An easier and quicker access to (benzenesulfonyl)difluoromethanesulfenamide reagent

Article abstract of DOI:10.1016/j.jfluchem.2017.07.001

(Benzenesulfonyl)difluoromethanesulfenamide (PhSO2-BB12H) is an interesting reagent to lead to various fluoroalkylselenotated molecules. This compound is obtained from [(benzenesulfonyl)difluoromethyl]trimethylsilane. Herein, a new process in two steps, w

Full text of DOI:10.1016/j.jfluchem.2017.07.001

Accepted Manuscript
Title: An easier and quicker access to
(benzenesulfonyl)difluoromethanesulfenamide reagent
Authors: Ermal Ismalaj, Thierry Billard
PII:
S0022-1139(17)30275-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2017.07.001
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Please cite this article as: Ermal Ismalaj, Thierry Billard, An easier and quicker
access to (benzenesulfonyl)difluoromethanesulfenamide reagent, Journal of Fluorine
Chemistryhttp://dx.doi.org/10.1016/j.jfluchem.2017.07.001
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An easier and quicker access to (benzenesulfonyl)difluoromethanesulfenamide reagent.
Ermal Ismalaj,a,b Thierry Billard a,b
a
Institute of Chemistry and Biochemistry (ICBMS – UMR CNRS 5246), Univ Lyon,
Université Lyon 1, CNRS, 43 Bd du 11 novembre 1918, 69622 Lyon (France).
b CERMEP-In vivo imaging, Groupement Hospitalier Est, 59 Bd Pinel, 69003 Lyon (France)
E-mail: thierry.billard@univ-lyon1.fr
In honor of Antonio Togni, with congratulations.
Graphical abstract
Highlights
• PhSO2CF2S group can be post-transformed
• Various fluoroalkylthiolated molecules can be obtained
• Direct electrophilic (benzenesulfonyl)difluoromethylthiolation by using PhSO2-BB12H
reagent
• Synthesis of this reagent needs to be optimized and simplified
• New access way through an easy synthesis of PhSO2SiMe3
Abstract.
(Benzenesulfonyl)difluoromethanesulfenamide (PhSO2-BB12H) is an interesting reagent to
lead to various fluoroalkylselenotated molecules. This compound is obtained from
[(benzenesulfonyl)difluoromethyl]trimethylsilane. Herein, a new process in two steps,
without intermediate purifications, is described to easily synthesize this product. With this

new method, preparation of PhSO2-BB12H reagent has been carried out in only 3 steps, with
only one final purification and with a good overall yield.
Keywords.
[(benzenesulfonyl)difluoromethyl]trimethylsilane,
(Benzenesulfonyl)difluoromethanesulfenamide, Ruppert-Prakash reagent,
fluoroalkanesulfenamide, fluoroalkylthiolation.
Introduction
Fluorinated compounds are more and more used in a large panel of applications, from
materials to life sciences [1-12]. Such particular interest for fluorinated molecules is mainly
due to the modifications of physico-chemical and electronic properties induced by fluorinated
moieties [13]. Among all the possible fluorinated substituents, the association of fluoroalkyl
moieties with chalcogens has known these last years a specific interest [14-18] because of
their specific properties as illustrated by their high lipophilicity [19].
Because phenylsulfonyl (PhSO2) group is characterized by high electronic parameters
(Hammett constants m = 0.62, p = 0.68; Swain-Lupton constants F = 0.58, R = 0.10) [20]
and a low lipophilicity parameter (R = 0.27) [19], PhSO2CF2S group brings some
opportunities to modulate molecular properties. Furthermore, the “chameleon”-like character
of the benzenesulfonyl part offers some possibilities of post-transformations to obtain new
fluorinated substituents [21]. This post-transforming ability paves the way to the synthesis of
various molecules with a –SCF2- part.[22-28]
Due to such an interest, we have recently described the direct electrophilic
(benzenesulfonyl)difluoromethylthiolation by designing a shelf-stable reagent, namely
(benzenesulfonyl)difluoromethanesulfenamide (PhSO2-BB12H) [29]. With this reagent, a
large panel of PhSO2CF2S-molecules have been obtained. Furthermore, some post-
transformations of the PhSO2 part have also been performed. In particular, an easy access to
the unknown DCF2S group has been developed [29].
Results and discussion

The
reagent
PhSO2-BB12H
was
synthesized
from
[(benzenesulfonyl)difluoromethyl]trimethylsilane (1), DAST (diethylaminosulfur trifluoride)
and aniline (Scheme 1) [29, 30].
This synthesis turned out very efficient and was scaled-up to 10 grams. However, the
synthesis of starting reagent 1 appeared to be a multi-step process using CF2Br2 as fluorinated
starting material which belongs to halon family and which is a class I ozone depleting
substance (Scheme 2) [31]. Furthermore, due to this eco-toxicity, CF2Br2 is a quite expensive
reagent.
To try to circumvent these drawbacks, alternatives to the synthesis of 1 were investigated. It
has been reported that this compound 1 could be prepared from the deprotonation of
difluoromethyl phenyl sulfone (3), commercially available, in presence of ClSiMe3, but no
yields were reported [32]. However, in our hand, only a low yield of the expected product 1
was obtained following this strategy (Scheme 3). Despite a few attempts to optimize this
reaction, no yield improvements were observed.
Consequently, an alternative approach was envisaged through a halogen-lithium exchange
with the bromodifluoromethyl phenyl sulfone (2) [29, 32]. This last compound being not
easily commercially available, it had to be first prepared. Based on literature procedures [33],
2 was obtained from 3 by action of NaOBr, generated in situ from NaOH and Br2 (Table 1).
If the expected product 2 was obtained with good yield on a small scale (entry 1), some
reproducibility issues were observed (entries 1-2). Furthermore, at larger scale, yield
underwent an important decrease. Such results being not in accordance with the production of
batch of reagent PhSO2-BB12H in higher quantity, another way of access was investigated.

Recently, the siladifluoromethylation of thiol has been described starting from Ruppert-
Prakash reagent (CF3SiMe3) [34]. Based on this work, a modified synthetic procedure was
applied to prepare the (difluoro(phenylthio)methyl)trimethylsilane (4) with an excellent yield
(Scheme 4). Following oxidation of 4 into 1 was first performed using m-chloroperbenzonic
acid (mCPBA) [35, 36], but the desilylative hydrolysis happened readily during the basic
workup, as previously observed in literature [32]. Consequently, alternative oxidation
conditions were considered to avoid acidic by-product production. By using ruthenium
tetraoxide, 4 was oxidized into 1 with good yield [37]. With this two-step approach, no further
purifications, after each step, were required and the final product 1 could be used directly
(Scheme 4).
With this new method, (benzenesulfonyl)difluoromethanesulfenamide reagent (PhSO2-
BB12H) was obtained in only 3 steps with a single final purification in a good overall yield
and this strategy has been scaled-up to large quantity without problem (Scheme 5).
Conclusion
To conclude, a new access to [(benzenesulfonyl)difluoromethyl]trimethylsilane (1) has been
developed from CF3SiMe3. This two-step process does not require purification and the
obtained
compound
has
been
engaged
in
the
synthesis
of
(benzenesulfonyl)difluoromethanesulfenamide (PhSO2-BB12H), an electrophilic reagent to
perform fluoroalkylthiolation. Up to 15 g of this reagent has been hence obtained in 3 steps
with an overall yield of 50%. This new strategy considerably improve the previously
described synthesis. Furthermore the easy access to 1, described in this work, opens the way
to the use of this silylated reagent in further applications. For instance, this reagent has been
already used to synthesize deuterodifluoromethylselenolated molecules [38].
Acknowledgments.
This work was supported by the European Union (EU) through the project Radiochemistry for
Molecular Imaging (project number EU FP7-PEOPLE-2012-ITN-RADIOMI). The CNRS is
thanked for its financial support. The French Fluorine Network is also thanked for its support.

Experimental
General information
Commercial reagents were used as supplied. NMR spectra were recorded in CDCl3 on a
Bruker AV 400 spectrometer at 400 MHz (1H NMR), 100 MHz (13C NMR), 376 MHZ (19F
NMR). All coupling constants were reported in Hz.
[difluoro(phenylsulfanyl)methyl]trimethylsilane (4)
Thiophenol (12.5 g, 113.46 mmol) is slowly added to a round-bottomed flask containing a
mixture of LiBF4 (12.76 g, 136.15 mmol) and LiH (1.08g, 136.15 mmol) in DMF (560 mL).
The resulting mixture was stirred for 5 minutes more under inert atmosphere. Addition of
TMSCF3 (16.77 mL, 113.46 mmol) was followed by a vigorous stirring until the reaction
went to completion (19F NMR check, needed approximately 15-30 min.). Then the reaction
mixture is diluted with Et2O and filtered over a pad of silica. The filtered mixture is extracted
(Et2O x3) and the organic layers collected and washed with water and brine. Removal of the
organic solvent under vacuum gave the expected compound 4 (26.13 g) in 99% yield.
1H NMR:  = 7.61 (m, 2H), 7.42-7.34 (massif, 3H), 0.23 (m, 9H). 13C NMR:  = 136.4 (t, J =
1 Hz), 134.3 (t, J = 300 Hz), 129.3, 128.9, 126.2 (t, J = 4 Hz), -4.0 (t, J = 1 Hz). 19F NMR:  =
-88.04 (s, 2F). In accordance with literature [36].
[(benzenesulfonyl)difluoromethyl]trimethylsilane (1)
To a round-bottomed flask containing compound 4 (25 g, 107.6 mmol) in CH3CN/CCl4/H2O
(0.5/0.5/1, 500 mL) RuCl3 (223.16 mg, 1.08 mmol) were added. The reaction flask is cooled
to 0 °C using an ice bath and NaIO4 (57.53 mg, 268.97 mmol) was slowly added in portions.
After addition of NaIO4, the ice bath was removed and the reaction was left under stirring for
2.5 hours reaching room temperature (20-25 °C). The reaction mixture was filtered and the
solution was extracted using ethyl acetate (x 3). Organic fractions were collected and washed
with water and brine. Removal of the solvent under vacuum led to the expected compound 1
(21.39 g) in 75 % isolated yield without further purification.
1H NMR:  = 7.94 (m, 2H), 7.73 (m, 1H), 7.59 (m, 2H), 0.43 (s, 9H). 19F NMR:  = -112.32
(s, 2F). In accordance with literature [29, 39].

N-{[(benzenesulfonyl)difluoromethyl]sulfanyl}aniline (PhSO2-BB12H)
In an oven-dried flask under N2 containing THF (150 mL), DAST (11 mL, 83.3 mmol) is
slowly added and the mixture is stirred for 10 min at room temperature. Silane (1) (20 gr, 75.7
mmol) is added to the solution and the reaction is stirred for 1 more hour. The reaction was
quenched with aniline (6.9 mL, 75.7 mmol) and left at room temperature overnight. The
reaction mixture was extracted with EtOAc (120 mL x 3) and the organic layers washed with
water, brine and dried over Na2SO4. After the removal of the solvent under vacuum the
compound PhSO2-BB12H was purified via silica gel column chromatography
(Cyclohaxane/EtOAc: 98/2 to 95/5). Brownish oil, 14.97 g (63%).
1H NMR:  =8.00-7.97(m, 2H), 7.79-7.74(m, 1H), 7.63-7.59 (m, 2H), 7.28-7.24 (m, 2H),
13
7.11-7.08(m, 2H), 6.97-6.93 (m, 1H), 5.21 (s, 1H). C NMR:  = 145.5, 135.8, 132.4, 130.8,
129.6, 129.3, 127.5 (t, J = 332 Hz), 122.0, 115.5. 19F NMR:  = -89.84 (s, 2F). In accordance
with literature [29].
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Scheme 1. Synthesis of (benzenesulfonyl)difluoromethanesulfenamide reagent
Scheme 2. Synthesis of [(benzenesulfonyl)difluoromethyl]trimethylsilane (1).
19
Scheme 3. Deprotonation of difluoromethyl phenyl sulfone (3). Yields determined by F
NMR spectroscopy using PhOCF3 as an internal standard

Scheme 4. Two-step synthesis of 1.

Scheme 5. Comparison of 2 synthetic pathways to obtain PhSO2-BB12H reagent.

Table 1. Synthesis of bromodifluoromethyl phenyl sulfone (2).
Entry
3 (mmol)
2 (%)a
75
1
2
3
4
1
1
70
5
40
10
45
a yields determined by 19F NMR spectroscopy using PhOCF3 as an internal standard