Direct Electrophilic (Benzenesulfonyl)Difluoromethylthiolation with a Shelf-Stable Reagent

Article abstract of DOI:10.1002/anie.201601280

The (benzenesulfonyl)difluoromethylsulfanyl (PhSO₂CF₂S) group is a valuable substituent with specific properties which can provide access to new applications of fluoroalkylthiolated compounds. Direct introduction of this moiety can be performed by in an electrophilic manner by using a new shelf-stable reagent, namely a (benzenesulfonyl)difluoromethanesulfenamide. Furthermore, mild magnesium-mediated reduction of the PhSO₂CF₂S group leads to a facile synthesis of difluoromethylthiolated molecules and their deuterated analogs. Chameleon-like reactivity: (Benzenesulfonyl)difluoromethanesulfenamide was developed as a new, shelf-stable reagent for the introduction of the PhSO₂CF₂S group into organic molecules (see scheme). The versatility of the PhSO₂ moiety also provides an entry into reductive deuterations.

Full text of DOI:10.1002/anie.201601280

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International Edition: DOI: 10.1002/anie.201601280
German Edition: DOI: 10.1002/ange.201601280
Fluorinating Reagents
Direct Electrophilic (Benzenesulfonyl)Difluoromethylthiolation with
a Shelf-Stable Reagent
Ermal Ismalaj, Didier Le Bars, and Thierry Billard*
Abstract:
The
(benzenesulfonyl)difluoromethylsulfanyl
trimethylsilane (2) was synthesized following literature pro-
cedures and subsequently reacted in the presence of DAST
(diethylaminosulfur trifluoride) and aniline (Scheme 1).
[13]
(
PhSO CF S) group is a valuable substituent with specific
2
2
properties which can provide access to new applications of
fluoroalkylthiolated compounds. Direct introduction of this
moiety can be performed by in an electrophilic manner by
using a new shelf-stable reagent, namely a (benzenesulfonyl)-
difluoromethanesulfenamide. Furthermore, mild magnesium-
mediated reduction of the PhSO CF S group leads to a facile
2
2
synthesis of difluoromethylthiolated molecules and their
deuterated analogs.
Scheme 1. Synthesis of (benzenesulfonyl)difluoromethanesulfenamide
(1).
F
luorinated compounds have received growing interest for
[1]
a large panel of applications. Accordingly, various fluori-
nated substituents have been screened to modulate the
properties of targeted products. In particular, association of
fluorinated groups with a sulfur atom yields very specific
In light of the difference in reactivity between CF SiMe
3
3
and 2, the original procedure had to be altered. Indeed, with
the original reaction conditions (CH Cl /DIEA/À208C) no
2
2
[2]
properties, as illustrated by the high lipophilicity (Hansch
parameter p = 1.44) of the CF S group. However, apart
from CF S,
reaction was observed with DAST. Optimization studies were
conducted revealing THF/RT, without DIEA (diisopropyl-
ethylamine) as optimal conditions. With these conditions,
1 was produced in 60% yield from 2 on a 10-gram scale.
With the new reagent 1 in hand, similar reactions to those
[
3]
R
2,4]
3
[
[5]
[6]
HCF2S and a number of R S groups, other
F
3
substituents, with other modulations, have rarely been
described. This can be explained by the lack of efficient
synthetic methods.
[
7]
[11a,b]
previously described with the CF S reagent were studied.
3
The phenylsulfonyl (PhSO ) group is characterized by
First, electrophilic addition reactions to alkenes were per-
formed (Scheme 2). In contrast to the corresponding
2
[
8]
high electronic parameters (s = 0.62 and s = 0.68) and
m
p
[14]
a low lipophilicity parameter (p = 0.27) which could be of
trifluoromethanesulfenamide, the best results are obtained
with para-toluenesulfonic acid (TsOH) as activator rather
than BF ·Et O. These addition reactions give satisfactory
R
interest for modulating molecular properties. Accordingly,
[
9]
this substituent is used in various fields such as polymers or
3
2
[
10]
life sciences. The association of PhSO with a CF S moiety
results with regioselectivities, stereospecificities and stereo-
selectivities in accordance with transient sulfenium forma-
tion. In the case of (E)-oct-4-ene (3d), a lower yield for 4d is
observed because the allylic by-product 5d is also formed.
The formation of 5d can be explained by the steric hindrance
of the sulfenium intermediate, which disfavors the attack of
tosylate and, consequently, favors deprotonation in a-position
of the sulfenium. The elimination product 5d can be obtained
as major product (62%) when triflic acid (TfOH) is used
instead of TsOH.
2
2
could constitute interesting new fluorinated substituents with
new properties.
To easily access molecules bearing this substituent,
a strategy of direct introduction of the PhSO CF S group to
2
2
organic substrates was envisaged. Since we have previously
demonstrated that trifluoromethanesulfenamides act as very
[4b, 11]
efficient electrophilic trifluoromethylthiolating reagents,
we envisaged the design of a (benzenesulfonyl)difluoro-
methanesulfenamide (1).
Based on the previously described synthesis of trifluoro-
In reactions of alkynes (6a–c) the BF ·Et O/TsONa
3
2
[12]
methanesulfenamides,
[(benzenesulfonyl)difluoromethyl]-
system gives better results as compared to TsOH, albeit at
slightly higher temperature (808C vs. 508C). Again, single
regio- and stereoisomers (7a–c) were obtained in satisfactory
yields (Scheme 2).
[
*] E. Ismalaj, Dr. D. Le Bars, Dr. T. Billard
Institute of Chemistry and Biochemistry (ICBMS-UMR CNRS 5246),
Univ Lyon, UniversitØ Lyon 1, CNRS
It is noteworthy that these electrophilic addition reactions
4
3 Bd du 11 novembre 1918, 69622 Villeurbanne (France)
lead to lower yields than with the corresponding trifluoro-
and
[11a,14]
methanesulfenamide
which can be ascribed to the higher
CERMEP – in vivo imaging, Groupement Hospitalier Est
steric hindrance of 1.
With the aromatic alkene 3e, cyclization was observed
when triflic acid was used instead of TsOH, thus providing 2-
5
9 Bd Pinel, 69003 Lyon (France)
E-mail: Thierry.billard@univ-lyon1.fr
Homepage: http://www.FMI-Lyon.fr
(
benzenesulfonyl)difluoromethylthiotetrahydronaphthalene
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601280.
8 (Scheme 3). It can be reasoned that the generated triflate
4
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Scheme 2. Electrophilic addition of 1 to alkenes and alkynes. Yields
shown are of isolated products; values in parentheses are yields as
1
9
determined by F NMR spectroscopy using PhOCF as an internal
3
standard. Conditions A: TsOH (2.5 equiv), CH Cl , 508C, 15 h. Con-
2
2
ditions B: BF ·Et O (5 equiv), TsONa (1.5 equiv), ClCH CH Cl, 808C,
3
2
2
2
2
4 h. [a] A mixture of 4d and 5d was obtained.
Scheme 4. Electrophilic aromatic substitution of electron-rich arenes
with 1. Yields shown are of isolated products; values in parentheses
1
9
are yields as determined by F NMR spectroscopy using PhOCF as
3
an internal standard. [a] TfOH (1 equiv). [b] ClSiMe (1 equiv), 808C,
3
CH CN. [c] ClSiMe (1 equiv), RT, CH CN.
3
3
3
Scheme 3. Cyclization reaction with 3e. Yield shown is of isolated
1
9
product; value in parentheses is yield as determined by F NMR
with free amino and carboxylic functions. For example, the
tryptophane derivative 10k can be synthesized with excellent
yield. For more sensitive pyrroles, milder conditions using
Lewis acids should be preferable along with temperature
control.
spectroscopy using PhOCF as an internal standard.
3
anion is not nucleophilic enough to open the sulfenium
species which, hence, reacts with the aromatic core.
In a next step we studied aromatic electrophilic substitu-
tions with 1. Based on previous work with trifluoromethane-
sulfenamide, where the reactivity was limited to electron-rich
substrates, a rapid screening of conditions was performed with
These results confirm 1 as a valuable, shelf-stable reagent
for facile introduction of the SCF SO Ph moiety in organic
molecules. Cross-coupling reactions with boronic acids were
2
2
envisaged to extend the panel of aromatic compounds,
[11a,15]
[16]
indole (Table S1 in the Supporting Information).
however, as previously demonstrated with CF S reagents,
3
Similar as in the addition reactions with alkenes and
alkynes, protic acids or Lewis acids are able to activate 1 for
this reaction. With TsOH, excess of the acid (2.5 equiv) at
no reaction was observed.
An interesting aspect of the SCF SO Ph group is the
2
2
[
17]
“chameleon”-like character of the benzenesulfonyl part. In
particular, reduction reactions could provide easy access to
difluoromethylated compounds which are interesting for
5
08C is required to obtain good results (89%). With the
strong protic acid TfOH lower quantities of the acid are
required (1 equiv) to obtain good yields (80%). A catalytic
amount can be even sufficient to obtain satisfactory results
[
18]
biological applications.
(LiAlH4)
Whereas reduction with hydride
leads to a moderate yield (50%), magnesium
gives good results (Scheme S1 in the Supporting Informa-
[19]
(
61%) at 808C. The soft Lewis acid ClSiMe gave also good
3
[20]
yields (83%) when used in a stoichiometric amount at 808C.
With the optimal conditions in hands, various arenes and
heteraoarenes were converted with good yields (Scheme 4).
tion).
By using this mild reduction reaction, a range of
difluoromethylthiolated
(Scheme 5).
compounds
were
prepared
[
15]
As previously demonstrated for the CF S series,
the
The reaction conditions are compatible with a free
3
reactivity was limited to electron-rich compounds. With less
electron-rich arenes (10c, e, f) the stronger acid TfOH is
required that increases the electrophilicity of 1 through better
activation. Among the heteroarene substrates, the most
reactive indoles and pyrroles give good to excellent yields.
Interestingly, protection of the free NH group of the indole or
pyrrole substrates is not required. The reaction is compatible
carboxylic acid group (11j). In the case of tosylate 4a, the
tosylate part is reduced to furnish the a-CF S alcohol 13a.
3
However, with compounds 7, degradation is observed
because the initially formed enols collapse under the reaction
conditions. Such a strategy could provide a valuable alter-
[
5]
native to many recently published strategies although it
[5k,l]
requires two steps as compared to recent direct methods.
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To conclude, the fluorinated sulfenamide reagent 1 ena-
bles the synthesis of various (benzenesulfonyl)difluorome-
thylthiolated compounds, thus providing an invaluable tool
for modulation of the properties of designed molecules. Given
the versality of the benzenesulfonyl group further post-
transformations can be envisaged. Furthermore, it is the first
method for the preparation of SCF D-substituted molecules.
2
This new reagent 1 confirms that fluoroalkylsulfenamides
constitute a valuable and important family of reagents for the
fluoroalkylthiolation of organic substrates.
Experimental Section
Synthesis of 10a: To a solution of 1 (158 mg, 0.5 mmol, 1 equiv) in dry
CH Cl (1m), m-dimethoxybenzene (9a) was added (65.5 mL,
2
2
0
1
.5 mmol, 1 equiv). To the resulting mixture p-TsOH (237.5 mg,
.25 mmol, 2.5 equiv) was added and the reaction mixture was heated
at 508C for 15 h. The reaction mixture was extracted with EtOAc
10 mL ” 2) and the organic phase was dried over Na SO . After
(
2
4
removal of the solvent under vacuum the compounds were purified
1
via silica gel column chromatography. H NMR (500 MHz, CDCl ):
3
d = 7.99–7.97(m, 2H), 7.75–7.71 (m, 1H), 7.61–7.54 (m, 3H), 6.51–
1
3
6
.46 (m, 2H), 3.83 ppm (d, J = 2.8 Hz, 6H). C NMR (126 MHz,
CDCl ): d = 164.2, 162.9, 140.9, 135.4, 133.0, 130.9, 129.3, 128.1 (t, J =
3
1
9
3
25.4 Hz), 105.7, 102.3, 99.3, 56.1, 55.66 ppm. F NMR (471 MHz,
CDCl ) d = À79.61 ppm (s, 2F).
3
Scheme 5. Reduction of sulfone. Yields shown are of isolated prod-
1
9
ucts; values in parentheses are yields as determined by F NMR
spectroscopy using PhOCF as an internal standard. [a] With CD OD
instead of MeOH as solvent.
Acknowledgements
3
3
This work was supported by the RADIOMI project (EU FP7-
PEOPLE-2012-ITN-RADIOMI), the CNRS, and the French
Fluorine Network.
Because of the higher metabolic stability of the CÀD
bond, deuterated molecules find a number of applications in
[21]
drug design. Molecules bearing a SCF D group could open
2
Keywords: aromatic substitution ·
new opportunities in medicinal chemistry. To the best of our
knowledge, with the exception of two kinetic isotope
(
benzenesulfonyl)difluoromethanesulfenamide ·
difluoromethylthiolation · electrophilic addition · fluorine
[
22]
exchange studies, such compounds have not been described
and no efficient synthetic methods have been proposed to
date.
How to cite: Angew. Chem. Int. Ed. 2016, 55, 4790–4793
Angew. Chem. 2016, 128, 4868–4871
By replacing MeOH by CD OD in the reduction reaction
described above, deuterium-labeled compounds are obtained
in good yields (Scheme 5). This constitutes the first efficient
3
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