Fluorination of α,α-dichlorosulfides: Access to gem-difluorothioethers as useful building blocks

Article abstract of DOI:10.1016/S0040-4039(03)01134-1

The synthesis of alkylsulfanyldifluoro-acetate and ketones by the Halex reaction is described. The remarkable reactivity of thiodifluoroacetate derivatives opened rapid access for the preparation of useful building blocks such as gem-difluoroketones and a

Full text of DOI:10.1016/S0040-4039(03)01134-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5061–5064
Fluorination of a,a-dichlorosulfides: access to
gem-difluorothioethers as useful building blocks
Sonia Gouault, Ce´cile Gue´rin, Laurent Lemoucheux, Thierry Lequeux* and Jean-Claude Pommelet*
Laboratoire de Chimie Mole´culaire et Thioorganique, Universite´ de Caen-ENSICaen, UMR CNRS 6507,
6 Boulevard du Mare´chal Juin 14050 Caen cedex, France
Received 9 April 2003; revised 5 May 2003; accepted 5 May 2003
Abstract—The synthesis of alkylsulfanyldifluoro-acetate and ketones by the Halex reaction is described. The remarkable reactivity
of thiodifluoroacetate derivatives opened rapid access for the preparation of useful building blocks such as gem-difluoroketones
and amides. © 2003 Elsevier Science Ltd. All rights reserved.
ment of a bromine atom with thiolates.3,4 This method
allows to obtain fluorosulfides in moderate to good
yields,13 but is limited by the cost of the commercially
available bromofluoroacetate derivatives. Another
strategy suggested in our previous studies, was based
upon a halogen exchange reaction from the gem-a,a-
dichloroalkylsulfanyl carbonyl compounds.12 The
replacement of a chlorine or bromine atom by a
fluorine atom into organic molecules depends on their
reactivity, i.e. upon the position of the halogen in the
molecule and on the corresponding bond energy. The
substitution of halogen atoms by fluorine atoms on
non-activated positions of a saturated aliphatic chain is
sometimes difficult, but relatively easy in the case of
a-alkylsulfanyl esters or ketones 1 or 2 (Scheme 1).
a-Fluoro alkyl- or aryl-sulfanyl groups are very ver-
satile building blocks useful for the introduction of
mono-, di- or trifluoro functionalized moieties into
complex molecules. Since the synthesis of aryl
fluoromethyl sulfoxides, prepared for the first time via a
halogen exchange reaction,1 several methods for the
preparation of fluorinated sulfoxides,2 or sulfones,3
were reported. Attention is always paid to the synthesis
of such compounds.4 Alkylsulfanyl groups, under dif-
ferent oxidation states, can be removed to introduce a
carbonꢀcarbon double bond,5 or to transfer a free
radical,6 or a carbanion.7 For example, fluoroalkenes
can be prepared from fluorosulfoxides by sulfenic acid
elimination,8a and also by sulfur dioxide extrusion.8b,c
Other important applications include the introduction
of a difluoromethylene group from alkenes and fluoro-
sulfides by trapping fluoroalkyl radical.6 The a,a-
difluoromethylketones are of great interest for the
synthesis of peptide isosters,9 and modified
aminoacids.10,11 In this field, we have been interested by
the synthesis of fluorosulfides bearing an electron with-
drawing group, as starting material for the preparation
of gem-difluoroketones and amides. We have already
described the preparation of a-monofluoro alkylsul-
fanyl esters or ketones.12 Herein we report the extension
of this methodology to prepare gem-difluoro alkylsul-
fanyl carbonyl compounds and their use in fluorinated
building block synthesis.
Moreover, the ability to remove the halogen oriented
the choice of the fluorinating reagent. We showed that
the potassium fluoride-18-crown-6 ether mixture can
convert a-chloro into a-fluorothioethers, but 3HF–
Et3N complex14 (the HF-base reagent most easy to
handle) was successfully employed to carry out the
same transformation at lower temperatures.12 The mod-
ulation of the reactivity of this reagent can be con-
The straightforward strategy for the preparation of
difluoroalkylsulfanyl esters or amides involves displace-
* Corresponding authors. Tel.: +33-231452853; fax: +33-231452877;
e-mail: pommelet@ismra.fr
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01134-1

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S. Gouault et al. / Tetrahedron Letters 44 (2003) 5061–5064
trolled, for example, by modifying the proportion of
HF and NEt3, by adding a co-reagent as IF5, or by
performing fluorination under electrochemical oxidative
conditions.15 Here are reported the preparations of
gem-a,a-difluoro thioethers from the corresponding
dichlorosulfides performed with 3HF–NEt3 in the pres-
ence of mild Lewis acid.
second step leading to difluorinated sulfides 5 the for-
mation of the sulfenium 7 appeared to be more difficult
due to the presence of the first fluorine atom. The use
of Lewis acid showed to be sufficient and necessary to
displace the equilibrium in favor of 7. Due to the ionic
character of these intermediates, the reaction must be
performed in rigorously anhydrous conditions, in order
to avoid the formation of a,b-dicarbonyl sulfides as
by-products. The sulfenium ions 6 or 7 were easily
hydrolyzed on exposure to moisture.
a,a-Dichloroalklylsulfanyl esters or ketones 2 were
obtained in two steps and in good overall yields: addi-
tion of the corresponding thiolate onto chloro- (or
bromo-)acetates or ketones followed by the treatment
of the resulting thioethers with two equivalents of sulfu-
ryl chloride or N-chlorosuccinimide. Our initial
attempts of fluorination carried out with Et3N–3HF
showed that the exchange of the first chlorine atom by
the fluorine atom was rapidly performed. The gem-
fluorochlorosulfides 3a–c and 3e–f were the only prod-
ucts obtained over 1 or 2 h in refluxing acetonitrile
(Table 1). These were isolated in 65–75% yields. The
phenylsulfanyl ester 2a reacted more slowly, and the
gem-chlorofluoro ester 3a was isolated in 52% yield
after 8 h in the presence of 4 equiv. of 3HF–NEt3.
When the same reactions were performed in the pres-
ence of one equivalent of Lewis acid (ZnBr2) and four
equivalents of 3HF–Et3N, the second chlorine atom
was displaced and the total conversions of dichloroth-
ioethers 2a–c and 2e–f into difluorosulfides 5a–c and
5e–f were observed. Resulting difluorosulfides were iso-
lated in fair to good yields (52–75%, Table 1). This
methodology was also generalized to the synthesis of
phenylsulfanyl ketones 5g–h, which were isolated in
54–68% yields. The benzyl and phenylketone deriva-
tives reacted more slowly, and the fluorination was
complete after 14–48 h under refluxed solvent (entries
6–8). From the acetylated b-hydroxysulfides, 2d, the
corresponding gem-difluoroester 5d16 was isolated in
80% yield (Table 1: entry 4). As indicated in Table 1,
the rate of the halogen-exchange strongly depends on
the nature of the alkylsulfanyl moiety and also on the
electron-withdrawing group. It decreased from ethyl- to
arylsulfanyl substituents, as shown for the ketones 2e
and 2h, and from esters to ketones (entries 1 and 8).
These results suggest a significant electronic effect of
these substituents on the stability of the sulfenium
intermediate 6 or 7 (Scheme 2). In addition, in the
Another strategy was also explored to prepare a,a-
difluoroalkylsulfanyl ketones from the easily available
ester 5a. Recently, the synthesis of antifungal key inter-
mediates was reported from difluorothioacetate and
aryllithium reagents.13 We investigated the synthesis of
ketones by using alkyllithium or alkylmagnesium
reagents. Treatment of the ethyl difluorophenylsulfanyl
acetate 5a by methyl lithium in THF at −78°C afforded
the difluoroketone 5g in 80% yield (Scheme 3). The
addition of vinyl- or allylmagnesium bromide on the
ester 5a was attempted in the same conditions. In these
Scheme 2.
Scheme 3.
Table 1. Mono- and difluorination of dichlorosulfides 2 via Scheme 1
Entry
Dichlorosulfide
2
R1
EWG
Et3N–3HF (equiv.),
time (h)
Sulfide 3,
ZnBr2
(equiv.)
Time
(h)
Sulfide 5,
%
a,b
(%)a,b
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
Ph
Bz
CO2Et
CO2Me
CO2Me
CO2Me
COPh
COMe
COMe
COPh
4, 8
2, 2
2, 2.5
–
2, 2
2, 2
–
3a, 52
3b, 70
3c, 75
–
3e, 70
3f, 65
–
1
1
1
1
1
1
1
2
5
4
5.5
2
5a,13 70
5b, 52
5c, 75
5d, 80
5e, 61
5f, 72
MeO2CCH2
AcO(CH2)2
Et
Bz
Ph
Ph
3
14
14
48
2g
2h
5g, 68
–
–
5h,4 54
a Isolated yield.
b All new compounds gave satisfactory analytical data.19

S. Gouault et al. / Tetrahedron Letters 44 (2003) 5061–5064
5063
cases, vinylic and allylic ketones 8a,b, were isolated in
70 and 82% yields, respectively. At higher temperature
or after a long reaction time (>2 h), tertiary alcohols
were formed as by-products. By contrast with the Halex
reaction, by this way ketone 5g was easily prepared in
good yield.
to handle large amounts of difluorinated material, espe-
cially in the case of the ester 5a. The use of these
fluorinated sulfides in the synthesis of lactams and
aminoacid analogues is under investigation.
Acknowledgements
Due to the current interest for the synthesis of fluoro-
amides as building blocks for the preparation of lac-
tams or peptide isosters, the chlorination and the
halogen-exchange reactions were also investigated to
prepare amide 9 or 10 (Scheme 4). However, this func-
tional group was sensitive and a major degradation of
products occurred during the chlorination and the
fluorination stages. The difluoroester 5a was used as
starting material for the direct synthesis of amides. By
addition of n-octylamine at room temperature to a
solution of 5a, the corresponding amide was obtained
after 30 min of stirring. When a stoichiometric amount
of amine was used the phenylsulfanyldifluoroacetamide
9 was isolated in 52% yield, and in the presence of
excess of amine (3 equiv.) in 74% yield.
We are grateful to the ‘Ministe`re de la Recherche’ for it
financial support and to C. Lebargy for his
contribution.
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lated in 64% overall yield (Scheme 4).
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Remy, J. M. Tetrahedron 1996, 52, 305–318.
In summary, we reported a convenient preparation of
a,a-difluoro alkylsufanyl or arylsulfanyl carbonyl com-
pounds as useful building blocks for the synthesis of
gem-difluoro ketones, esters and amides. The gem-
difluoro ketones can be obtained by two different ways:
by treatment of the corresponding gem-dichlorocar-
bonyl compounds with Et3N–3HF, ZnBr2 mixture as
fluorinating reagent, or by addition of organolithium or
Grignard reagents onto the ethyl a,a-difluorophenylsul-
fanyl acetate 5a at low temperature. The second route
afforded
a
range of saturated or unsaturated
difluoroketones. The difluorosulfide 5a can be used also
as starting material for the synthesis of difluoroamides,
by its direct addition to primary amine or by using the
corresponding acyl chloride. The Halex reaction can be
easily performed on a scale of several grams, permitting
10. Konas, D. W.; Coward, J. K. Org. Lett. 1999, 1, 2105–
2107.
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Lett. 1996, 37, 2413–2416; (b) Jouen, C.; Pommelet, J. C.
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Lemaˆıtre, S.; Lequeux, T.; Pommelet, J. C. Tetrahedron
1998, 54, 10801–10810.
13. Eto, H.; Kaneko, Y.; Takeda, S.; Tokizawa, M.; Sato, S.;
Yoshida, K.; Namiki, S.; Ogawa, M.; Maebashi, K.;
Ishida, K.; Matsumoto, M.; Asaoka, T. Chem. Pharm.
Bull. 2001, 49, 173–182.
Scheme 4.

5064
S. Gouault et al. / Tetrahedron Letters 44 (2003) 5061–5064
14. McClinton, M. A. Aldrichimica Acta 1995, 28, 31.
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m/z (%) 232 (100), 159 (82), 109 (15), 77 (19), 65 (10); IR
(film) w 1746 cm−1; HMRS calcd for C10H10F2O2S
232.0370, found 232.0352. N-Octyl-2,2-difluoro-2-phenyl-
sulfanyl acetamide 9. Freshly distillated n-octylamine
(0.63 mL, 3.87 mmol) was added dropwise at room
temperature to a solution of ethyl phenylsulfanyldifl-
uoroacetate 5a (0.3 g, 1.29 mmol) in dichloromethane (5
mL). After 30 min of stirring the solution was washed
with HCl (1N) and brine, then dried over MgSO4. The
crude product was recrystallized in pentane leading to
amide 9 (0.3 g, 74%) as white solid (mp=54–56°C). 1H
NMR (CDCl3) l=0.90 (t, 3JHH=6.8 Hz, 3H, CH3),
1.10–1.40 (m, 12H, CH2), 3.12 (dt, 3JHH=6.8 Hz, 2H,
NCH2), 6.40 (s br, 1H, NH), 7.30–7.50 (m, 5H, Ph); 13C
NMR (CDCl3) l=14.8 (s, CH3), 23.4, 27.4, 29.7, 29.9,
17. Joullie´, M. M. J. Org. Chem. 1955, 77, 6662–6663.
18. Benedetti, M.; Forti, L.; Ghelfi, F.; Pagnoni, U. G.;
Ronzoni, R. Tetrahedron 1997, 53, 14031–14042.
19. Typical procedure: Ethyl phenylsulfanyldifluoroacetate 5a.
Sulfuryl chloride (6.98 mL, 86 mmol) was added slowly
to a cooled (0°C) solution of ethyl phenylsulfanylacetate
(8.4 g, 42.8 mmol) in dichloromethane (100 mL). After 2
h of stirring at room temperature, the solvent was evapo-
rated and the crude oil (10.4 g) was used in the next step
without purification. 1H NMR (CDCl3) l=1.24 (t,
3JHH=7.1 Hz, 3H, CH3), 4.23 (q, 3JHH=7.1 Hz, 2H,
CH2), 7.38–7.68 (m, 5H, Ph); 13C NMR (CDCl3) l=13.7
(CH3), 64.5 (CH2), 88.0 (CHCl), 128.9, 129.0, 131.1,
137.2 (Ph), 163.8 (CO). Crude ethyl phenylsul-
fanyldichloroacetate (10.4 g, 39.2 mmol) was added at
room temperature under nitrogen to a suspension of
freshly dried zinc bromide (8.85 g, 40 mmol) in anhy-
drous acetonitrile (100 mL). Neat 3HF–NEt3 complex (26
mL, 157 mmol) was then added to the yellow solution,
and the mixture was heated to reflux under nitrogen over
5 h. The solution was cooled down to room temperature
and poured into saturated aqueous solution of NH4Cl (50
mL). The organic layer was extracted with
dichloromethane (100 mL), and then washed with a
saturated aqueous solution of NaHCO3 and brine until
neutral pH, and dried over MgSO4. The resulting crude
oil (12.5 g) obtained after concentration under vacuum
was purified by distillation (125°C/3×10−2 mmHg), lead-
ing to ethyl phenylsulfanyldifluoroacetate 5a (6.4 g, 27.6
1
32.5 (s, (CH2)6), 40.7 (s, CH2N), 123.3 (t, JCF=289 Hz,
2
CF2), 125.9, 130.0, 131.2, 137.4 (s, Ph), 162.4 (t, JCF=28
Hz, CO); 19F NMR (CFCl3, CDCl3) l=−82.8 (s, CF2).
MS (EI) m/z (%) 315 (5), 206 (29), 156 (100), 77 (15), 71
(37), 57 (30); Anal. calcd for C16H23F2NOS: C, 60.92, H,
7.35, N, 4.44, S, 10.17, Found: C, 60.77, H, 7.45, N, 4.42,
S, 10.13. 1,1-Difluoro-1-phenylsulfanyl-4-pentenone 8b. A
solution of vinylmagnesium bromide (4.5 mL, 1 M in
Et2O, 4.5 mmol) was added dropwise over 5 min to a
solution of ethyl phenylsulfanylacetate 5a (1 g, 4.31
mmol) in anhydrous THF (10 mL) at −78°C. The mixture
was stirred for 30 min and then hydrolyzed by addition
of an aqueous 1N solution of HCl (3 mL). The mixture
was warmed up to room temperature and the aqueous
layer was extracted with CH2Cl2 (10 mL). The organic
layer was washed with brine, dried over MgSO4 and
concentrated under vacuums. The crude oil was purified
by bulb-to-bulb distillation (80–85°C/7×10−2 mmHg) to
1
afford ketone 8b (0.68 g, 70%) as a yellow oil. H NMR
3
(CDCl3) l=3.33 (d, JHH=6.8 Hz, 2H, CH2), 5.05 (dd,
3JHH=17.2 Hz, 2JHH=1.5 Hz, 1H, CH), 5.14 (dd, 3JHH
=
2
3
10.2 Hz, JHH=1.5 Hz, 1H, CH), 5.85 (ddd, JHH=17.2
Hz, 3JHH=10.2 Hz, 3JHH=6.8 Hz, 1H, CH), 7.23–7.50
(m, 5H, Ph); 13C NMR (CDCl3) l=40.6 (s, CH2), 120.5,
3
1
129.8 (Csp2), 124.8 (t, JCF=2.8 Hz, Ph), 122.9 (t, JCF
=
1
mmol, 70%) as colorless oil. H NMR (CDCl3) l=1.23
3
3
291.1 Hz, CF2), 128.4, 131.0, 137.0 (s, Ph), 194.2 (t,
2JCF=29 Hz, CO); 19F NMR (CFCl3, CDCl3) l=−85.8
(s, CF2); MS (EI) m/z (%) 228 (15), 159 (49), 109 (28),
77(43), 69 (100), 65 (24), 51 (18), 41 (68); HMRS calcd
for C11H10F2OS 228.0420, found 228.0395.
(t, JHH=7.1 Hz, 3H, CH3), 4.22 (q, JHH=7.1 Hz, 2H,
CH2), 7.30–7.62 (m, 5H, Ph); 13C NMR (CDCl3) l=13.7
1
(CH3), 63.6 (CH2), 120.8 (t, JCF=287.2 Hz, CF2), 124.8,
129.2, 130.6, 136.7 (Ph), 161.6 (t, 2JCF=37.7 Hz, CO);
19F NMR (CFCl3, CDCl3) l=−82,6 (s, CF2); MS (EI)