Sulfilimines and sulfoximines by reaction of nitriles with perfluoroalkyl sulfoxides

Article abstract of DOI:10.1002/ejoc.200900410

The species obtained by activation of perfluoroalkylated sulfoxides with trifluoromethanesulfonic anhydride behaves as highly electrophilic entities. Their reaction with nitriles allows a Ritter-like process leading to the new fluorinated acylsulfilimines

Full text of DOI:10.1002/ejoc.200900410

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900410
Sulfilimines and Sulfoximines by Reaction of Nitriles with Perfluoroalkyl
Sulfoxides
Yohan Macé,[a] Céline Urban,[a] Charlotte Pradet,[b] Jérôme Marrot,[a]
Jean-Claude Blazejewski,[a] and Emmanuel Magnier*[a]
Keywords: Synthetic methods / Fluorine / Sulfilimines / Sulfoximines / Nitriles
The species obtained by activation of perfluoroalkylated sulf- permanganate. This oxidation may be performed either after
oxides with trifluoromethanesulfonic anhydride behaves as
highly electrophilic entities. Their reaction with nitriles al-
lows a Ritter-like process leading to the new fluorinated acyl-
sulfilimines 1–21 after hydrolysis. This flexible methodology
allows some variation of both the sulfoxide and nitrile com-
ponents. Derived acylsulfoximines 22–25 or free sulfoximines
26–28 could be selectively obtained, as needed, by further
controlled oxidation with the cheap and nontoxic potassium
isolation of the intermediate sulfilimine, or more conve-
niently in a one-pot process directly from fluorinated sulfox-
ides. This versatile, solvent and metal free, reaction is thus
an opening way through the synthesis of new ligands or elec-
trophilic trifluoromethylating reagents.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
fluoromethyl thioether in the absence of an external nucleo-
phile.[2,6] This points to a very high electrophilic reactivity
which seems to have been overlooked previously.[7]
Introduction
The introduction of the trifluoromethyl group has grown
in importance in all fields of chemistry thanks to the modi-
fications induced by its presence. Materials science, agroch-
emistry, pharmaceuticals and ligand chemistry have taken
advantage of this substituent through the development of
molecules possessing original properties and/or increased
stability.[1] In this context, we have recently developed a re-
search program devoted to the preparation of electrophilic
trifluoromethylating reagents and proposed a general one
step synthesis of trifluoromethyl sulfonium salt deriva-
tives.[2] Our simple methodology has unlocked the access to
these kind of reagents, previously limited by their cumber-
some preparation,[3] which are now complemented by new
reagents proposed recently by Togni and Shibata.[4,5] Dur-
ing this work, we were intrigued by the uncommon reactiv-
ity of the species obtained by activation of a trifluoromethyl
sulfoxide with trifluoromethanesulfonic anhydride. We and
others have shown that this intermediate can react easily
with weak nucleophiles like aromatics to produce trifluoro-
methylating agents (vide supra) or more curiously is sub-
jected to a reduction process leading ultimately to a tri-
Results and Discussion
These remarks led us to envisage that the active species
could also react with other weak nucleophilic entities. In
this work, we described its novel reaction with nitriles open-
ing an easy access to fluorinated sulfilimines.[8] To the best
of our knowledge, only one example of nitrile as nitrogen
source for the production of sulfilimines (nonfluorinated)
has been described.[9] This later function is an emergent
group in organic chemistry due to numerous and increased
applications in medicinal chemistry, organic synthesis and
also catalysis as coordination ligands.[10] Extensive synthetic
works are devoted to their preparation with recent special
emphasis to enantioselective synthesis.[10,11] They are usu-
ally obtained by reaction of a thioether or a sulfoxide with
various elaborated imination reagents both assisted or un-
assisted by a transition metal catalyst.[12]
Our metal free methodology involves a simple mix of
phenyl trifluoromethyl sulfoxide with acetonitrile and tri-
fluoromethanesulfonic anhydride affording, after a quench
with water, the corresponding N-acylsulfilimine 1 (Table 1,
entry 1). This process is very simple, solvent free and highly
versatile. Indeed, the length of the perfluorinated chain can
be increased without loss of efficiency as depicted by entries
2, 6, 11 and 12. The substitution pattern of the aromatic
has also been studied. With an electron-donating group like
methyl, we noticed a beneficial effect on the isolated yield
[a] ILV-CNRS, UMR 8180, Université de Versailles-Saint-
Quentin,
45 Avenue des Etats-Unis, 78035 Versailles Cedex, France
Fax: +33-1-3925-4452
E-mail: magnier@chimie.uvsq.fr
[b] GlaxoSmithKline, Synthetic Chemistry,
Gunnels Wood Road, Stevenage SG1 2NY, England
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900410.
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of Sulfilimines and Sulfoximines from Nitriles
whatever its position on the ring (entries 3 to 5). Halogen
substitution is well tolerated (entries 7 to 11) with a de-
crease of yield in the case of the meta position (entry 8) as
expected for an electrophilic reaction. We also succeed in
the preparation of the methylsulfilimine 12 but obtained
unreproducible results with nonfluorinated sulfoxide like
methyl phenyl sulfoxide or diphenyl sulfoxide. All the sulfili-
mines are stable compounds and can be kept at room tem-
perature for many weeks.
Table 1. Preparation of perfluoroalkylated sulfilimines.
Figure 1. X-ray structure of sulfilimine 5.
We also studied the possibility of variation of the nitrile
engaged in this reaction. Such modifications will allow the
description of a rich family of sulfilimines with varied func-
tionalities for further applications. Table 2 illustrates the
wide range of chemical functions compatible with the reac-
tion conditions. Aliphatic, benzylic, ether and aromatic ni-
triles gave rise to target sulfilimines with correct yield (en-
tries 1 to 6). The main limitation seems to be the presence
of an electron-withdrawing group on the benzene ring
decreasing the nucleophilic character of the nitrogen rea-
gent and consequently resulting in modest isolated yield
(entries 7 to 9).
Entry
R
RF
% Yield of isolated product[a]
1
2
3
4
5
6
7
8
Ph
Ph
CF3
C4F9
1
2
75
80
87
94
97
97
78
50
96
99
81
56
o-Me-C6H4 CF3
m-Me-C6H4 CF3
p-Me-C6H4 CF3
p-Me-C6H4 C4F9
o-Cl-C6H4
m-Cl-C6H4
p-Cl-C6H4
p-Br-C6H4
p-Br-C6H4
CH3
3
4
5
6
CF3
CF3
CF3
CF3
C4F9
C8F17
7
8
9
9
10
11
12
10
11
12
Table 2. Variation of the nitrile.
[a] In all cases 1.5 equiv. of CH3CN and 1.5 equiv. of Tf2O are
introduced.
We propose the following mechanism (Scheme 1). At low
temperature (–15 °C) the activated species (complex of sulf-
oxide and trifluoromethanesulfonic anhydride) is stable
enough to be attacked by the nitrogen atom with concomi-
tant addition of the triflate anion on the carbon of the ni-
trile function. The resulting sulfonium species is then con-
verted into a more stable acetal intermediate and further
transformed into the desired sulfilimine by addition of
water during the final quenching step.[13]
Entry
R
% Yield of isolated product
1
2
3
4
5
6
7
8
9
nPr
13
14
15
16
17
18
19
20
21
64
75
74
63
60
63
44
44
22
cyclo-Pr
MeOCH2
PhCH2
Ph
p-Me-C6H4
p-Br-C6H4
o-Br-C6H4
m-O2N-C6H4
With sulfilimines at hand, their oxidation to highly
praised sulfoximines seemed to be a logical extension to the
present study as they are also key intermediates for the syn-
thesis of this sulfur(VI) heteroatomic group.[16] Many syn-
thetic efforts have been devoted to preparation of the latter
for biological purposes or the development of chiral auxilia-
ries.[17]
Scheme 1. Tentative mechanism proposal.
The chemistry of fluorinated sulfoximines has been initi-
The structure of all these new sulfilimines has been ascer- ated by the group of Yagupolskii and continued by us.[18,19]
tained by classical analytical data and secured for com- These highly electron-withdrawing derivatives have found
pounds 5 and 10 by X-ray analysis.[14] Figure 1 discloses the applications for liquid crystals and more recently for the
structure of molecule 5. Interestingly, it appears that the S– invention of electrophilic trifluoromethylating reagents.[20,5]
CF3 bond lies almost perpendicular to the plane defined by Nevertheless, their preparation is cumbersome, especially
the aromatic ring. This very particular conformation has the imination step which is undertaken by heating an oleum
already been observed for dibenzothiophenium salts.[15]
solution of sodium azide and sulfoxide.[21]
Eur. J. Org. Chem. 2009, 3150–3153
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3151

E. Magnier et al.
SHORT COMMUNICATION
We tried to ameliorate oxidation conditions to be able to or sulfoximines by simple mix of sulfoxide, nitrile and tri-
give rise either to the sulfoximine with the keto functionali- fluoromethanesulfonic anhydride. This versatile pathway al-
zation kept on the nitrogen atom or free sulfoximine. lows the introduction of functional diversity. The synthetic
Amongst the classical reagents tested, disappointing results potential of this new reaction and of the new compounds
(partial transformations, lack of selectivity) occurred with is under evaluation in our laboratory.
metachloroperbenzoic acid, trifluoroperacetic acid, ruthe-
nium dioxide and hydrogen peroxide.[22–25] We were pleased
Experimental Section
to observe that the cheap and nontoxic potassium perman-
ganate was the candidate of choice.[26] The controlled oxi-
dation of sulfilimines has been undertaken with excellent to
modest (due to incomplete conversion of the starting mate-
rial) yields depending on substrate (Table 3, entries 1–4).
When the same reaction was run in the presence of a base,
deprotection of the nitrogen atom occurs concomitantly
(entries 5–7).
General Procedure for the Synthesis of Sulfilimines Compounds as
Exemplified by the Preparation of 1: Trifluoromethanesulfonic an-
hydride (1.3 mL, 7.5 mmol, 1.5 equiv.) was added under argon to a
precooled (–15 °C) mixture of phenyl trifluoromethyl sulfoxide[28]
(0.97 g, 5 mmol) and acetonitrile (0.4 mL, 7.5 mmol, 1.5 equiv.).
The reaction mixture was stirred for 24 h at –15 °C, then hy-
drolyzed with water (5 mL), extracted with CH2Cl2 (3ϫ15 mL),
dried with MgSO4, and concentrated under reduced pressure. The
residue was purified by flash chromatography (diethyl ether/pen-
tane, 7:3) to give 0.89 g (75%) of a yellow oil. 19F NMR (CDCl3,
Table 3. Oxidation to sulfoximines.
1
188 MHz): δ = –64.7 (s, 3 F) ppm. H NMR (CDCl3, 300 MHz): δ
= 7.87 (d, J = 8.3 Hz, 2 H, ArH), 7.72–7.57 (m, 3 H, ArH), 2.22
(s, 3 H, CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 183.7, 134.3,
130.2, 128.7, 127.3, 124.2 (q, J = 324 Hz, CF3), 24.0 ppm. Pos.
ESI MS: m/z = 189 ([MNa – CF3]·+), 258 [MNa+], 493 (2MNa+).
C9H8F3NOS (235.03): calcd. C 45.95, H 3.43, N 5.95; found C
45.54, H 3.53, N 5.89.
Entry
R
RЈ
RF
Method Compound % Yield
General Procedure for the Basic Oxidation of Sulfilimines Com-
pounds as Exemplified by the Preparation of 26:[5] A mixture of
N-[phenyl(trifluoromethyl)-λ4-sulfanylidene]acetamide (1) (118 mg,
0.5 mmol), sodium hydroxide (40 mg, 1 mmol, 2 equiv.) and potas-
sium permanganate (80 mg, 0.4 mmol, 1 equiv.) in water (2 mL)
was heated at 110 °C for 2 h. The mixture was cooled, cleared with
Na2S2O4, then diluted with water (3 mL) and extracted with
CH2Cl2 (3ϫ15 mL). The organic layers were dried with MgSO4
and concentrated under reduced pressure. The residue was purified
by preparative plate (diethyl ether/pentane, 3:7) to give 50 mg
(48%) of a white solid; m.p. 89 °CϮ0.2 °C. 19F NMR (CDCl3,
1
2
3
4
5
6
7
H
CH3
CH3
CH3
CH2Ph
CH3
CH3
CH3
CF3
CF3
C4F9
CF3
CF3
CF3
C4F9
A[a]
A
A
22
23
24
25
26
27
28
69
95
40
44
48
72
36
Me
Br
H
H
Me
Br
A
B[b]
B[b]
B[c]
[a] One equiv. of KMnO4 in water. [b] One equiv. of KMnO4 and
two equiv. of NaOH in water. [c] See footnote b, but 5 equiv. of
KMnO4 for this sluggishly reacting substrate.
In order to avoid the isolation of the sulfilimine for the
production of sulfoximine, we have also studied a one pot
process. After completion of sulfilimine formation, the oxi-
dant and the base are directly added to the reaction me-
dium (Scheme 2). Sulfoximines were thus formed in excel-
lent yields, better in fact than those obtained via the two
step process. This new smooth and convenient pathway now
allows the preparation of original fluorinated sulfoximine
like 27 and the easy synthesis of a precursor 26 of recently
described new electrophilic trifluoromethylating rea-
gent.[5,27]
1
188 MHz): δ = –79.3 (s, 3 F) ppm. H NMR (CDCl3, 300 MHz): δ
= 8.16 (d, J = 7.3 Hz, 2 H, ArH), 7.83–7.75 (m, 1 H, ArH), 7.69–
7.61 (m, 2 H, ArH), 3.62 (br. s for NH, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 35.5, 131.6, 130.6, 129.5, 120.9 (q, J =
332 Hz, CF3) ppm. Pos. ESI (m/z): 210 [MH+], 232 [MNa+], 441
(2MNa+).
General Procedure for the Oxidation of Sulfilimines Compounds as
Exemplified by the Preparation of 22: A mixture of 1 (118 mg,
0.5 mmol) and potassium permanganate (80 mg, 0.5 mmol,
1 equiv.) in water (5 mL) was stirred at room temperature overnight
and then treated and purified as above to give 87 mg (69%) of an
oil. 19F NMR (CDCl3, 188 MHz): δ = –74.9 (s, 3 F) ppm. 1H NMR
(CDCl3, 300 MHz): δ = 8.06 (d, J = 7.7 Hz, 2 H, ArH), 7.87–7.80
(m, 1 H, ArH), 7.73–765 (m, 2 H, ArH), 2.27 (s, 3 H, CH3) ppm.
13C NMR (CDCl3, 75 MHz): δ = 178.6, 136.2, 130.4, 130.2, 130.1,
120.3 (q, J = 328 Hz, CF3), 26.8 ppm. pos. ESI (m/z): 251 [MNa+].
C9H8F3NO2S (251.02): calcd. C 43.03, H 3.21, N 5.58; found C
43.19, H 3.35, N 5.61.
General Procedure for the One-Pot Synthesis of Sulfoximines: After
the water hydrolysis (vide supra), sodium hydroxide (2 equiv.) and
potassium permanganate (1 equiv.) were added, the reaction heated
at 110 °C for 2 h and then treated and purified as above.
Scheme 2. One-pot preparation of sulfoximines.
Conclusions
Supporting Information (see also the footnote on the first page of
this article): Crystal data and X-ray structures for compounds 5,
In summary, we have developed a new methodology for
straightforward synthesis of either fluorinated sulfilimines 10 and 23. 19F NMR spectra of the crude mixture as experimental
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Eur. J. Org. Chem. 2009, 3150–3153

Synthesis of Sulfilimines and Sulfoximines from Nitriles
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[10] F. Collet, R. H. Dodd, P. Dauban, Org. Lett. 2008, 10, 5473–
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[11] C. S. Tomooka, E. M. Carreira, Helv. Chim. Acta 2002, 85,
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Acknowledgments
[12] a) H. Okamura, C. Bolm, Org. Lett. 2004, 6, 1305–1307; b)
G. X. Cho, C. Bolm, Tetrahedron Lett. 2005, 46, 8007–8008; c)
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[13] Some evidence for a bis triflate acetal intermediate has been
obtained by 19F NMR spectroscopy. See the corresponding
spectra in Supporting Information.
Y. M. thanks GlaxoSmithKline and Centre National de la Recher-
che Scientifique (CNRS) for financial support (BDI grant) and
C. U. thanks the French Ministry of Research for a PhD grant.
Sophie Clift is acknowledged for English language polishing of this
article.
[14] X-ray structure of sulfoximine 23 has also been obtained. The
crystal data for 5, 10 and 23 are detailed in the Supporting
Information. CCDC-724941 (5), -724942 (10) and -724943 (23)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_r-
equest/cif.
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Received: April 15, 2009
Published Online: May 15, 2009
Eur. J. Org. Chem. 2009, 3150–3153
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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