JCF = 26.3 Hz), 83.05
(ddd, CHF, 1JCF = 206.6 Hz, 2JCF = 33.2 Hz, 2JCF = 18.3 Hz), 118.57 (dt,
dihydroxypentanoate (36)
Refluxing of dihydroxyester 36 (820 mg, 4.06 mmol) with
TsOH.H2O (39 mg, 0.21 mmol) in toluene (5 mL) gave 543 mg of a
mixture of dihydrofuranone 37 (21% rel.), furanone 39 (11% rel.),
dihydropyranone 38 (60% rel.) and pyranone 40 (8% rel.). The ratio
of diastereoisomers of 37 = 100/0 and ratio of diastereoisomers of
38 = 39/61. The mixture was separated from salts by short column
chromatography (silica gel 5 g, diethyl ether). All attempts to
separate products failed.
1
2
2
CF2, JCF = 257.6 Hz, JCF = 16 Hz), 162.74 (dd, C55O, JCF = 25.2 Hz,
3JCF = 13.1 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ119.85 (dddd, 1F,
2JFF = 247 Hz, JFF = 15.3 Hz, JFH = 5.1 Hz, JFH = 6.6 Hz), ꢀ124.42
3
3
3
(ddt, 1F, JFF = 247 Hz, JFF = 3JFH = 16.7 Hz), ꢀ217.18 (dt, 1F, CHF,
2
3
2JFH = 48.8 Hz, JFF = 7.7 Hz) ppm. GC–EIMS: m/z (rel. int.): 154
3
(0.25), 139 (3), 133 (0.75), 120 (1.0), 111 (6.2), 103 (22), 95 (14), 91
(18), 77 (31), 72 (16), 60 (34), 56 (62), 41 (100).
3,4,4-Trifluoro-5-hydroxymethyldihydrofuran-2-one (37). 19F
2
5.5.5. 3,4,4-Trifluoro-5-heptyldihydrofuran-2-one (30)
NMR (CDCl3):
d
ꢀ119.7 (dm, 1F, JFF = 246.4 Hz), ꢀ131.9 (dm,
Refluxing a mixture of hydroxyester 11 (1.05 g, 3.89 mmol) and
TsOH.H2O (37 mg, 0.19 mmol) in toluene (20 mL) for 2 days gave
mixture of dihydrofuranone 30 and furanone 34 (858 mg,
3.61 mmol, 92.8%) as a colourless oil. The ratio of 30/34 was 92/
8 and the ratio of diasteromers of 30 (A/B) was 93/7. Diastereo-
1F, 2JFF = 246.8 Hz), ꢀ224.3 (dm, 1F, 2JHF = 23.6 Hz) ppm. GC–EIMS:
m/z (rel. int.): 171 (1.6) [M + 1]+, 151 (10), 133 (2.4), 120 (98), 105
(1.6), 91 (29), 71 (10), 63 (21), 44 (16), 37 (4), 31 (100).
3,4,4-Trifluoro-5-hydroxytetrahydropyran-2-one (38). Diastereo-
isomer A: 19F NMR (CDCl3):
d
ꢀ115.3 (dm, 1F, 2JFF = 244), ꢀ123.3–
isomer A: 1H NMR (CDCl3):
d
0.82–0.98 (m, 3H), 1.19–1.88 (m, 12H),
(ꢀ124.3) (m, 1F), ꢀ217.5 (dm, 1F, JHF = 48.6 Hz);
2

J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
57
Diastereoisomer B: 19F NMR (CDCl3):
d
ꢀ118.0 (dm, 1F,
diethyl ether (10 mL) afforded furanone 34 (679 g, 3.08 mmol,
93.4%). 1H NMR (CDCl3): 0.88 (t, 3H, 3JHH = 6.6 Hz), 1.14–1.62 (m,
10H), 1.63–1.78 (m, 1H), 1.92–2.07 (m, 1H), 5.49 (ddt, 1H,
2JFF = 241.3 Hz), ꢀ123.3–(ꢀ124.3) (m, 1F), ꢀ218.73 (dm, 1F,
2JHF = 49.3 Hz) ppm. GC–EIMS: m/z (rel. int.): 171 (11) [M + 1]+,
151 (4), 140 (7.3), 120 (35), 111 (4), 91 (30), 82 (19), 77 (12), 64
(13), 51 (15), 43 (45), 31 (100).
d
3JHH = 7.5 Hz, JHF = 5 Hz, JHF = 3.9 Hz) ppm. 13C NMR (CDCl3):
d
3
4
14 (s, CH3), 22.5–31.6 (m, (CH2)6), 73.6 (d, CH, 2JCF = 19.5 Hz), 127.7
(d, CF, 1JCF = 272.5 Hz), 156.8 (d, CF, 1JCF = 296.6 Hz), 162.6 (dd, C O,
5.6. Dehydrofluorination
2JCF = 25.2 Hz, 3JCF = 13.1 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ125.7 (dd,
1F, JFF = 3JFH = 3.8 Hz), ꢀ164 (d, 1F, JFF = 3.8 Hz) ppm. GC–EIMS:
m/z (rel. int.): 203 (0.5) [M ꢀ 15]+, 189 (1.5) [M ꢀ 19]+, 183 (1), 169
(6), 155 (8), 144 (6), 133 (45), 119 (32), 111 (9.5), 97 (15), 97 (15),
82 (17), 69 (12), 57 (81), 55 (54). C11H16F2O2 (218.24): calcd C
60.54, H 7.39; found C 60.47, H 7.48.
3
3
5.6.1. General procedure
A mixture of dihydrofuranone and furanone, diethylether and
triethylamine (1.1 mol based on the content of dihydrofuranone)
was stirred for 45 min at r.t, which led to complete conversion of
dihydrofuranone to the targeted furanones (check by 19F NMR).
The mixture was neutralised with an equivalent of conc. HCl. The
precipitated salts were filtered off and diethyl ether was
evaporated. Crude furanone was purified by column chromatog-
raphy (silica gel 10 g, CH2Cl2) or distilled under vacuum.
5.6.6. 5-(3-Bromopropyl)-3,4-difluorofuran-2(5H)-one (44)
Reaction of a mixture of dihydrofuranone 43 and furanone 44
(7.21 g, 9.12 mmol) with triethylamine (1.12 g, 10.9 mmol) in
diethyl ether (50 mL) afforded furanone 44 (6.78 g, 28.1 mmol,
88.3%), b.p. 100–102 8C/0.08 mmHg. 1H NMR (CDCl3):
d 1.76–2.28
3
5.6.2. 3,4-Difluoro-5-methylfuran-2(5H)-one (31)
(m, 4H), 3.44 (t, 2H, JHH = 6 Hz), 4.9–5.01 (m, 1H) ppm. 13C NMR
4
Reaction of a mixture of dihydrofuranone 27 and furanone 31
(5.20 g, 33.8 mmol) with triethylamine (3.76 g, 37.1 mmol) in
diethyl ether (30 mL) afforded furanone 31 (4.77 g, 35.6 mmol,
(CDCl3):
d
27 (d, BrCH2CH2, JCF = 6.2 Hz), 29.7 (s, BrCH2), 32 (d,
3
2
CH2CH, JCF = 7.4 Hz), 72.8 (d, CH, JCF = 18.8 Hz), 127.8 (d, CF,
1JCF = 270.9 Hz), 156.3 (d, CF, JCF = 294.8 Hz), 162.1 (dd, C55O,
1
91.7%), b.p. 40–41 8C/2 mmHg. 1H NMR (CDCl3):
d
1.59 (dd, 3H,
2JCF = 25.1 Hz, 3JCF = 13.1 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ125.8 (dd,
3JHH = 6.6 Hz, 4JHF = 1.1 Hz), 5.0 (ddq, 1H, 3JHH = 6.6 Hz,
1F,
3JFF = 3JFH = 3.2 Hz),
ꢀ163.1
(dd,
1F,
3JFF = 5.2 Hz,
4
3JHF = 5.5 Hz, JHF = 3.3 Hz) ppm. 13C NMR (CDCl3)
d
16.9 (s, CH3),
3JFH = 3.2 Hz) ppm. GC–EIMS: m/z (rel. int.): 242 (3.8) [M + 1]+,
240 (4.4) [M ꢀ 1]+, 213 (1.9), 211 (1.9), 186 (3.2), 184 (2.5), 162
(1.3), 160 (16), 151 (24), 149 (26), 133 (83), 132 (77), 120 (13), 119
(100), 117 (10), 106 (22), 97 (7), 95 (9), 91 (39), 90 (13), 75 (10), 71
(9), 63 (30), 57 (11), 51 (7.6), 41 (42). C7H7F2O2Br (241.03): calcd C
34.88, H 2.93; found C 35.11, H 2.93.
2
3
70.1 (dd, CH, JCF = 19.8 Hz, JCF = 2.4 Hz), 127.4 (d, CF,
1JCF = 271.6 Hz), 157.6 (d, CF, JCF = 297.2 Hz), 162.5 (dd, C55O,
2JCF = 24.9 Hz, JCF = 12.8 Hz) ppm. 19F NMR (CDCl3):
1
3
d
ꢀ126.4 (s,
1F), ꢀ164.7 (s, 1F) ppm. GC–EIMS: m/z (rel. int.): 134 (4.1) [M]+,
119 (34), 105 (3.7), 91 (12), 88 (0.5), 77 (1.8), 71 (3.7), 64 (0.9), 63
(14), 51 (3.7), 44 (2.3), 43 (100). C5H4F2O2 (134.08): calcd C 44.79,
H 3.01; found C 44.49, H 3.06.
5.6.7. 3,4-Difluoro-5-(3-iodopropyl)furan-2(5H)-one (45)
A mixture of furanone 44 (2.31 g, 9.59 mmol), dry NaI (2.88 g,
19.2 mmol) and acetone (50 mL) was reacted at r.t. under inert
atmosphere until complete conversion of 44 (check by 19F NMR).
Precipitate was filtered off, the solvent evaporated (rotary
evaporator) and the residue purified by column chromatography
(silica gel 10 g, CH2Cl2) to afford 45 (2.62 g, 94.8%) as slightly
yellow oil.
5.6.3. 5-Ethyl-3,4-difluorofuran-2(5H)-one (32)
Reaction of a mixture of dihydrofuranone 28 and furanone 32
(852 mg, 5.07 mmol) with triethylamine (341 mg, 3.37 mmol) in
diethyl ether (10 mL) afforded furanone 32 (721 g, 4.87 mmol,
96.0%). 1H NMR (CDCl3):
d
1.01 (t, 3H, 3JHH = 7.7 Hz), 1.77 (pseudo
sept, 1H, 3JHH = 7.1 Hz), 1.96–2.1 (m, 1H), 4.9 (m, 1H) ppm. 13C NMR
(CDCl3):
7.85 (s, CH3), 24.35 (s, CH2), 74.37 (d, CH, 2JCF = 18.9 Hz,),
127.9 (d, CF, JCF = 273.9 Hz), 156.38 (d, CF, JCF = 290.3 Hz) ppm.
19F NMR (CDCl3):
d
1H NMR (CDCl3):
d
1.77–2.22 (m, 4H), 3.22 (t, 3H, 3JHH = 6.6 Hz),
1
1
3
3
4
4.95 (ddt, 1H, JHF = 8.2 Hz, JHF = 5.2 Hz, JHF = 3.6 Hz) ppm. 13C
d
ꢀ126.16 (s, 1F), ꢀ163.67 (s, 1F) ppm. GC–EIMS:
NMR (CDCl3):
1JCF = 269.9 Hz), 155.95 (d, 1JCF = 296 Hz), 161.8 (dd, 2JCF = 24.9 Hz,
3JCF = 12.9 Hz) ppm. 19F NMR (CDCl3):
d
27.5 (s), 31.7 (bs), 72.4 (d, 2JCF = 18.6 Hz), 127.3 (d,
m/z (rel. int.): 149 (24.2) [M + 1]+, 131 (2.4), 119 (100), 103 (3.2), 91
(23), 83 (4), 75 (4.8), 71 (10), 63 (10), 57 (44), 51 (6), 43 (48), 39 (9),
29 (22). C6H6F2O2 (148.11): calcd C 48.66, H 4.08; found C 48.60, H
4.12.
d
ꢀ125.9 (s, 1F), ꢀ162.95 (s,
1F) ppm. GC–EIMS: m/z (rel. int.): 289 (4.8) [M + 1]+, 271 (0.4), 243
(2.4), 197 (0.8), 161 (100), 141 (6.5), 119 (92), 85 (21), 77 (8.1), 57
(7.7), 39 (29), 31 (2.8). C7H7F2IO2 (288.03): calcd C 29.19, H 2.45;
found C 29.41, H 2.63.
5.6.4. 3,4-Difluoro-5-propylfuran-2(5H)-one (33)
Reaction of a mixture of dihydrofuranone 29 and furanone 33
(805 mg, 4.42 mmol) with triethylamine (495 mg, 4.89 mmol) in
diethyl ether (10 mL) afforded furanone 33 (637 mg, 3.93 mmol,
5.6.8. Dehydrofluorination of mixture of dihydrofuranone 37 and
dihydropyranone 38
88.8%). 1H NMR (CDCl3):
d
0.94 (t, 3H, 3JHH = 8.1 Hz), 1.40–1.54 (m,
Reaction of a mixture (508 mg, 2.99 mmol) of dihydrofuranone
37 (21%), furanone 39 (8%), dihydropyranone 38 (60%) and
pyranone 40 (11%) with triethylamine (335 mg, 3.31 mmol) in
diethyl ether (15 mL) afforded a mixture of furanone 39 and
pyranone 40 (458 mg, 3.05 mmol, 90.1%) in a ratio of 39/40 = 33/
67.
2H), 1.61–1.73 (m, 1H), 1.87–1.98 (m, 1H), 4.92 (ddt, 1H,
3
4
3JHF = 11 Hz, JHH = 4 Hz, JHF = 1.6 Hz) ppm. 13C NMR (CDCl3):
d
13.29 (s, CH3), 17.16 (s, CH2), 32.9 (s, CH2), 73.35 (d, CH,
1
2JCF = 18.9 Hz), 127.58 (d, CF, JCF = 271.4 Hz), 156.76 (d, CF,
1JCF = 296.6 Hz),
162.47
(dd,
C55O,
d
2JCF = 23.9 Hz,
ꢀ124.53 (d, 1F,
3JCF = 11.9 Hz) ppm. 19F NMR (CDCl3):
3,4-Difluoro-5-(hydroxymethyl)furan-2(5H)-one (39). IR: 1058
3JFF = 4.4 Hz), ꢀ162.19 (d, 1F, JFF = 4.4 Hz) ppm. GC–EIMS: m/z
(rel. int.): 162 (1.5) [M]+, 144 (0.5), 134 (1), 133 (14), 120 (22), 106
(0.5), 97 (1.5), 91 (7.5), 85 (1), 71 (19), 63 (11), 57 (4), 43 (100).
C7H8F2O2Br (242.04): calcd C 51.86, H 4.97; found C 51.79, H 5.05.
(primary OH), 1739, 1801, 3443 cmꢀ1
1H, JHH = 13 Hz), 4.48 (dd, 1H, JHH = 12.8 Hz, JHH = 3.2 Hz), 5.0
.
1H NMR (CDCl3):
d
4.12 (d,
3
2
2
3
(dd, 1H, 3JHH = 4.8 Hz, 3JHH = 3 Hz) ppm. 19F NMR (CDCl3):
(dd, 1F,
3JFF = 3.7 Hz, 3JHF = 3.6 Hz);
ꢀ161.8
3JFF = 3.7 Hz) ppm.
3,4-Difluoro-5-hydroxy-5,6-dihydropyran-2-one (40). IR: 1191
(secondary OH), 1765, 3443 cmꢀ1. 1H NMR (CDCl3):
3.89 (dd, 1H,
2JHH = 13 Hz, 3JHH = 3 Hz); 4.43 (dd, 1H, 2JHH = 12.8 Hz,
d
ꢀ126.4
(d, 1F,
5.6.5. 3,4-Difluoro-5-heptylfuran-2(5H)-one (34)
Reaction of a mixture of dihydrofuranone 30 and furanone 34
(786 mg, 3.30 mmol) with triethylamine (365 mg, 3.61 mmol) in
d

58
J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
3JHH = 4.2 Hz), 4.66 (ddd, 1H, 3JHH = 4.2 Hz, 3JHH = 3 Hz,
3JHH = 8 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ114.4 (dd, CClF,
0.88 (t, CH3,
3
3JHF = 3.6 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ123.4 (dd, 1F, 3JFF = 9.8 Hz,
3JHF = 20 Hz, JHF = 22 Hz) ppm.
3
3JHF = 4.6 Hz), ꢀ155.1 (d, 1F, JFF = 3.7 Hz) ppm.
Diastereoisomer B: 1H NMR (CDCl3):
d
C5H4F2O3 (150.08): calcd C 40.01, H 2.69; found C 40.77, H 3.72.
3JHH = 7 Hz), 1.75 (m, 5 ꢁ CH2), 2.39 (ddd, Ha of 3-CH2,
2JHH = 14 Hz, 3JHH = 10 Hz, 3JHF = 15 Hz), 2.96 (dd, Hb of 3-CH2,
5.7. Synthetic sequence to 3-chloro-3-fluoro-5-hexyldihydrofuran-2-
one (49) and attempted 3-chloro-3-fluoro-5-methoxydihydrofuran-
2-one (53)
2JHH = 14 Hz, 3JHH = 5 Hz), 4.53 (ddt, CH, 3JHH = 5 Hz,
3
3JHH = 8 Hz, JHH = 10 Hz) ppm. 19F NMR (CDCl3):
d
ꢀ119.2
3
(d, CClF, JHF = 15 Hz) ppm. C10H16ClFO2 (222.69) (mixture of
diastereoisomers): calcd C 53.94, H 7.24; found C 53.87, H
7.37.
5.7.1. Methyl 2-bromo-2-chloro-2-fluoroacetate (46)
For experimental details see Supplementary data.
5.7.5. Methyl 4-acetoxy-4-bromo-2-chloro-2-fluorobutanoate (50)
The reaction was carried out in the apparatus as for 47.
Dibenzoyl peroxide (0.2 g, 0.8 mmol) was dispersed in vinyl
acetate (1.5 g, 17.4 mmol). Halogenoacetate 46 (10.73 g,
52.2 mmol) in flask was cooled to ꢀ20 8C and deoxygenated with
argon for 30 min. Then was heated to 90 8C and the dispersion was
added dropwise through septum while stirring, the mixture was
then heated to 80 8C for 1 h. Volatile components were removed
under reduced pressure (40 Pa, bath 80 8C) and the residue was
chromatographed (toluene) to afford 50, yield 3.15 g (61%). 1H
5.7.2. Methyl 4-bromo-2-chloro-2-fluorodecanoate (47)
The reaction was carried out under argon in double-necked
flask (25 mL) equipped with low temperature reflux condenser. A
mixture of dibenzoyl peroxide (0.5 g, 2 mmol), halogenoacetate
46 (25.2 g, 0.123 mol) and oct-1-ene (5 g, 41 mmol) was cooled
to ꢀ20 8C and deoxygenated with argon for 30 min. The mixture
was then heated to 90 8C for 3.5 h while stirring. Unreacted
components were then distilled off (bath 80 8C, 40 Pa), the
residue was dissolved in dichloromethane (100 mL), filtered
through silica gel and chromatographed (CHCl3–petroleum ether
1:10) to afford separated diastereoisomers of 47 in total yield of
6.57 g (51%).
NMR (D2O):
d 2.08 (t, CH3), 3.4 (m, CH2), 3.96 (s, OCH3), 6.8 (m,
CHBr) ppm. Diastereoisomer A: 19F NMR (D2O):
d
ꢀ120.4 (dd, CClF,
3JHF = 13 Hz, JHF = 22 Hz) ppm.
3
Diastereoisomer A: 1H NMR (CDCl3):
d
0.85 (t, CH3, 3JHH = 6 Hz),
Diastereoisomer B: 19F NMR (D2O):
d
ꢀ116.7 (dd, CClF,
2
3
1.8 (m, 5-CH2), 1.25 (m, 8H), 2.88 (ddd, Ha of 3-CH2, JHH = 16 Hz,
3JHF = 14 Hz, JHF = 20 Hz) ppm.
3
2
3JHH = 7 Hz, JHF = 19 Hz), 3.05 (ddd, Hb of 3-CH2, JHH = 16 Hz,
C6H9BrClFO2 (247.49) (mixture of diastereoisomers): calcd C
29.12, H 3.67; found: C 28.97, H 3.84.
3
3JHH = 6 Hz, JHF = 19 Hz), 3.9 (s, OCH3), 4.25 (m, CHBr) ppm. 19F
3
NMR (CDCl3):
d
ꢀ114.4 (t, CClF, JHF = 19 Hz) ppm.
Diastereoisomer B: 1H NMR (CDCl3):
1.85 (m, 5-CH2), 1.25 (m, 8H), 2.88 (ddd, Ha of 3-CH2, 2JHH = 16 Hz,
d
0.9 (t, CH3, JHH = 6 Hz),
5.7.6. Methyl 2-chloro-2-fluoro-4,4-dimethoxybutanoate (51)
Under dry conditions, a mixture of butanoate 50 (3.55 g,
12.2 mmol) and methanol (1.5 g, 46.9 mmol) was stirred for 12 h
under RT. The product 51 was extracted in CFC-113 and the extract
neutralised with solid NaHCO3. After filtration and evaporation of
CFC, the product 51 was obtained by distillation in minimised
apparatus, bp 87–88 8C/67 Pa, yield 1.21 g (46.8%). 1H NMR (D2O):
3
2
J = 4 Hz, J = 11 Hz), 3.06 (ddd, Hb of 3-CH2, JHH = 16 Hz, J = 9 Hz,
J = 27 Hz), 3.9 (s, OCH3), 4.15 (m, CHBr) ppm. 19F NMR (CDCl3):
d
ꢀ119.9 (m, CClF) ppm. C11H19BrClFO2 (317.62) (mixture of
diastereoisomers): calcd C 41.60, H 6.03; found C 41.78, H 6.22.
2
3
3
5.7.3. Sodium 4-bromo-2-chloro-2-fluorodecanoate (48)
A mixture of halogenodecanoate 47 (0.5 g, 1.57 mmol), sodium
hydrogencarbonate (0.2 g, 2 mmol), methanol (4 mL) and water
(3 mL) was refluxed for 12 h. Evaporation of solvents and drying
under vacuum afforded the salt 48 (532 mg), which was used in
cyclisation attempts.
d 2.61 (ddd, Ha, CH2, JHH = 14.5 Hz, JHH = 7.9 Hz, JHF = 29.6 Hz),
2
3
3
2.79 (ddd, Hb, CH2, JHH = 14.5 Hz, JHH = 3.6 Hz, JHF = 8.9 Hz), 3.3
(s, OCH3), 3.32 (s, OCH3), 4.57 (dd, CH, 3JHH = 3.5 Hz,
3JHH = 8.9 Hz) ppm. 19F NMR (D2O):
J = 12.3 Hz, J = 25.8 Hz) ppm.
d
ꢀ117.6 (dd, CClF,
C7H12ClFO4 (214.62): C 39.17, H 5.64, Cl 17.52, F 9.26; found C
39.04, H 5.26, Cl 18.53; F 9.76.
1H NMR (D2O):
d
0.99 (t, CH3, 3JHH = 7 Hz), 1.5 (m, 10H), 2.55 (m,
3-CH2), 4.04 (m, CHBr) ppm. 19F NMR (D2O): diastereoisomer A:
d
d
3
3
ꢀ118.7 (dd, CClF, JHF = 18 Hz, JHF = 27 Hz); diastereoisomer B:
5.7.7. 2-Chloro-2-fluoro-4,4-dimethoxybutanoic acid (52) and its
attempted cyclisation
3
ꢀ109.4 (t, CClF, JHF = 17 Hz) ppm.
Water solution of sodium hydroxide (0.151 M) was added
5.7.4. 2-Chloro-2-fluoro-4-hexyltetrahydrofuran-2-one (49)
dropwise to a mixture of dimethoxy-butanoate 51 (0.5 g,
Procedure A: A mixture of methyl halogenodecanoate 47 (4.29 g,
13.5 mmol), conc. hydrochloric acid (0.5 mL), methanol (25 mL)
and water (2 mL) was refluxed for 80 h. The mixture was then
neutralised with conc. solution of NaHCO3 and the raw product 49
extracted with CFC-113. After evaporation of the solvent, pure 49
was isolated by column chromatography (toluene) in yield of
2.18 g (74%).
1.72 mmol), methanol (5 mL), solution of sodium hydroxide
(0.151 M, 10 mL) and drop of phenolphtaleine at 50 8C while
stirring until pink coloration of the mixture. The solution was
evaporated and the residue was dried in vacuum to obtain 0.521 g
(100%) of sodium 2-chloro-2-fluoro-4,4-dimethoxybutanoate. 19F
3
NMR (D2O):
In
d
ꢀ107.9 (t, CClF, JHF = 20 Hz) ppm.
a
dropping funnel, water solution (1 mL) of sodium
Procedure B: Sodium halogenodecanoate 48 (1 g, 3.07 mmol)
was dispersed in dimethylsulfoxide (5 mL) and heated to 80 8C for
3 h while stirring. The mixture was then diluted with water and
extracted with Freon 113. After evaporation of the solvent, pure 49
was isolated by column chromatography (toluene) in yield 0.511 g
(66%).
butanoate 51 (0.3 g, 1.35 mmol) was mixed with diethyl ether
(10 mL) and hydrochloric acid was added to pH = 1. Organic layer
was evaporated, the residue appeared to be a mixture of products
(
19F NMR, GC, CC) and the separation of the expected product 53
was unsuccessful.
A mixture of sodium butanoate 51, p-toluenesulfonic acid
(110 mol% of 51) and toluene was refluxed. Analysis of the
reaction progress (19F NMR, GC) identified formation of a mixture
of products. Separation of the expected product 53 was
unsuccessful.
Diastereoisomer A: 1H NMR (CDCl3):
d
0.88 (t, CH3, 3JHH = 7 Hz),
1.75 (m, 5 x CH2), 2.52 (ddd, Ha of 3-CH2, 2JHH = 15 Hz, 3JHH = 7 Hz,
2
3
3JHF = 22 Hz), 3.09 (ddd, Hb of 3-CH2, JHH = 15 Hz, JHH = 7 Hz,
3JHF = 19 Hz), 3JHH = 6 Hz, 3JHH = 7 Hz,
4.64 (ddt, CH,

J. Hajduch et al. / Journal of Fluorine Chemistry 162 (2014) 45–59
59
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ical Materials and Pharmaceuticals, Elsevier, Amasterdam, 2008, pp. 553–778;
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(m) W.K. Hagmann, J. Med. Chem. 51 (2008) 4359–4369;
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(o) D. O’Hagan, J. Fluorine Chem. 131 (2010) 1071–1081.
Acknowledgements
The research was supported by the Ministry of Education of the
Czech Republic (Project MSM 6046137301) and by the Technology
Prague (Grant 110010055).
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