N -Trifluoromethylthiolated Sulfoximines

Article abstract of DOI:10.1021/acs.orglett.5b01384

Air- and moisture-stable N-trifluoromethylthio sulfoximines have been prepared from N-H-sulfoximines via the corresponding N-Br derivatives in excellent yields. The two-step process starts with an easy-to-perform bromination at the sulfoximine nitrogen, followed by a reaction with silver trifluoromethanethiolate. A one-pot reaction sequence allows difficult to prepare products to be obtained.

Full text of DOI:10.1021/acs.orglett.5b01384

Letter
pubs.acs.org/OrgLett
N‑Trifluoromethylthiolated Sulfoximines
Christian Bohnen and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: Air- and moisture-stable N-trifluoromethylthio
sulfoximines have been prepared from N−H-sulfoximines via
the corresponding N−Br derivatives in excellent yields. The
two-step process starts with an easy-to-perform bromination at
the sulfoximine nitrogen, followed by a reaction with silver
trifluoromethanethiolate. A one-pot reaction sequence allows difficult to prepare products to be obtained.
he incorporation of fluoro and fluoroalkyl moieties in
organic molecules offers powerful synthetic opportunities
sulfenyl chloride) and its isolation (by gas chromatography), we
aimed at development of a more general access of N-SCF3-
substituted sulfoximines 6. Here, the realization of this idea is
described.
T
for obtaining biologically active compounds.1 Along these lines,
the trifluoromethylthio (SCF3) group has received particular
attention,2,3 as its presence enhances the lipophilicity of
molecules4 affecting their bioavailability.
The key to success was the combination of two readily
available reagents, N-bromo sulfoximines and silver(I) trifluoro-
methanethiolate (Table 1).12 The former compounds could
easily be prepared in high yields by treatment of the
corresponding N−H-sulfoximines with N-bromo succinimide
(NBS).13 In this manner, for example, compound 8a was
obtained from N−H-S,S-diphenyl sulfoximine (7a) in 94% yield
after 30 min in DCM at room temperature (Table 1, entry 1).14
Analogously, S-alkyl S-aryl sulfoximines 7b−l reacted well
affording the respective N-brominated products 8b−l in yields
ranging from 86% to 99% (Table 1, entries 2−12). Neither
steric nor electronic effects of the substituents had an apparent
impact on the yield. Attempts to prepare N-bromo-S-
trifluoromethyl-S-phenyl sulfoximine (8m) and N-bromo-S,S-
dimethyl sulfoximine (8n) by this protocol remained
unsuccessful (Table 1, entries 13 and 14).
Most traditional methods for introducing trifluoromethylthio
substituents are characterized by harsh reaction conditions and
a pronounced toxicity of the required reagents. In this context,
halogen−fluorine exchange reactions, trifluoromethylations of
thiols, and the use of gaseous trifluoromethylthiolating agents
such as trifluoromethanesulfenyl chloride (ClSCF3),
bistrifluoromethyl disulfide (F3CSSCF3), or trifluoromethane-
thiol (F3CSH) are particularly noteworthy.2,3 Recent develop-
ments have focused on using advanced reagents such as N-
trifluoromethylthiophthalimide (1), N-trifluoromethylthio sac-
charin (2), and trifluoromethanesulfanylanilides 3 (Figure 1).2,5
Furthermore, milder methods employing metal-based reagents
and catalysts have been described.6
For the introduction of the SCF3 substituent, silver(I)
trifluoromethanethiolate was selected, as it is commercially
available, easy to handle, and chemically well-studied.6
Furthermore, the expected formation of insoluble AgBr was
envisaged to promote the N-trifluoromethylthiolations of the
sulfoximines.
To obtain the desired products 6, the corresponding N-
bromo sulfoximines 8 were treated with 1.2 equiv of AgSCF3 in
acetonitrile. The results of these transformations are
summarized in Table 1 (entries 1−12). In general, the yields
of the resulting N-trifluoromethylthio sulfoximines 6 were high
(75−98%) irrespective of the substitution pattern. The only
exception was the reaction of p-nitro substituted derivative 8e,
which led to 6e in only 51% yield (Table 1, entry 5).
Particularly noteworthy is the good yield in the formation of S-
cyclopropyl-S-phenyl sulfoximine 6b (Table 1, entry 2) because
this substitution pattern occurs in Bayer’s kinase inhibitor BAY
Figure 1. Trifluoromethylthiolating reagents (1−3) and trifluorome-
thylthiolated imines (4−6).
Sulfoximines are monoaza analogs of sulfones,7 and in
contrast to the latter they can chemically be modified at the
sulfur fragment by N-substitution allowing fine-tuning and
adjusting of chemical and physical properties.8 Recent industrial
work illustrates the importance of such structural variability.9
Fluorinated sulfoximines play a particular role, as they exhibit a
broad range of reactivity.7h,i,10 Derivatives with fluorinated
substituents at the sulfoximine nitrogen are particularly scarce
with compound 5 being one of the very few examples.11 In light
of the very special substitution patterns of 5 and considering
the synthetic challenges in the preparation of this compound
(involving a large excess of low-boiling, toxic trifluoromethyl-
Received: May 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01384
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
Table 1. N-Brominations of N−H-Sulfoximines 7 and
Subsequent Trifluoromethylthiolations of 8 To Give
Products 6
The authors declare no competing financial interest.
a
ACKNOWLEDGMENTS
The authors thank Prof. Dr. Peer Kirsch (Merck KGaA,
Darmstadt, Germany) for stimulating discussions.
■
REFERENCES
■
entry
R1
R2
yield of 8 (%)
yield of 6 (%)
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1
Ph
Ph
Ph
Ph
94 (8a)
99 (8b)
94 (8c)
99 (8d)
99 (8e)
91 (8f)
94 (8g)
98 (8h)
94 (8i)
95 (8j)
90 (8k)
86 (8l)
− (8m)
− (8n)
85 (6a)
88 (6b)
91 (6c)
80 (6d)
51 (6e)
93 (6f)
75 (6g)
98 (6h)
86 (6i)
94 (6j)
87 (6k)
90 (6l)
55 (6m)
62 (6n)
2
cyclopropyl
Me
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o-Br-Ph
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6
Me
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Reaction conditions: (N-Brominations) 7 (2.0 mmol) and NBS (2.0
mmol) in CH2Cl2 (50 mL) at rt for 30 min; (N-Trifluoromethylth-
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b
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and NBS (0.5 mmol) in CH3CN (1.0 mL) at rt for 30 min; then
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1000394.9a Furthermore, the high yields of the various halo-
substituted S-aryl products (Table 1, entries 4, 8, 9, 11, and 12)
have to be highlighted because those sulfoximines may serve as
starting materials for more densely functionalized derivatives
resulting from metal-catalyzed cross-coupling reactions.15
Because of the aforementioned inaccessibility of N-bromo
sulfoximines 8m and 8n, an alternative approach toward the
respective N-trifluoromethylthio derivatives 6m and 6n had to
be developed. To our delight, those two products could be
obtained by a one-pot cascade reaction avoiding the isolation of
8m and 8n. Accordingly, NBS was added to a solution of the
corresponding N−H-sulfoximine in acetonitrile, and a sub-
sequent reaction with AgSCF3 gave 6m and 6n in yields of 55%
and 62%, respectively (Table 1, entries 13 and 14).
In summary, we prepared novel functionalized sulfoximines
with trifluoromethylthio substituents at the sulfoximine nitro-
gen in high yields. Readily available N-bromo derivatives serve
as intermediates, which lead to the products upon treatment
with AgSCF3. In some cases, a one-pot cascade reaction is
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization of all products.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01384.
■
S
(9) (a) Lucking, U. Angew. Chem., Int. Ed. 2013, 52, 9399.
̈
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C.; Babcock, J. M.; Thomas, J. D. Pestic. Biochem. Physiol. 2013, 107, 1.
(10) For SF5-substituted sulfoximines, see: Hendriks, C. M. M.;
Reball, J.; Bolm, C. Synlett 2015, 26, 73.
AUTHOR INFORMATION
Corresponding Author
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*E-mail: Carsten.Bolm@oc.rwth-aachen.de.
(11) Sauer, D. T.; Shreeve, J. M. Inorg. Chem. 1972, 11, 238.
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DOI: 10.1021/acs.orglett.5b01384
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(12) Emeleu
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́
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̈
̈
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corresponding N-iodo sulfoximine [Ph2S(O)NI] by using NIS instead
of NBS failed. For illustrative examples of syntheses and applications
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C
DOI: 10.1021/acs.orglett.5b01384
Org. Lett. XXXX, XXX, XXX−XXX