Direct Perfluoroalkylthiolation of Few Chalcogenols

Article abstract of DOI:10.1002/cjoc.201500913

Trifluoromethanesulfenamide reagent can react with alcohols, in basic conditions, or with thiols, in catalytic acid conditions, to afford the corresponding trifluoromethanesulfenates or trifluoromethyldisulfides. The use of higher homologs of this reagent

Full text of DOI:10.1002/cjoc.201500913

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DOI: 10.1002/cjoc.201500913
Direct Perfluoroalkylthiolation of Few Chalcogenols
Quentin Glenadela and Thierry Billard*,a,b
a Institute of Chemistry and Biochemistry (ICBMS-UMR CNRS 5246), Université de Lyon, Université Lyon 1,
CNRS, 43 Bd du 11 novembre 1918, 69622 Villeurbanne, France
b CERMEP-in vivo imaging, GroupementHospitalierEst, 59 BdPinel, 69003 Lyon, France
Trifluoromethanesulfenamide reagent can react with alcohols, in basic conditions, or with thiols, in catalytic
acid conditions, to afford the corresponding trifluoromethanesulfenates or trifluoromethyldisulfides. The use of
higher homologs of this reagent leads to synthesis of the nearly unknown perfluoroalkanesulfenates and perfluoro-
alkyldisulfides.
Keywords perfluoroalkylthiolation, perfluoroalkyldisulfide, perfluoroalkanesulfenate, trifluoromethylthiolation,
trifluoromethanesulfenamide
Introduction
sulfides can be synthetized by reaction of organolithium
reagents with non-commercially available bis(trifluoro-
methyl) trisulfide.[12] Direct trifluoromethylthiolations
of thiols have been also described with CF3SCl[13] or a
CF3S-pyrrole derivative[14] (arising from CF3SCl). Al-
ternatives to these previous toxic reagents[15] have been
more recently developed by employing other electro-
philic reagents such as N-trifluoromethylthiophthali-
mide,[16] N-trifluoromethylthiosaccharin[17] or the 1st
generation of trifluoromethanesulfenamide.[18]
Trifluoromethanesulfenates have been less studied
and only CF3SCl,[19] the CF3S-pyrrole derivative[14] and
N-trifluoromethylthiosaccharin[17,20] have been able to
react with alcohols. A specific rearrangement of hyper-
valent species could also lead to few trifluoromethane-
sulfenates.[21]
If trifluoromethylthiochalcogenides have been still
little described, the fluoroalkyl versions descriptions are
still more sporadic. Some difluoromethyldisulfides
have been obtained with N-difluoromethylthiosaccharin
reagent[22] and the methyl heptafluoroisopropylsulfenate
has been described from heptafluoroisopropylsulfenyl
chloride.[19]
Trifluoromethanesulfenamides constitute an efficient
family of shelf-stable reagents (BB reagents-Figure 1),
easy to obtain in multigram scale at low cost (up to 100
g at 15 €/g), to perform various trifluoromethylthio-
lation reactions.[23] Furthermore, higher homologs of
these reagents have been also described.[24] Therefore,
the reactivity of fluoroalkylsulfenamides with chalcoge-
nols has been studied to easily access fluoroalkylthio-
chalcogenides.
Since the elementary fluorine isolation by Moissan,[1]
the development of fluorine chemistry has considerably
grown.[2] Such an interest is essentially due to the
exceptional properties of fluorinated compounds.[2b,2c,3]
From materials to life sciences, all the fields of appli-
cations are impacted by fluorine characteristics.[3c,4]
Modulation of molecules properties for various util-
izations can be achieved by introducing diverse fluor-
inated substituents. Among all fluorinated groups, the
association of a CF3 part with sulfur atom is of partic-
ular interest.[5] Thus, the high lipophilicity induced by
the CF3S group (Hansch parameter πR＝1.44)[6] can
contribute to favor transmembrane permeation of CF3S-
substituted molecules, which, consequently, present an
improved bioavailability.[7] Furthermore, higher per-
fluorinated groups can also present interesting prop-
erties,[8] as illustrated by Fulvestrant, an estrogen recep-
tor antagonist used in treatment of hormone receptor-
positive metastatic breast cancer.[9]
Consequently, the association of fluoroalkyl groups
with several heteroatoms could contribute to expand the
molecules properties modulations. Such a concept
has been already validated by designing the CF3SN
group which presents a higher lipophilicity than CF3S.[10]
Therefore, because of specific properties of chalcogens
such as oxygen or sulfur,[11] fluoroalkylsulfenates
(RFSO) and fluoroalkyldisulfides (RFSS) substituents
could bring interesting new properties.
To this day, only a few methods to obtain com-
pounds bearing these substituents have been described,
and almost mainly in CF3 series. Trifluoromethyldi-
*
E-mail: thierry.billard@univ-lyon.fr
Received December 28, 2015; accepted January 26, 2016; published online March 8, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500913 or from the author.
Chin. J. Chem. 2016, 34, 455—458
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455

Glenadel & Billard
COMMUNICATION
1－2). Activation of thiol, in basic conditions, did not
lead to expected reaction. In acid conditions, electro-
philicity of reagent BB23 is exacerbated. If Lewis acid
ClSiMe3 was not very efficient (Table 1, Entries 5－7),
protic acid TfOH, in catalytic amount, gave rise to good
results (Table 1, Entries 8－12). If a better yield was
obtained by increasing temperature from 20 to 40 ℃,
no effect was observed at 80 ℃ (Entries 8－10).
Catalytic amount of triflic acid could be decreased while
retaining a satisfactory yield (Table 1, Entries 11－12).
In a mechanistic point of view, proton from TfOH
certainly activates BB23, through an interaction with
nitrogen, which becomes electrophilic enough to react
with thiol 1a. The released proton from thiol can, then,
activate another BB23, justifying the catalytic amount
of TfOH.
Figure 1 BB reagents.
Experimental
General procedure for the perfluoroalkylthiolation
of thiols
To a tube equipped with a magnetic stirrer were
added thiols 1 (0.50 mmol, 1.0 equiv.), dry DCM (1 mL)
and BB2x (0.6 mmol, 1.2 equiv.). The reaction mixture
was stirred for 1 min followed by the addition of TfOH
(0.1 mmol, 20 mol%). The reaction mixture was stirred
at 40 ℃ for 15 h. Conversion was checked by 19F
NMR with PhOCF3 as internal standard. The reaction
mixture was partitioned between DCM and water. The
aqueous layer was extracted with DCM and the
combined organic layers were dried over Na2SO4,
filtered and concentrated to dryness (under moderate
vacuum: 400 mbar at 25 ℃). The crude residue was
purified by flash chromatography to afford the desired
product 2 (or 3 or 4).
Table 1 Reactivity of BB23 with 4-fluorobenzenethiol
SH
SSCF3
additive
+
F
N
S
solvent, T
F3CS
O
F
2a
1a
O
BB23
(1.2 equiv.)
Entry
Additive
Solvent T/℃ t/h 2aa/%
1
2
－
－
－
CH3CN
CH3CN
CH2Cl2
THF
80
20
20
20
20
40
80
20
40
80
40
40
19
19
23
15
17
17
17
15
15
15
15
15
25
36
＜1
0
General procedure for the perfluoroalkylthiolation
of alcohols
3
To a flame-dried-tube equipped with a magnetic
stirrer were added alcohols 5 (0.50 mmol, 1.0 equiv.)
and dry THF (1 mL). The flask was evacuated and
refilled with nitrogen three times and the reaction
mixture cooled to 0 ℃. n-BuLi (0.55 mmol, 1.1 equiv.)
was added at 0 ℃ and the reaction let stirred for 5
min before the addition of BB2x (0.60 mmol, 1.2
equiv.). The reaction mixture was stirred at 0 ℃ under
nitrogen for 3 h. Conversion was checked by 19F NMR
with PhOCF3 as internal standard. The reaction mixture
was partitioned between Et2O and water and the
aqueous layer was extracted with Et2O. The combined
organic layers were dried over Na2SO4, filtered and
concentrated to dryness (under moderate vacuum: 400
mbar at 25 ℃). The crude residue was purified by flash
chromatography to afford the desired product 6 (or 7 or
8).
4
BuLi (1.1 equiv.)
5
ClSiMe3 (1.1 equiv.) CH3CN
ClSiMe3 (0.2 equiv.) CH3CN
ClSiMe3 (0.2 equiv.) CH3CN
13
36
30
79
98
98
92
75
6
7
8
TfOH (0.2 equiv.)
TfOH (0.2 equiv.)
TfOH (0.2 equiv.)
TfOH (0.1 equiv.)
CH2Cl2
CH2Cl2
DCEb
9
10
11
12
CH2Cl2
TfOH (0.05 equiv.) CH2Cl2
a
Yield of products, as determined by 19F NMR spectroscopy
using PhOCF3 as an internal standard. b DCE: 1,2-dichloroethane.
With the optimal conditions (Table 1, Entry 9), some
perfluoroalkylthiolations of thiols have been performed
(Figure 2).
The reaction leads to medium to excellent yields in
aromatic, heteroaromatic and aliphatic series. There is
no major influence of aromatic substituents. Steric
hindrance appears also to be not deleterious in aromatic
or aliphatic series. Pentafluoroethyl- and heptafluoro-
propyl-disulfides can be also obtained in the same
conditions with satisfactory yields.
Pefluoroalkylthiolation of alcohols to obtain per-
fluoroalkanesulfenates has been also envisaged. In
contrast with thiols, alcohols did not react under acid
activation. However, in basic conditions, the in situ gen-
erated alkoxides underwent the expected electrophilic
Results and Discussion
The 2nd generation of trifluoromethanesulfenamides
(BB2) being more reactive,[23a] this family of fluoro-
alkylated reagents (BB2x) has been selected.
The reactivity with thiols has been first studied and
the optimal conditions have been sought with CF3
reagents (BB23) and 4-fluorobenzenethiol (Table 1).
By simply mixing BB23 with thiol 1a, in acetonitrile,
a modest amount of 2a has been observed; heating
seems to be deleterious to the reaction (Table 1, Entries
456
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Chin. J. Chem. 2016, 34, 455—458

Direct Perfluoroalkylthiolation of Few Chalcogenols
Conclusions
To conclude, 2nd generation of trifluoromethane-
sulfenamide (BB2) turns out electrophilic enough to
react with chalcogenols and, thus, joins the few reagents
able to perform such a reaction, particular with alcohols.
The possibility to obtain higher homologs of this
reagent has opened the way to the synthesis of various
perfluoroalkyldisulfides or perfluoroalkanesulfenates,
which have been scarcely described. These results
introduce new fluorinated groups which could be of
interest for further applications.
Acknowledgement
The CNRS and the French Ministry of Research are
thanked for their financial support. The French Fluorine
Network is also thanked for its support.
Figure 2 Perfluoroalkylthiolations of some thiols. Yields
shown are of isolated products; values in parentheses are yields as
determined by 19F NMR spectroscopy using PhOCF3 as an
internal standard.
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Scheme 1 Perfluoroalkylthiolation of some alcohols (Yields
shown are of isolated products; values in parentheses are yields as
determined by 19F NMR spectroscopy using PhOCF3 as an
internal standard.)
BuLi (1.1 equiv.)
THF, 0 oC, 3 h
R OSRF
+
R
OH
N
RFS
Ts
5
BB2x
(1.2 equiv.)
OSCF3
H
H
6a
H
H
65% (82%)
F3CSO
6b
H
40% (60%)
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H
H
H
H
F3CF2CSO
7b
H
70% (74%)
H
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H
H
F3CF2CF2CSO
8b
H
50% (70%)
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www.cjc.wiley-vch.de
457

Glenadel & Billard
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Chin. J. Chem. 2016, 34, 455—458