Facile synthesis of α,α-difluoroalkyl aryl thioethers and their oxidative desulfurization-fluorination to trifluorides

Article abstract of DOI:10.1016/j.jfluchem.2010.06.010

Alkyl 2-arylthio-2,2-difluoroacetates are synthesized in 52-77% yield from alkyl 2-(arylthio)acetates via two succeeding fluoro-Pummerer rearrangements using the reagents combination of N-haloimides as electrophiles and excess Py·9HF as the fluoride source at room temperature. Subsequent treatment of the formed fluorinated thioethers with the same reagents at elevated temperature gave alkyl trifluoroacetates in almost quantitative yield under optimised conditions by oxidative desulfurization-fluorination.

Full text of DOI:10.1016/j.jfluchem.2010.06.010

Journal of Fluorine Chemistry 131 (2010) 942–950
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Facile synthesis of
a,a-difluoroalkyl aryl thioethers and their oxidative
desulfurization–fluorination to trifluorides
*
Verena Hugenberg, Gu¨nter Haufe
Organisch-Chemisches Institut, Corrensstr. 40, and European Institute for Molecular Imaging, Mendelstraße 11, Westfa¨lische Wilhelms-Universita¨t, D-48149 Mu¨nster, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
Alkyl 2-arylthio-2,2-difluoroacetates are synthesized in 52–77% yield from alkyl 2-(arylthio)acetates via
two succeeding fluoro-Pummerer rearrangements using the reagents combination of N-haloimides as
electrophiles and excess PyÁ9HF as the fluoride source at room temperature. Subsequent treatment of the
formed fluorinated thioethers with the same reagents at elevated temperature gave alkyl
trifluoroacetates in almost quantitative yield under optimised conditions by oxidative desulfuriza-
tion–fluorination.
Received 13 May 2010
Received in revised form 4 June 2010
Accepted 11 June 2010
Available online 18 June 2010
Keywords:
ß 2010 Elsevier B.V. All rights reserved.
Fluorinated thioethers
Fluoro-Pummerer rearrangement
Oxidative desulfurization-fluorination
Alkyl trifluoroacetates
Polyfluoroalkanoates
1. Introduction
rangement and a subsequent oxidative desulfurization–fluorina-
tion reaction. Various terminal difluorinated compounds bearing
The introduction of fluorine atoms into biologically active
substances is known to modify their pharmacological properties
and their therapeutical potency. The particular properties of
fluorine, such as high electronegativity, relatively small size, low
polarisability of the C–F-bond and, in many cases, increased
lipophilicity of fluorine containing organic molecules can have
considerable impact on the behavior of such molecules in a
biological environment [1,2]. Due to their specific properties
organofluorine compounds hold huge promise as building blocks
for the construction of biologically active compounds [3].
additional reactive functionalities in
moderate to excellent yields (Scheme 1) [7].
However, also -difluoroalkyl aryl thioethers belong to an
interesting class of difluoromethylene compounds. They are very
important as building blocks for the construction of complex
difluorinated molecules and are expected to be good precursors to
difluoromethyl radicals by homolytic cleavage of the S–CF2 bond.
Fuchigami and co-workers investigated the photoinduced S–CF2
v-position were obtained in
a,a
bond cleavage of various
a,a-difluorinated sulfides in order to
generate corresponding difluoromethyl radicals, which could be
trapped with various unsaturated compounds [8a]. Lequeux et al.
reported the homolytic cleavage of the S–CF2 bond of sulfanyldi-
fluoromethylphosphonate using AIBN/n-Bu3SnH in the presence of
various olefins to provide unsaturated difluoromethylphosphonate
Especially, difluoromethylene compounds with their exceeding
characteristics have attracted much interest in bioorganic and
medicinal chemistry [4]. The CF2/O transposition in difluoro-
methylenephosphonates as phosphonate mimics has a stabilizing
effect and prevents hydrolytic decomposition [5]. Also
a
,a
-
adducts [9]. Moreover, these authors and Eto et al. used a,a-
difluorinated ketones and difluoromethylene groups adjacent to
glycosidic and other acetal moieties do stabilize the molecules and
are used as transition state mimics in biological systems [6].
Therefore, their synthesis came into the focus of organic
chemists. In our previous work we reported a new oxidative
desulfurization–difluorination method for alkyl aryl thioethers
delivering geminal difluorides via a fluoro-Pummerer-like rear-
difluoroalkyl aryl thioethers as building blocks for the synthesis of
acrylthionucleosides [10] and 1,2,4-triazoles with a difluoro
substituted sulfonylmethylene unit [11]. Furthermore, Yagupolskii
and co-workers oxidized difluorinated sulfides to sulfoxides and
converted them to aryl-(N-trifluoromethylsulfonylimino)thiodi-
fluoroacetic acids in order to check their optical properties [12].
Several methods for the synthesis of
a,a-difluorosulfides
are already known in literature. In 1990 Fuchigami et al.
synthesized ethyl 2,2-difluoro-2-(phenylthio)acetate by electro-
chemical fluorination of ethyl 2-fluoro-2-(phenylthio)acetate
with Et3NÁ3HF as a fluoride source [13]. Seven years later
* Corresponding author. Tel.: +49 251 83 33281; fax: +49 251 83 39772.
E-mail addresses: hugenber@uni-muenster.de (V. Hugenberg),
haufe@uni-muenster.de (G. Haufe).
the direct electrochemical
a,a-difluorination of ethyl
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.06.010

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V. Hugenberg, G. Haufe / Journal of Fluorine Chemistry 131 (2010) 942–950
943
Scheme 1. Desulfurization–difluorination of alkyl aryl thioethers 1 with DBH/PyÁ9HF.
2-(phenylthio)acetate with Et4NFÁ4HF was successful [8]. More-
over, 2,2-difluorinated building blocks were frequently used for
the construction of ethyl 2-arylthio-2,2-difluoroacetates. By way
of example, Yagupolskii et al. obtained ethyl 2,2-difluoro-2-
(phenylthio)acetates by nucelophilic substitution of ethyl difluor-
oiodoacetate with thiophenols in the presence of a base [12b].
Also ethyl bromodifluoroacetate was successfully applied to
synthesize the latter compound [14]. Furthermore, the Na2S2O4
mediated addition of difluoroiodomethylsulfanyl benzene to
alkenes and alkynes gave 2,2-difluoro-4-iodoalkyl aryl sulfides
[15]. The synthesis of alkyl 2-arylthio-2,2-difluoroacetates is also
possible from arylthioacetates with IF5-Et3NÁ3HF [16] or difluor-
oiodotoluene [17] and also from corresponding dichloro com-
pounds by chloride–fluoride exchange with Et3NÁ3HF and ZnBr2
[18]. However, the mentioned reactions require special equip-
ment for anodic fluorination or the use of IF5-Et3NÁ3HF. For the
approach did not lead exclusively to the geminal difluorides of type
2. The reaction of arylthioacetates 4, bearing a carboxyl function in
a
-position to the potential fluorinating position, led to corre-
sponding 2,2-difluoro-2-arylthioacetates 5. Thus, reacting alkyl 2-
(arylthio)acetates (4a–h) with 2 equiv. of DBH and 6 equiv. of
Olah’s reagent the alkyl 2-arylthio-2,2-difluoroacetates (5a–d, 5f–
h) were obtained in good yields (Table 1). The reaction with the p-
methoxy substituted thioether 4e, however, did not proceed
selectively. Though product 5e was identified in the product
mixture by ESI mass spectrometry and 19F NMR spectroscopy, its
separation from also formed bromoaryl compounds was not
possible. However, pure compound 5e was synthesized from ethyl
2-bromo-2,2-difluoroacetate by nucleophilic substitution with 4-
methoxythiophenol [19].
Under the standard reaction conditions (3 equiv. of DBH,
6 equiv. of Olah’s reagent, room temperature) [7], oxidation of
sulfur in difluorides 5 occurred and, after aqueous work up, the
corresponding 2,2-difluoroacetyl sulfoxide was found as a by-
product in some cases. However, no alkyl trifluoroacetates were
found.
The suggested mechanism of formation of the alkyl 2-arylthio-
2,2-difluoroacetates 5 involves two fluoro-Pummerer-like rear-
rangements (Scheme 2). Compounds 6, the products of the first
rearrangement, were not found in the product mixture. Also
difluoroacetates 7, the products of oxidative desulfurization–
difluorination [7] of 6, were not identified. Obviously, due to the
additional strong electron withdrawing effect of the carbonyl
group, the elimination of the arylthio group does not occur.
Instead, compounds 6 are attacked by the electrophile again and
subsequent HBr elimination from III with formation of IV is faster
than the formation of 7 by oxidative desulfurization–fluorination.
Finally, fluoride is added to the carbenium ion IV forming the
thioethers 5 (Scheme 2).
other transformations
a,a-dichlorinated starting materials or
application of expensive building blocks are necessary.
In this paper we present a new method for the synthesis of alkyl
2-arylthio-2,2-difluoro-acetates, by direct introduction of two
fluorine atoms into arylthioacetates in good yields and its
transformation to trifluorides. The chemicals used in this work
are inexpensive, easy to handle and do need the safety precautions
for experiments with PyÁ9HF (Olah’s reagent).
2. Results and discussion
Using the oxidative desulfurization–difluorination approach
various aliphatic
v-substituted thioethers were converted to
geminal difluorinated alkanes in good yields [7]. However,
treatment of alkyl aryl thioethers with electron withdrawing
substituents like fluorine, oxygen, carbonyl or carboxyl in
b-
position under the conditions of the desulfurization–difluorination
Table 1
Synthesis of alkyl 2-arylthio-2,2-difluoroacetates.
[TD$INLINE]
Entry
Compound
X
n
Yield (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
NO2
Cl
1
1
1
1
1
7
7
7
77
72
65
71
60a
25b
67
52
F
Me
OMe
NO2
Cl
5g
5h
Me
a
Synthesized by nucleophilic substitution of ethyl 2-bromo-2,2-difluoroacetate with 4-methoxythiophenol according to Ref. [19].
Low yield because of decomposition during column chromatography on silica gel.
b

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V. Hugenberg, G. Haufe / Journal of Fluorine Chemistry 131 (2010) 942–950
Scheme 2. Plausible mechanism of formation of the alkyl 2-arylthio-2,2-difluoro-acetates 5.
The conversion of ethyl 3-(arylthio)propionate (8), with a CH2-
Pummerer rearrangement, we prepared methyl 10-fluoro-11-(4-
nitrophenylthio)undecanoate (13) according to our earlier proto-
col of arylsulfenyl fluorination of olefins [20]. The reaction of this
thioether with DBH and Olah’s reagent under standard conditions
gave a mixture of the trifluoride 14, the dibromodifluoride 15 and
the trifluorinated thioether 16 in a ratio of 1:1.2:2 (Scheme 4).
Longer reaction time or bigger amounts of DBH did not lead to
higher yields or to a complete conversion of the thioether 13 to the
geminal difluoride 14, but rather to the formation of polybromi-
nated and polyfluorinated substances and partial decomposition.
After 3 days of reaction time, decomposition was complete and 1-
bromo-4-nitrobenzene was identified as the main product. Due to
group between the reaction centre and the ester group, with
3 equiv. of N,N-dibromo-5,5-dimethylhydantoine (DBH) and
6 equiv. of Olah’s reagent did not lead to ethyl 3-arylthio-3,3-
difluoropropionate. The main product of this reaction was ethyl
3,3-difluoropropionate (9, 35%, 19F NMR). Additionally, ethyl
3-bromo-3-fluoropropionate (10, 2%), ethyl 3,3-dibromo-3-fluor-
opropionate (11, 17%) and ethyl 2,3,3-tribromo-3-fluoropropio-
nate (12, 2%) were found by 19F NMR spectroscopy besides other
not identified products (Scheme 3). This result shows that the
electron withdrawing effect of an ester group in
b-position to the
reaction centre is not sufficient to prevent the desulfurization step,
but decelerated the reaction rate and directed the reaction towards
oxidative desulfurization–difluorination and desulfurization–
polybromination.
the electron withdrawing effect of the fluorine atom in b-position,
the electron density at sulfur is reduced in comparison to the non-
fluorinated compound. So the attack of the bromonium ion and
particularly the HBr elimination from I to form the carbenium ion
In order to find out whether a fluorine substituent in b-position
t[(Scheme_3)TD$FIG] o the potential fluorination position is influencing the fluoro-
II, which is destabilized by the
b-fluoro substituent, is slowed
Scheme 3. Oxidative desulfurization–difluorination of ethyl 3-(arylthio)propionate (8).
[(Scheme_4)TD$FIG]
Scheme 4. Oxidative desulfurization–difluorination and geminal difluorination of methyl 10-fluoro-11-(4-nitrophenylthio)undecanoate (13).

[
V. Hugenberg, G. Haufe / Journal of Fluorine Chemistry 131 (2010) 942–950
945
Scheme 5. Suggested mechanism of products formation from methyl 10-fluoro-11-(4-nitrophenylthio)undecanoate (13).
down (Scheme 5). The carbenium ion II is reacting with fluoride to
the vicinal difluoride 17. This compound was not found among the
products, but reacted in a second fluoro-Pummerer rearrangement
via III either to the carbenium/sulfonium ion IV, which isattackedby
fluoride to form 16. Alternatively, the sulfonium ion III can also be
attacked directly by a fluoride ion to form the difluoride 14 by
desulfurization. By addition of a bromide to IV, subsequent attack of
a bromonium ion at sulfur of 18 (not identified among the products)
and elimination of the arylthio group by the attack of a second
bromide at V, the dibromodifluoride 15 is formed (Scheme 5).
The electronic nature of the intermediate III is obviously
decisive for the reaction pathway after the first fluoro-Pummerer
Another motivation for the substitution of an arylthio group by
fluoride was given by the work of Gome`z et al. They managed to
transform unprotected thioglycosides to glycosyl fluorides using the
combination of NIS/Olah’s reagent or N-chlorosuccinimide (NCS)/
Et3NÁ3HF. Unfortunately, for this oxidative desulfurization fluorina-
tion a large excess of Olah’s reagent (20–40 equiv.) or triethylamine
trishydrofluoride (40–120 equiv.) was needed [22]. Nevertheless,
this reaction was interesting for future syntheses, because of the
presenceofelectronwithdrawinggroups nexttothe reaction centre.
Due to the influence of electron withdrawing groups the elimination
of the arylthio group – as already shown above for compounds 4 and
13 – is disfavored under our standard conditions.
`
rearrangement occurred. The ability of an
positive charge and the electron withdrawing effect of the
-fluorine substituent on the other hand cause the higher acidity
of the proton at the -C-atom. Therefore, the probability of
deprotonation of III rises over thioether elimination compared to
the situation of compounds without the electron withdrawing
a
-fluorine to stabilize a
Based on the results of Kuroboshi and Hiyama [21] and Gomez
and co-workers [22] we tried to substitute the arylthio group of
b
different para-substituted
a
,a
-Àdifluoroalkyl aryl thioethers by
a
fluoride. Instead of n-Bu4N+H2F3 our standard conditions for the
oxidative desulfurization–difluorination (3 equiv. of DBH, 6 equiv.
of PyÁ9HF) were used. The reactions were carried out in a 0.1 mmol
scale. Due to the high volatility of the products the solvent was not
removed after aqueous workup, but the organic layer was directly
investigated by 19F NMR spectroscopy.
effect of a
b-fluorine substituent.
A valuable amplification of the alkyl 2-arylthio-2,2-difluoro-
acetates 5 seemed to be their adoption in a oxidative desulfuriza-
tion–fluorination to form the corresponding trifluorides. In this
way a difluoro alkyl aryl thioether would be converted into a CF3
group in the last reaction step of a given reaction sequence. Hence,
this method might be appropriate for 18F-labelling of medicinally
relevant ligands for the positron-emission-tomography (PET).
For initial experiments we have chosen ethyl 2,2-difluoro-2-(4-
nitrophenylthio)acetate (5a) as a model compound, because in
earlier studied desulfurization–difluorination reactions the p-nitro-
substituent at the arylthio group accelerated the reaction rate [7].
However, under standard conditions no conversion to the trifluoride
was observed by 19F NMR spectroscopy after 20 h of reaction time at
room temperature (Table 2, entry 1). Also the use of NIS as an
electrophile and 20 or 40 equiv. of Olah’s reagent, according to the
Examples for
a fluorodesulfurization of a,a-difluorinated
molecules are already known in literature. Methyl arenedithio-
carboxylates are readily converted into Ar–CF3 by treatment with
DBH as the electrophile and n-Bu4N+H2F3 as a fluorinating
results of Gomez et al., did not lead to any reaction (entries 2 and 3).
À
`
reagent. Replacing DBH by N-bromosuccinimide (NBS) or
N-iodosuccinimide (NIS) led to difluorom(methylthio)methyl
substituted aromatic compounds. These difluorinated products,
Ar–CF2SMe, were shown to be suitable as precursors for the
synthesis of trifluoro compounds. By a further oxidative desulfuri-
InthereactionwithDBH,enhancementoftheamountoffluorinating
reagent to20 equiv. led to little conversion of5a to trifluoride19 and
bromofluoride 20a (entry 4). Finally, heating of the reaction mixture
to 40 8C resulted in complete conversion to trifluoride 19 in 18 h
(entry 5). Shortening of the reaction time up to 6.5 h at 40 8C was
possible (entry 6), but decreasing the amount of Olah’s reagent to 10
and 5 equiv. led to lower conversion (entries 7–9). Due to
decomposition of the fluorinating reagent, heating of the reaction
mixture above 50 8C is not possible.
zation–fluorination step with DBH and n-Bu4N+H2F3 these
À
compounds were converted to the corresponding trifluorides.
However, only trifluoromethyl substituted aromatics have been
synthesized by this method so far [21].

946
V. Hugenberg, G. Haufe / Journal of Fluorine Chemistry 131 (2010) 942–950
Table 2
Oxidative desulfurization–fluorination of ethyl 2-arylthio-2,2-difluoroacetates 5.
[TD$INLE]
Products (19F NMR)
19
˚
Entry
Elektrophile (equiv.)
PyÁ9HF (equiv.)
Y
Temperature (C)/time (h)
5
20
21
22
Others
1
2
DBH (3.0)
NIS (1.2)
NIS (1.2)
DBH (3.0)
DBH (3.0)
DBH (3.0)
DBH (3.0)
DBH (3.0)
DBH (3.0)
NCS (3.0)
DBH (3.0)
DBH (3.0)
DBH (3.0)
NCS (3.0)
DBH (3.0)
DBH (3.0)
DBH (3.0)
DBH (3.0)
NCS (3.0)
NCS (3.0)
6.0
20.0
40.0
20.0
20.0
20.0
10.0
10.0
5.0
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
Cl
30 min, 0 8C; 20 h, RT
30 min, À10 8C; 20 h, RT
30 min, 0 8C; 18 h, RT
30 min, 0 8C; 18 h, RT
30 min, 0 8C; 18 h, 40 8C
6.5 h, 40 8C
20 h, 45 8C
7 h, 45 8C
20 h, 45 8C
1 h, 45 8C
7 h, 45 8C
3 h, 45 8C
6 h, 45 8C
1 h, 45 8C
7 h, 45 8C
3 h, 45 8C
6 h, 45 8C
1 h, 45 8C
50
–
–
–
50
–
–
–
–
–
100
100
65
–
–
–
3
–
–
–
4
12
100
88
76
43
55
–
23
–
–
–
–
5
–
–
–
6
3
9
–
–
–
7
12
33
38
90
–
12
24
7
–
–
–
8
–
–
–
9
–
–
–
10
11
12
13
14
15
16
17
18
19
20
1.1
–
10
–
–
–
10.0
10.0
5.0
61
68
37
15
66
37
19
2
39
32
37
–
–
–
Cl
–
–
–
–
Cl
6
20
19
–
–
–
1.1
Cl
45
–
21
–
–
10.0
10.0
5.0
Me
Me
Me
Me
Me
Me
8
26a
35a
7a
32a
–
22
66
48
–
6
–
–
8
–
–
1.1
–
18
–
–
1.1
1 h, 45 8C
18 h, 45 8C
50
75
–
50
25
1.1
a
Substances from starting material.
Changing the p-substituent at the phenyl ring from nitro to
chloride, which is less electron withdrawing, the reaction occurred
also with lower amount of Olah’s reagent and less reaction time.
With 3 equiv. of DBH and 10 equiv. of PyÁ9HF complete conversion
was obtained in 3 h at 45 8C with a good ratio of 68:32 (trifluoride/
bromodifluoride) (Table 2, entry 12). With 5 equivalents of Olah’s
reagent almost complete conversion of 5b was observed after 6 h
at 45 8C, but besides 19 and 20a the sulfoxide 21b (20%) was
detected (entry 13). The formation of the sulfoxide 21b after
aqueous workup proves that a bromosulfonium ion of type I (see
Scheme 6) was already formed from 5b, but the next reaction step
towards 19 is slow. The formation of sulfoxides by reaction of
thioethers with halogens in the presence of water is already known
[23]. Changing the electrophile NCS prevented the formation of the
chlorodifluoride 20b, but did not lead to better results concerning
the trifluoride 19 (entry 14).
arylthio group should be slower compared to the reaction with p-
chloro and p-nitro compounds.
The experiments proved that the thioether 5d needed longer
reaction time for conversion, compared to the chlorophenyl
thioether 5b and showed lower conversion using DBH as the
electrophile (Table 2, entries 15–18). However, changing the
electrophile from DBH to NCS did not only prevent the formation of
compound 20b but also led to much better conversion towards the
trifluoride 19. The only by-product found in the product mixture
was the sulfone 22d formed by oxidation of the sulfur with NCS
and hydrolysis as principally known in literature [23]. After 1 h at
45 8C a 1:1 mixture of trifluoride 19 and sulfone 22d was formed
(entry 19). Elongation of the reaction time to 18 h did not show
complete conversion to the trifluoride, 25% of sulfone 22d were
still found in the product mixture showing that the desulfuriza-
tion/fluorination step is very slow due to the stabilization of the
intermediary sulfonium ion by the tolyl group (entry 20).
The described experiments reveal that the oxidative desulfuri-
zation–fluorination of ethyl 2-arylthio-2,2-difluoroacetates 5 is
significantly depending on the electronic properties of the
substituent at the phenyl ring. For the relative rate two controlling
Using ethyl 2,2-difluoro-2-(4-methylphenylthio)acetate 5d
with a p-methyl substituent on the phenyl ring, the first step of
the reaction, the attack of the electrophile on sulfur should proceed
faster because of the electron donating properties of the methyl
group, while the second reaction step, the elimination of the
[(Scheme_6)TD$FIG]
Scheme 6. Formation of the trifluoride 19 by oxidative desulfurization–fluorination of 5.

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V. Hugenberg, G. Haufe / Journal of Fluorine Chemistry 131 (2010) 942–950
947
led to a mixture of fluorinated and brominated compounds,
arylthio acetates 4 bearing a carboxyl function in -position are
a
converted to 2-arylthio-2,2-difluoroacetates 5. This reaction
proceeds via two succeeding fluoro-Pummerer-like rearrange-
ments. Due to the strong electron withdrawing effect of the
carbonyl group the elimination of the arylthio group is disfavoured
and dehydrobromination and subsequent fluorination leads to
arylthio-difluoroacetates.
Scheme 7. Synthesis of octyl trifluoroacetate (23).
By treatment of the 2-arylthio-2,2-difluoroacetates 45 with an
electrophile, a large excess of PyÁ9HF and heating to 45 8C, the
corresponding trifluorides 19 were obtained. When NCS was used
as an electrophile, the formation of the chlorodifluoride 20b was
avoided. Depending on the substituent of the arylthio group, the
reaction was also possible with lower amounts of fluorinating
reagent and in a shorter reaction time.
steps are important. The first step is the attack of the bromonium
ion at the sulfur, the second step is the addition of a fluoride with
elimination of the arylthio group (Scheme 6).
The nitro group impedes the electrophilic attack at sulfur by ÀI
and ÀM-effects, while it accelerates the attack of fluoride at the
a-
position with elimination of the arylthio group. The p-chloro
substituent with a weaker ÀI- and a +M-effect in contrast to the
nitro group accelerates the attack of the electrophile, but slows
down the desulfurization/fluorination step. This explains the
occurrence of the sulfoxide after hydrolytic workup. By the positive
inductive effect of the methyl substituent at the phenyl ring the
electrophilic attack is further facilitated, but the elimination of the
arylthio group is even slower.
4. Experimental
4.1. General methods
Column chromatography was performed on Merck silica gel 60
(0.040–0.063 mm). For HPLC, a Merck-Hitachi system D-7000 with
a pump L-7150 and a refractometer Shodex RI-72 were used. GC
analyses were performed with HP-1 column (30 m, 0.32 mm
Moreover, the experiments prove the reaction to be also
dependent on the electrophile and the reaction time. The use of
DBH led to better results with thioethers 5a (Table 2, entries 4–9)
and 5b (Table 2, entries 11–13), while NCS favored the formation of
19 from the p-methyl substituted thioether 5d (Table 2, entries 19
and 20). Carrying out the reaction with NCS and 1.1 equivalents of
Olah’s reagent over 1 h at 45 8C, the p-methyl substituted
compound 5d showed the best conversion to the trifluoride 19
(50%) and the sulfone 22d (50%) (Table 2, entry 19), while the
product mixture of the p-chloro compound 5b still possessed 45%
(Table 2, entry 14) and the p-nitro compound 5a even 90% (Table 2,
entry 10) of the respective starting material.
The first reaction step, the attack of the electrophile on sulfur is
most fast in the case of the p-methyl substituted compound 5d.
Therefore, in short reaction time more of the starting material is
already converted to the carbenium/sulfonium ion I (Scheme 6)
and the possibility of further reaction by attack of fluoride and
elimination of the arylthio group is given. However, due to the
electron donating effect of the methyl group at the phenyl ring the
second reaction step is disfavored and the formed carbenium/
sulfonium ion I is reacting very slowly. Therefore, the sulfone 22 is
formed during the aqueous work up. For a complete conversion of
the formed carbenium/sulfonium ion I to the trifluoride 19 even
longer reaction time is needed (Table 2, entry 20).
For the complete analytical characterization higher boiling
compounds are necessary. Therefore alkyl 2-arylthio-2,2-difluoro-
acetates with a longer alkyl chain were synthesized and adopted to
the oxidative desulfurization–fluorination reaction (Scheme 7).
Octyl 2,2-difluoro-2-(4-nitrophenylthio)acetate (5f) and octyl 2-(4-
chlorophenylthio)-2,2-difluoro-acetate (5g) were converted suc-
cessfully to their corresponding trifluorides 23 with 3 equiv. of DBH
and 20 equiv. of Olah’s reagent in dry CH2Cl2 at 45 8C over night.
After column chromatography the trifluoride 23 was isolated in 68%
yield. No bromodifluoride, sulfoxide or sulfone were detected.
diameter, film 0.25
mm) from Hewlett-Packard. NMR spectra were
recorded on a Bruker ARX300 and a Bruker DPX300 (1H NMR,
300 MHz; 13C NMR, 75 MHz; 19F NMR, 282 MHz), Bruker AMX 400
(1H NMR, 400 MHz; 13C NMR, 100 MHz) and Varian Inova (1H NMR,
500 MHz; 13C NMR, 126 MHz; 19F NMR, 470 MHz) spectrometers.
TMS (1H), CDCl3 13C) and CFCl3 19F) were used as internal
( (
standards. Mass spectra were recorded on Thermo-Finningan
MAT8200 (EI, 70 eV), Waters-Micromass GCT (GCToF, EI), and
Waters-Micromass Quatromicro GC (GC/CI and EI, 70 eV) instru-
ments. All air and moisture-sensitive reactions were performed
under argon atmosphere. Solvents were purified and dried where
necessary by literature methods. The reactions with Olah’s reagent
were performed in TeflonTM flasks. The alkyl aryl thioethers were
prepared from the corresponding thiophenols and alkyl halides
under basic conditions [19].
4.2. Synthesis of
a,a-difluoro alkyl aryl thioethers 5
4.2.1. General procedure
Olah’s reagent (0.69 mL, 3 mmol, 6 equiv.) was added to a
solution of the corresponding thioether (0.5 mmol) in dry CH2Cl2
(10 mL) in a TeflonTM flask via a polypropylene/polyethylene
syringe. DBH (1.0 mmol, 2 equiv.) was added and the mixture was
stirred for 17 h at room temperature. Then ice-water was added
and the reaction mixture was neutralized with concentrated NH3.
The phases were separated and the aqueous layer was extracted
with Et2O (3Â 20 mL). The combined organic phases were washed
with 0.1 N aq. HCl (2Â 20 mL) and 5% aqueous NaHCO3 (2Â 20 mL)
and dried over anhydrous MgSO4. After concentration under
reduced pressure, the products were purified by column chroma-
tography.
4.2.1.1. Ethyl 2,2-difluoro-2-(4-nitrophenylthio)acetate (5a). The
reaction was carried out in a 0.5 mmol scale with ethyl 2-(4-
nitrophenylthio)acetate (4a) in 17 h at room temperature. After
column chromatography (silica gel, pentane/diethyl ether, 95:5)
5a was isolated as a yellow crystalline compound. Yield: 107 mg
3. Conclusion
Application of the new oxidative desulfurization–difluorination
method to alkyl aryl thioethers with electron withdrawing
substituents like fluorine, oxygen, carbonyl or carboxyl did not
lead to the geminal difluorinated compounds exclusively. While
the reaction with an electrophile (DBH or NCS) and PyÁ9HF (Olah’s
reagent) of alkyl aryl thioethers with a fluorine or an ester group in
(77%). Mp.: 51 8C. 1H NMR (CDCl3, 300 MHz):
d 1.33 (t, 3H, CH3,
3
3JH,H = 7.2 Hz), 4.34 (q, 2H, CH2, JH,H = 7.2 Hz), 7.81 (d, 2H, CH,
3JH,H = 8.9 Hz), 8.25 (d, 2H, CH, JH,H = 8.9 Hz). 13C NMR (CDCl3,
3
1
75 MHz):
d
13.8 (q), 64.1 (t), 119.5 (st, JC,F = 289.7 Hz), 124.1 (d),
3
b
-position to the potential desulfurization/fluorination position
133.3 (st, JC,F = 2.3 Hz), 136.5 (d), 148.9 (s), 160.9 (st,

948
V. Hugenberg, G. Haufe / Journal of Fluorine Chemistry 131 (2010) 942–950
2JC,F = 31.8 Hz). 19F NMR (CDCl3, 282 MHz):
d
À81.0 (s, 2F). MS (EI-
by-products. 1H NMR (CDCl3, 300 MHz):
3JH,H = 7.2 Hz), 3.82 (s, 3H, CH3), 4.26 (q, 2H, CH2, JH,H = 7.2 Hz),
d 1.27 (t, 3H, CH3,
GC-inlet): m/z (%) 277 (100) [M+], 204 (79) [C7H4F2NO2S+], 188 (24)
[C7H4F2NOS+], 158 (40) [C7H4F2S+], 155 (24) [C6H4NO2S+], 123 (15)
[C4H5F2O2+], 45 (15) [C2H4O+]. HRMS (ESI): [M+Na+] calcd. for
3
3
3
6.91 (d, 2H, CH, JH,H = 8.9 Hz), 7.53 (d, 2H, CH, JH,H = 8.9 Hz). 13C
NMR (CDCl3, 75 MHz): 13.8 (q), 55.4 (q), 63.5 (t), 115.0 (d), 115.1
d
3
1
C
C
10H9F2NO4SNa+: 300.0113; found: 300.0113. Anal. calcd. for
10H9F2NO4S: C, 43.32; H, 3.27; N, 5.05. Found: C, 42.89; H, 3.05; N,
(st, JC,F = 2.7 Hz), 120.0 (st, JC,F = 286.6 Hz), 138.5 (d), 161.7 (s),
161.8 (st, JC,F = 32.6 Hz). 19F NMR (CDCl3, 282 MHz):
2
d
À83.7 (s,
4.89.
2F). MS (EI-GC-inlet): m/z (%) 262 (42) [M+], 189 (4) [C8H7F2OS+],
139 (100) [C7H7OS+], 124 (8) [C6H4OS+], 45 (2) [C2H4O+]. HRMS
(ESI): [M+Na+] calcd. for C11H12F2O2SNa+: 285.0367; found:
285.0358. Anal. calcd. for C11H12F2O3S: C, 50.37; H, 4.61. Found:
C, 50.63; H, 4.74.
4.2.1.2. Ethyl
2-(4-chlorophenylthio)-2,2-difluoroacetate
(5b)
[8,24]. The reaction was carried out in a 4.55 mmol scale with
ethyl 2-(4-chlorophenylthio)acetate (4b) in 17 h at room temper-
ature. After column chromatography (silica gel, pentane/diethy-
lether 98:2) 5b was isolated as a colorless oil. Yield: 871 mg (72%).
4.2.1.6. Octyl 2,2-difluoro-2-(4-nitrophenylthio)acetate (5f). The re-
action was carried out in a 2.0 mmol scale with octyl 2-(4-
nitrophenylthio)acetate (4f) in 17 h at room temperature. After
column chromatography (silica gel, pentane/diethyl ether, 95:5)
the product 5f was isolated as a yellow oil. Yield: 180 mg (25%). 1H
3
1H NMR (CDCl3, 300 MHz):
d
1.29 (t, 3H, CH3, JH,H = 7.2 Hz), 4.29
(q, 2H, CH2, 3JH,H = 7.1 Hz), 7.38 (d, 2H, CH, 3JH,H = 8.7 Hz), 7.55 (d,
2H, CH, 3JH,H = 8.5 Hz).13C NMR (CDCl3, 75 MHz):
d 13.8 (q), 63.7 (t),
119.7 (st, 1JC,F = 287.9 Hz), 123.1 (st, 3JC,F = 2.6 Hz), 129.5 (d), 137.4
(s), 137.9 (d), 161.4 (st, 2JC,F = 32.2 Hz). 19F NMR (CDCl3, 282 MHz):
NMR (CDCl3, 300 MHz): d
0.89 (t, 3H, 14-CH3, 3JH,H = 6.7 Hz), 1.20–
d
À82.6 (s, 2F). MS (EI-GC-inlet): m/z (%) 266 (60) [M+], 193 (100)
1.40 (m, 10H, CH2), 1.62 (m, 2H, CH2), 4.27 (t, 2H, CH2,
[C7H4F2ClS+], 143 (28) [C6H4ClS+], 108 (36) [C6H4S+]. HRMS (ESI):
[M+Na+] calcd. for C10H9ClF2O2SNa+: 288.9878; found: 288.9875.
Anal. calcd. for C10H9ClF2O2S: C, 45.04; H, 3.40. Found: C, 44.69; H,
3.32.
3JH,H = 6.7 Hz), 7.80 (d, 2H, CH, JH,H = 8.9 Hz), 8.25 (d, 2H, CH,
3
3JH,H = 9.0 Hz). 13C NMR (CDCl3, 75 MHz):
d 14.1 (q), 22.6 (t), 25.5
(t), 25.7 (t), 28.2 (t), 29.1 (t), 31.7 (t), 68.1 (t), 119.5 (st,
3
1JC,F = 289.6 Hz,), 124.0 (d), 133.4 (st, JC,F = 2.3 Hz), 136.4 (d),
2
148.9 (s), 161.0 (st, JC,F = 31.8 Hz). 19F NMR (CDCl3, 282 MHz):
d
4.2.1.3. Ethyl
2,2-difluoro-2-(4-fluorophenylthio)acetate
(5c)
À80.8 (s, 2F). MS (EI-GC-inlet): m/z (%) 361 (17) [M+], 344 (2)
[M+ÀOH], 331 (3) [M+ÀNO], 249 (16) [C8H5F2NO4S+], 204 (18)
[C7H4F2NO2S+], 157 (16) [C9H17O2+], 71 (69) [C5H11+], 57 (100)
[C4H9+], 43 (100) [C3H7+]. HRMS (ESI): [M+Na+] calcd for
[12b]. The reaction was carried out in a 3.0 mmol scale with ethyl
2-(4-fluorophenylthio)acetate (4d) in 17 h at room temperature.
After column chromatography (silica gel, pentane/diethyl ether,
99:1) the product 5c was isolated as a colorless oil. Yield: 484 mg
C
16H21F2NO4SNa+: 384.1052; found: 384.1104.
(65%). 1H NMR (CDCl3, 300 MHz):
d
1.30 (t, 3H, CH3, 3JH,H = 7.1 Hz),
4.28 (q, 2H, CH2, 3JH,H = 7.2 Hz), 7.10 (m, 2H, CH), 7.61 (m, 2H, CH).
4.2.1.7. Octyl 2-(4-chlorophenylthio)-2,2-difluoroacetate (5g). The
reaction was carried out in a 2.0 mmol scale with octyl 2-(4-
chlorophenylthio)acetate (4g) in 17 h at room temperature. After
column chromatography (silica gel, pentane/diethyl ether, 95:5)
5g was isolated as a colorless oil. Yield: 466 mg (67%). 1H NMR
13C NMR (CDCl3, 75 MHz):
d 13.8 (q), 63.6 (t), 116.5 (dd,
1
6
3JC,F = 22.2 Hz), 119.7 (std, JC,F = 287.5 Hz, JC,F = 1.9 Hz), 120.0
(sm), 138.9 (dd, 3JC,F = 9.0 Hz), 161.5 (st, 2JC,F = 32.3 Hz), 164.4 (sd,
2JC,F = 252.1 Hz). 19F NMR (CDCl3, 282 MHz):
d
À83.0 (s, 2F), À109.6
(m, 1F). MS (EI-GC-inlet): m/z (%) 250 (73) [M+], 177 (100)
[C7H4F3S+], 157 (6) [C7H3F2S+], 127 (42) [C6H4FS+], 108 (3)
[C6H4S+], 95 (33) [C6H4F+], 83 (55) [C4H3O2+]. HRMS (ESI):
[M+Na+] calcd for C10H9F3O2SNa+: 273.0168; found: 273.0174.
(CDCl3, 300 MHz): d
0.89 (t, 3H, CH3, 3JH,H = 6.7 Hz), 1.20–1.40 (m,
10H, CH2), 1.62 (m, 2H, CH2), 4.21 (t, 2H, CH2, 3JH,H = 6.7 Hz), 7.38
(d, 2H, CH, 3JH,H = 8.7 Hz), 7.55 (d, 2H, CH, 3JH,H = 8.6 Hz). 13C NMR
(CDCl3, 75 MHz):
d 14.1 (q), 22.6 (t), 25.6 (t), 28.2 (t), 29.0 (t), 29.1
1
(t), 31.7 (t), 66.8 (t), 119.7 (st, JC,F = 289.7 Hz), 123.2 (st,
3JC,F = 2.7 Hz), 129.6 (d), 137.4 (s), 137.9 (d), 161.5 (st,
2JC,F = 32.2 Hz). 19F NMR (CDCl3, 282 MHz):
(EI-GC-inlet): m/z (%) 350 (50) [M+], 238 (38) [C8H5ClF2O2S+], 193
(38) [C7H4ClF2S+], 43 (16) [C6H4ClS+], 108 (25) [C6H4S+], 122 (75)
[C3H3O2+], 57 (100) [C4H9+], 43 (100) [C3H7+]. HRMS (ESI): [M+Na+]
calcd. for C16H21F2ClO2SNa+: 373.0811; found: 373.0834. Anal.
calcd. for C16H21ClF2O2S: C, 54.77; H, 6.03. Found: C, 54.06; H, 6.02.
4.2.1.4. Ethyl
2,2-difluoro-2-(4-methylphenylthio)acetate
(5d)
[11]. The reaction was carried out in a 3.0 mmol scale with ethyl
2-(4-methylphenylthio)acetate (4d) in 3 days at room temperature
or as an alternative 22 h at 45 8C. However, heating to 45 8C causes
the formation of ring brominated thioethers as by-products. After
column chromatography (silica gel, pentane/diethyl ether, 97:3) 5d
was isolated as a colorless oil. Yield: 87 mg (71%). 1H NMR (CDCl3,
d
À82.4 (s, 2F). MS
300 MHz):
d
1.27 (t, 3H, CH3, 3JH,H = 7.2 Hz), 2.38 (s, 3H, CH3), 4.26
3
3
(q, 2H, CH2, JH,H = 7.2 Hz), 7.20 (d, 2H, CH, JH,H = 7.9 Hz), 7.49 (d,
2H, CH, 3JH,H = 8.1 Hz). 13C NMR (CDCl3, 75 MHz):
13.8 (q), 21.3 (q),
63.5 (t), 120.0 (st, JC,F = 286.9 Hz), 121.1 (st, JC,F = 2.7 Hz), 130.0
(d), 136.7 (d), 141.1 (s), 161.7 (st, JC,F = 32.4 Hz). 19F NMR (CDCl3,
4.2.1.8. Octyl 2,2-difluoro-2-(4-methylphenylthio)acetate (5h). The
reaction was carried out in a 2.0 mmol scale with octyl 2-(4-
methylphenylthio)acetate (4h) in 3 days at room temperature.
After column chromatography (silica gel, pentane/diethyl ether,
200:1) 5h was isolated as a colorless oil. Yield: 369 mg (52%). As
by-products ringbrominated thioethers were detected, which
could not be separated completely from the wished product. 1H
d
1
3
2
282 MHz):
d
À83.1 (s, 2F). MS (EI-GC-inlet): m/z (%) 246 (100) [M+],
173 (89) [C8H7F2S+], 153 (17) [C8H6FS+], 123 (29) [C7H7S+], 91 (33)
[C7H7+], 45 (21) [C2H4O+]. HRMS (ESI): [M+Na+] calcd. for
C
11H12F2O2SNa+: 269.0418; found: 269.0418.
NMR (CDCl3, 300 MHz): d
0.89 (t, 3H, CH3, 3JH,H = 6.7 Hz), 1.24–1.37
(m, 10H, 13-CH2), 1.56–1.69 (m, 2H, CH2), 2.37 (s, 3H, CH3), 4.19 (t,
4.2.1.5. Ethyl 2,2-difluoro-2-(4-methoxyphenylthio)acetate (5e)
[8,24]. According to the method described by Dong et al. [19] ethyl
2-bromo-2,2-difluoroacetate and methoxythiophenol were con-
verted to ethyl 2,2-difluoro-2-(4-methylphenylthio)acetate (5e) in a
1 mmol scale. After column chromatography (silica gel, pentane/
diethyl ether, 40:1) a colorless oil was isolated (156 mg, 60%).
Using the difluorination conditions the thioether 4e could be
converted to the difluoro alkyl aryl thioether, but the isolation
was only possible in low yields because of the formation of many
2H, CH2, 3JH,H = 6.7 Hz), 7.19 (d, 2H, CH, 3JH,H = 7.9 Hz), 7.49 (d, 2H,
3
CH, JH,H = 8.1 Hz). 13C NMR (CDCl3, 75 MHz):
d 14.0 (q), 22.6 (t),
25.5 (t), 28.1 (t), 29.0 (t), 31.7 (t), 67.5 (t), 120.0 (st, 1JC,F = 286.9 Hz),
3
121.1 (st, JC,F = 2.6 Hz), 130.0 (d), 136.6 (d), 141.0 (s), 162.3 (st,
2JC,F = 32.6 Hz). 19F NMR (CDCl3, 282 MHz):
d
À83.0 (s, 2F). MS (EI-
GC-inlet): m/z (%) 330 (100) [M+], 218 (79) [C9H8F2O2S+], 173 (46)
[C8H7F2S+], 123 (50) [C7H7S+], 91 (21) [C7H7+], 71 (21) [C3H3O2+],
57 (29) [C4H9+], 43 (25) [C3H7+]. HRMS (ESI): [M+Na+] calcd. for
C17H24F2O2SNa+: 353.1357; found: 353.1357.

V. Hugenberg, G. Haufe / Journal of Fluorine Chemistry 131 (2010) 942–950
949
3
3
4.3. Oxidative desulfurization–fluorination of ethyl 3-(4-
2JH,F = 55.0 Hz, JH,F = 5.8 Hz, JH,H = 4.2 Hz). 13C NMR (CDCl3,
chlorophenylthio)propionate (8)
75 MHz): d
24.2 (td, 3JC,F = 3.0 Hz), 24.9 (t), 28.1 (tdt, 2JC,F = 20.4 Hz,
3JC,F = 3.0 Hz), 29.0, 29.1, 29.2 (t), 34.0 (t), 51.4 (q), 90.3 (dddd,
1JC,F = 175.8 Hz, 2JC,F = 26.9 Hz, 2JC,F = 25.8 Hz), 113.7 (dtd,
The reaction was carried out in a 0.5 mmol scale with ethyl 3-
(4-chlorophenylthio)propionate (8), 3 equiv. (1.5 mmol) of DBH
and 6 equiv. (3.0 mmol) of Olah’s reagent in 17 h at room
temperature. As the main product ethyl 3,3-difluoropropionate
was formed. After column chromatography fractions enriched in
compounds 9, 10, 11 or 12, respectively, were separated and used
for NMR spectroscopy. Due to the high volatility of the products
and small scale of the reaction no yields could be defined.
1JC,F = 244.6 Hz, JC,F = 31.7 Hz), 174.3 (s). 19F NMR (CDCl3,
2
2
3
282 MHz):
d
À129.9 (dddd, 1F, JF,F = 296.1 Hz, JF,F = 12.0 Hz,
3
2JH,F = 55.0 Hz, JH,F = 9.9 Hz), (AB-spectra); À132.9 (m, 1F,
2JF,F = 296.2 Hz, 3JF,F = 13.5 Hz, 2JH,F = 55.0 Hz, 3JH,F = 10.2 Hz,
4JH,F = 1.7 Hz), (AB-spectra); À201.9 (m, 1F, JF,F = 13.4 Hz,
3
3JF,F = 12.1 Hz). MS (EI-GC-inlet): m/z (%) 254 (0.1) [M+], 223 (6)
[M+ÀCH3O], 143 (2) [C8H15O2+], 101 (4) [C5H9O2+], 87 (36)
[C4H7O2+], 74 (100) [C3H6O2+], 59 (9) [C2H3O2+], 55 (11) [C4H7+],
43 (11) [C3H7+], 41 (11) [C3H5+]. HRMS (ESI): [M+Na+] calcd. for
4.3.1. Ethyl 3,3-difluoropropionate (9) [25]
1H NMR (CDCl3, 300 MHz):
d
1.21 (t, 3H, CH3, JH,H = 7.15 Hz),
C
12H21F3O2Na+: 277.1390; found: 277.1390.
3
3
3
2.91 (dt, 2H, CH2, JH,F = 15.5 Hz, JH,H = 4.9 Hz), 4.12 (q, 2H, CH2,
3JH,H = 7.1 Hz), 6.18 (tt, 1H, CH, JH,F = 55.6 Hz, JH,F = 5.0 Hz). 19F
2
3
4.4.2. Methyl 11,11-dibromo-10,11-difluoroundecanoate (15)
After column chromatography (silica gel, pentane/diethyl ether,
90:3) 15 was isolated as a colorless oil. Yield: 60 mg (31%). 1H NMR
(CDCl3, 300 MHz):
CH2), 1.82–2.12 (m, 2H, CH2), 2.30 (t, 2H, CH2, 3JH,H = 7.5 Hz), 3.67 (s,
3H, CH3), 4.60 (tdd, 1H, CH, JH,F = 47.4 Hz, JH,F = 9.2 Hz,
3JH,H = 2.6 Hz). 13C NMR (CDCl3, 75 MHz): 24.7 (td, 3JC,F = 2.0 Hz),
24.9 (t), 29.0, 29.1, (t), 34.0 (t), 30.5 (td, 2JC,F = 20.6 Hz), 51.4 (q), 96.7
2
NMR (CDCl3, 282 MHz):
d
À117.0 (dt, 2F, JH,F = 55.6 Hz,
3JH,F = 15.5 Hz). MS (EI-GC-inlet): m/z (%) 138 (13) [M+], 123 (5)
[C4H5F2O2+], 111 (66) [C3H5F2O2+], 93 (100) [C3H3F2O+], 73 (44)
[C3H5O2+], 65 (59) [C2H3F2+], 51 (31) [CHF2+], 45 (56) [C2H5O+].
d 1.27–1.39 (m, 10H, CH2), 1.41–1.65 (m, 2H,
2
3
4.3.2. Ethyl 3-bromo-3-fluoropropionate (10)
d
19F NMR (CDCl3, 282 MHz):
d
À134.8 (m, 1F). MS (EI-GC-inlet):
m/z (%) 200/198 (2/2) [M+], 171/169 (4/4) [C3H3BrFO2+], 170/168
(23/22), 151/153 (98/100) [C3H3BrFO+], 125/123 (16/16)
[C2H2BrF+], 117 (26) [C5H6FO2+], 89 (15) [C4H9O2+], 72 (14)
[C3H4O2+], 45 (44) [C2H5O+].
(sdd, JC,F = 321.1 Hz, JC,F = 27.4 Hz), 97.2 (ddd, JC,F = 192.7 Hz,
1
2
1
2JC,F = 22.9 Hz), 174.2 (s). 19F NMR (CDCl3, 282 MHz):
d
À63.4(dd, 1F,
3
2
3JF,F = 27.0 Hz, JH,F = 8.8 Hz); À174.9 (dddd, 1F, JH,F = 47.3 Hz,
3JH,F = 38.4 Hz, JF,F = 27.0 Hz, JH,F = 15.5 Hz). MS (EI-GC-inlet): m/
z (%) 396/394/392 (<0.1/<0.1/<0.1) [M+], 365/363/361 (14/24/14)
[M+ÀCH3O], 315/313 (14/14) [M+ÀBr], 295/293 (3/3) [M+ÀBrÀHF],
168 (44) [C7H6NO2S+], 101 (3) [C5H9O2+], 87 (14) [C4H7O2+], 74 (100)
[C3H6O2+], 59 (10) [C2H3O2+]. HRMS (ESI): [M+Na+] calcd. for
3
4
4.3.3. Ethyl 3,3-dibromo-3-fluoropropionate (11) [26,27]
3
1H NMR (CDCl3, 300 MHz):
d
1.32 (t, 3H, CH3, JH,H = 7.2 Hz),
3
3
3.81 (d, 2H, CH2, JH,F = 15.9 Hz), 4.26 (q, 2H, CH2, JH,H = 7.1 Hz).
13C NMR (CDCl3, 75 MHz):
d
14.0 (q), 56.5 (td, 2JC,F = 20.4 Hz), 61.8
C
12H20Br2F2O2Na+:
418.9660/416.9675/414.9698.
418.9655/416.9675/414.9696;
found:
(t), 86.6 (qd, 1JC,F = 320.5 Hz), 165.3 (s). 19F NMR (CDCl3, 282 MHz):
3
d
À48.7 (t, 1F, JH,F = 15.9 Hz). MS (EI-GC-inlet): m/z (%) 280/278/
276 (<0.1/<0.1/<0.1) [M+], 265/263/261 (21/41/24) [C4H4Br2F+],
251/249/247 (13/26/19), 235/233/231 (14/30/16) [C3H2Br2F+],
207/205/203 (12/20/12) [C2H2Br2F+], 171/169 (57/57), 151 (24),
126/124 (19/20) [C2H2BrF+], 89 (100) [C4H9O2+], 73 (26) [C3H5O2+],
45 (76) [C2H4O+]. HRMS (ESI): [M+Na+] calcd. for C5H7Br2FO2Na+:
4.4.3. Methyl 10,11,11-trifluoro-11-(4-nitrophenylthio)undecanoate
(16)
After column chromatography (silica gel, pentane/diethylether
90:3) the product 16 was isolated as a yellow, waxy substance.
Yield: 150 mg (37%). 1H NMR (CDCl3, 400 MHz):
d 1.29–1.48 (m,
302.8648/300.8669/298.8689;
298.8681.
found:
302.8643/300.88659/
10H, CH2), 1.57–1.82 (m, 4H, CH2), 2.31 (t, 2H, CH2, 3JH,H = 7.5 Hz),
2
3.67 (s, 3H, CH3), 4.63 (dm, 1H, CH, JH,F = 47.3 Hz), 7.80 (d, CH,
3JH,H = 8.8 Hz), 8.24 (d, CH, JH,H = 8.9 Hz). 13C NMR (CDCl3,
3
4.3.4. Ethyl 2,3,3-tribromo-3-fluoropropionate (12)
101 MHz):
d 24.6 (t), 24.8 (t), 28.6, 28.8, 28.9, 29.0, (t), 34.0 (t),
3
1H NMR (CDCl3, 300 MHz):
d 1.29 (t, 3H, CH3, JH,H = 7.2 Hz),
51.4 (q), 92.4 (ddt, 1JC,F = 185.1 Hz, 2JC,F = 29.3 Hz), 123.9 (d), 127.1
3
3
1
2
4.20 (q, 2H, CH2, JH,H = 7.2 Hz), 5.68 (d, 1H, CHBr, JH,F = 27.2 Hz).
(m, JC,F = 284.9 Hz, JC,F = 27.1 Hz), 134.0 (s), 136.2 (d), 148.6 (s),
2
13C NMR (CDCl3, 75 MHz):
d
14.1 (q), 61.1 (td, JC,F = 9.5 Hz), 61.8
174.2 (s). 19F NMR (CDCl3, 282 MHz):
d
À80.9 (ddd, 1F,
(t), 105.7 (qd, JC,F = 320.5 Hz), 165.3 (s). 19F NMR (CDCl3,
1JF,F = 214.8 Hz, JF,F = 18.4 Hz, JH,F = 6.9 Hz), (AB-spectra); À85.8
1
2
3
3
1
2
3
282 MHz):
d
À45.7 (d, 1F, JH,F = 27.2 Hz).
(ddd, 1F, JF,F = 214.7 Hz, JF,F = 16.9 Hz, JH,F = 10.3 Hz), (AB-spec-
tra); À191.9 (m, 1F, 3JF,F = 17.6 Hz). MS (EI-GC-inlet): m/z (%): 407
(8) [M+], 390 (5) [M+ÀOH], 376 (6) [M+ÀCH3O], 370 (1) [M+ÀOH-
HF], 334 (1) [C15H19F3NO2S+], 292 (1) [C12H13F3NO2S+], 278 (1)
[C11H11F3NO2S+], 155 (28) [C6H5NO2S+], 59 (68) [C2H3O2+], 55
(100) [C4H7+], 43 (52) [C3H7+], 41 (76) [C3H5+]. HRMS (ESI):
[M+Na+] calcd. for C18H24F3NO4SNa+: 430.1270; found: 430.1278.
4.4. Oxidative desulfurization–difluorination of methyl 10-fluoro-11-
(4-nitrophenylthio)undecanoate (13)
According to the general procedure methyl 10-fluoro-11-(4-
nitrophenylthio)undecanoate (13, 0.5 mmol) was treated with
3 equiv. of DBH and 6 equiv. of Olah’s reagent for 17 h at room
temperature. Three products were obtained: methyl 10,11,11-
trifluoroundecanoate (14), methyl 11,11-dibromo-10,10-difluor-
oundecanoate (15) und methyl 10,11,11-trifluoro-11-(4-nitrophe-
nylthio)undecanoate (16) in a ratio: 1:1.2:2 (19F NMR).
4.5. Oxidative desulfurization–fluorination of alkyl 2-arylthio-2,2-
difluoroacetates
4.5.1. General procedure
The reaction was carried out in a 20 mL-TeflonTM screwed
vessel. To a solution of electrophile (DBH, NIS, NCS) in absolute
CH2Cl2 (2 mL) Olah’s reagent was added via a polypropylene/
polyethylene syringe. The reaction mixture was cooled to 0 8C
before the ethyl 2-arylthio-2,2-difluoroacetate, dissolved in abs.
CH2Cl2 (1 mL), was added. The vessel was screwed tightly and
reaction was stirred at the temperature and time given in Table 2.
4.4.1. Methyl 10,11,11-trifluoroundecanoate (14)
The product was identified from a mixture (17:83) of methyl
10,11,11-trifluoroundecanoate (14) and 13. No yield could be
determined. 1H NMR (CDCl3, 300 MHz):
d 1.27–1.39 (m, 10H, CH2),
1.41–1.65 (m, 2H, CH2), 1.82–2.12 (m, 2H, CH2), 2.30 (t, 2H, CH2,
3JH,H = 7.5 Hz), 3.47 (m, 1H, CH), 3.67 (s, 3H, CH3), 5.77 (tdd, 1H, CH,

950
V. Hugenberg, G. Haufe / Journal of Fluorine Chemistry 131 (2010) 942–950
Then the reaction mixture was neutralized with aqueous NaHCO3
(first 5%, then saturated solution), transferred into an extraction
funnel and washed with 10% aqueous Na2S2O3 (10 mL). The
organic layer was dried over anhydrous MgSO4 and directly used
for 19F NMR measurements. For the corresponding amounts of
electrophile and Olah’s reagent as well as for the reaction
conditions see Table 2.
Project B1), University of Mu¨nster, Germany, and from Siemens
Medical Solutions to the European Institute for Molecular Imaging
(EIMI) at the University of Mu¨nster, Germany.
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d
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(CDCl3, 282 MHz): À61.3 (s, 2F).
d
4.5.1.3. Ethyl 2-chloro-2,2-difluoroacetate (20b) [30]. 19F NMR
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NMR (CDCl3, 282 MHz):
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d
À107.5 (d, 1F, 2JF,F = 229.4 Hz); À110.6 (d,
2
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À111.7 (d, 1F, JF,F = 227.8 Hz) (AB-spectra).
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2
´
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d
À110.6 (d, 1F,
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2
4.5.1.7. Ethyl 2,2-difluoro-2-(4-chlorophenylsulfonyl)acetate (22b)
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d
À108.0 (s, 2F).
4.5.1.8. Ethyl-2,2-difluoro-2-(4-methylphenylsulfonyl)acetate
(22d). 19F NMR (CDCl3, 282 MHz):
À108.5 (s, 2F).
d
(b) A.V. Matsnev, N.V. Kondratenko, Y.L. Yagupolskii, L.M. Yagupolskii, Tetrahe-
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4.5.2. Octyl 2,2,2-trifluoroacetate (23) [31]
A solution of DBH (88 mg, 0.3 mmol, 3 equiv.) and Olah’s reagent
(0.46 mL, 2.0 mmol, 20 equiv.) in abs. CH2Cl2 (2 mL) was cooled to
0 8C. After the addition of octyl 2,2-difluoro-2-(4-chlorophe-
nylthio)acetate (5f, 35 mg, 0.1 mmol), dissolved in abs. CH2Cl2
(1 mL), the reaction was stirred for 30 min at 0 8C and at 40 8C over
night. Then the reaction mixture was neutralized with aqueous
NaHCO3 (first 5%, then saturated solution), transferred into an
extraction funnel and washed with 10% aqueous Na2S2O3 (10 mL).
The phases were separated and the organic layer was dried over
anhydrous MgSO4. After concentration under reduced pressure, and
column chromatography (silica gel, pentane) the product 23 was
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3
300 MHz):
d
0.88 (t, 3H, CH3, JH,H = 6.9 Hz), 1.24–1.39 (m, CH2),
1.56–1.81 (m, 4H, CH2), 4.35 (t, 2H, CH2, JH,H = 6.7 Hz). 13C NMR
(CDCl3, 126 MHz): 13.5 (q), 22.2 (t), 25.1 (t), 27.6 (t), 28.7, 28.6 (t),
31.9 (t), 68.1 (t), 114.21 (qq, JC,F = 285.6 Hz), 157.07 (sq,
2JC,F = 41.7 Hz). 19F NMR (CDCl3, 282 MHz):
(EI-GC-inlet): m/z (%) 226 (<0.1) [M+], 157 (3) [C9H17O2+], 127 (1)
[C3H2F3O2+], 112 (4) [C2F3O2+], 99 (5) [C7H15+], 97 (7) [C2F3O+], 83
(53) [C6H11+], 84 (45) [C6H12+], 70 (66) [C5H10+], 69 (100) [CF3+], 55
(72) [C4H9+], 43 (46) [C3H7+], 41 (65) [C3H5+].
3
d
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d
À75.6 (s, 3F). MS
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Acknowledgements
These investigations were supported by the Deutsche For-
schungsgemeinschaft (DFG), Collaborative Research Center (Son-
derforschungsbereich) 656 ‘‘Molecular Cardiovascular Imaging’’