Selective and scalable synthesis of trifluoromethanesulfenamides and fluorinated unsymmetrical disulfides using a shelf-stable electrophilic SCF3 reagent

Article abstract of DOI:10.1002/chem.201405654

The chemoselective trifluoromethylthiolation of nitrogen nucleophiles and thiols using N-(trifluorome-thylthio)phthalimide under mild, metal-free conditions is described. A series of trifluoromethanesulfenamides and unsymmetrical disulfides is prepared from the corresponding aliphatic and aromatic amines and thiols in good yields. The reactions are operationally simple and tolerate a wide variety of functional groups. Trifluoromethanesulfenamides and disulfides belong to interesting classes of organic molecules which possess remarkable properties for medicinal and agrochemical applications.

Full text of DOI:10.1002/chem.201405654

DOI: 10.1002/chem.201405654
Communication
&
Synthetic Methods
Selective and Scalable Synthesis of Trifluoromethanesulfenamides
and Fluorinated Unsymmetrical Disulfides using a Shelf-Stable
Electrophilic SCF3 Reagent
Roman Pluta and Magnus Rueping*[a]
tabolized in cells to provide the active compound.[4,5] In partic-
Abstract: The chemoselective trifluoromethylthiolation of
nitrogen nucleophiles and thiols using N-(trifluorome-
thylthio)phthalimide under mild, metal-free conditions is
described. A series of trifluoromethanesulfenamides and
unsymmetrical disulfides is prepared from the correspond-
ing aliphatic and aromatic amines and thiols in good
yields. The reactions are operationally simple and tolerate
a wide variety of functional groups. Trifluoromethanesulf-
enamides and disulfides belong to interesting classes of
organic molecules which possess remarkable properties
for medicinal and agrochemical applications.
ular the latter activity is of high interest.
In this context, fluorine-containing sulfenamides (RFSÀNR1R2)
have also received attention due to the characteristics of the
RFSÀN group. The strong electron-withdrawing effect and high
lipophilicity increase the ability of such molecules to cross lipid
membranes and create opportunities for the modification of
known drugs. Measurements showed that the Hansch parame-
ter (lipophilicity values) for the NSCF3 group (pR =1.50) is con-
siderably higher than the value of the CF3 group (pR =0.88)
and SCF3 group (pR =1.44),[6–7] which is of great interest in the
development of new drugs and agrochemicals.
Hence, improved methodologies for the efficient synthesis
of complex organic molecules containing these perfluorinated
functional groups (RFSÀNR1R2) are important for both academic
and industrial research. Unfortunately, direct access to this im-
portant class of compounds is complicated and general, mild,
safe, and efficient methods still need to be developed. Where-
as several modern methodologies exist for the direct introduc-
tion of the trifluoromethanesulfenyl group (SCF3) into both ar-
omatic and aliphatic compounds,[8–15] resulting in the construc-
tion of C(sp2)ÀSCF3 and C(sp3)ÀSCF3 bonds, the reaction be-
tween trifluoromethane-sulfenylating reagents and nitrogen
nucleophiles is less explored.
Compounds bearing fluoroalkylated groups have attracted in-
creased attention due to their remarkable biological and thera-
peutic properties.[1] Among the wide range of fluorinated com-
pounds known to date, those containing perfluorinated alkyl-
sulfenyl groups (RFS-) are valuable for both pharmaceutical and
agrochemical industries,[2] as they exhibit unique physical,
chemical and biological properties if compared to the non-flu-
orinated parent compounds.
Sulfenamides are compounds containing an SÀN bond
(Figure 1). The presence of two reactive centers in these mole-
cules leads to specific properties which can be used in various
fields of application. Whereas some simple sulfenamides have
found utilization in the rubber vulcanization process and poly-
mer industry, others possess interesting biological activities
and have been applied in pharmaceutical and agrochemical in-
dustries.[3] They can act as a drug or as a prodrug that is me-
There are only a few known methods for the formation of
a trifluoromethanesulfenamide group. One of them consists in
the reaction of secondary amines (R1R2NH) with either bis(tri-
fluoromethyl) disulfide or trifluoromethanesulfenyl chloride
(F3CSSCF3, F3CSCl).[16–18] Both reagents are highly toxic and diffi-
cult to handle due to their high volatility. The second approach
consists of a thiolation reaction in which secondary amines in
combination with strong bases are employed and, as a result,
moderate yields are obtained.[19] The third protocol makes use
of diethylaminosulfur trifluoride (DAST) and Ruppert–Prakash
reagent (TMSCF3).[12a,20]
Given the limitations of these protocols and the increasing
interest in these valuable fluorinated compounds, we decided
to develop an efficient procedure for the synthesis of trifluoro-
methylsulfenamides, which, at best, should not use any toxic
reagents, metal catalysts, or harsh conditions including strong
acids and bases and which could be applied to a wide range
of amines.
Figure 1. Examples of bioactive compounds bearing a sulfenamide group.
[a] R. Pluta, Prof. Dr. M. Rueping
Institute of Organic Chemistry
RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: Magnus.Rueping@rwth-aachen.de
Herein we describe the direct and selective synthesis of tri-
fluoromethanesulfenamides under mild reaction conditions
using the shelf-stable N-(trifluoromethylthio)phthalimide (1) as
the SCF3 source (Scheme 1).
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405654.
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Table 1. Reaction scope of trifluoromethanesulfenamides.[a]
Scheme 1. Preparation of trifluoromethanesulfenamides.
In order to succeed in developing a general protocol and
achieving high yields, various reaction parameters were initially
evaluated for the reaction of 1 with benzylamine (2a; see
Table S1 in the Supporting Information). The reaction occurred
in most of the common organic solvents (see Table S1, en-
tries 1–13); however, trifluorotoluene was the solvent of choice
as it provided the best yield within short reaction time (see
Table S1, entries 13–16). No metal catalyst was required and
most of the tested additives did not improve the reaction out-
come (see Table S1, entries 19–30). The reaction conditions are
mild and no effect of moisture or air on the reaction yield was
observed.
With the optimized conditions in hand, we decided to inves-
tigate the scope and limitations of this method. The reaction
worked well for simple aliphatic and benzylic amines 2a–
e, j, m–o and gave the desired products 3a–e, j, m–o in good
yields (Table 1). Interestingly, 2c and 2j reacted selectively at
the benzylic amine allowing the use of unprotected anilines
and secondary amines under the reaction conditions.
Substituted heterocycles including furan, imidazole, indole
or pyridine derivatives also allowed selective formation of the
desired products 3 f–i, k–l, s (Table 1). The ferrocene derivative
2p was also compatible with the reaction conditions, affording
the product 3p. When a free hydroxyl group was present in
the starting material, the yield of the corresponding product
3q dropped. However, protection of the alcohol group ena-
bled the reaction, affording the product 3r in satisfactory
yield. Furthermore, amino acids such as histidine and cysteine
could be converted into the desired NHSCF3-derivatives 3s
and 3t (Table 1).
In order to show the potential practical applicability of our
method in the preparation of compounds with potent biologi-
cal activity, we decided to demonstrate the feasibility of this
approach in the modification of steroid, carbohydrate, and al-
kaloid derivatives. When amine derivatives 2u–w were applied
as substrates, the corresponding products 3u–w were ob-
tained in good yields (Figure 2).
In order to bring about the trifluoromethanesulfenylation of
the less reactive secondary amines and anilines (R1R2NH,
ArNH2, ArRNH) with reagent 1, an alternative protocol needed
to be applied. Here, the reaction with secondary amines and
anilines was performed by simply employing their Li salts. The
reactions were performed in THF for 2 h and provided the de-
sired products 4a–d in good yields (65–85%, Table 2).
[a] Reaction conditions: Amine 2 (0.3 mmol) and 1 (0.36 mmol) in PhCF3
(4 mL) were heated at 808C for 0.25–6 h. Yields of the isolated products
after column chromatography; [b] reaction performed with 2.0 equiva-
lents of 1; [c] reaction performed on 3 mmol scale.
Finally, the stability of the trifluoromethanesulfenamide
group was investigated with model compound 3a. Studies
showed that this functional group possesses stability similar to
non-fluorinated sulfenamides. The group is stable under mod-
erate acidic and basic conditions. Strong protic acids, such as
triflic acid or mesylic acid, resulted in protonation of the nitro-
gen and gave moderately stable salts. Milder acids, such as tri-
fluoroacetic acid, did not decompose the sulfenamide group
for several hours at room temperature and weaker acids did
not affect this group at all. Similar behavior was observed
under basic conditions. Strong bases, such as 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) or 1,1,3,3-tetramethylguanidine
(TMG), slowly decomposed the sulfenamide group but weaker
bases, such as triethylamine (TEA), and other tertiary amines,
did not have any effect. Oxidizing agents such as meta-chloro-
perbenzoic acid (m-CPBA) first form trifluoromethanesulfin-
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Table 3. Reaction of thiols with reagent 1.[a]
Figure 2. Natural product derivatives 3u–w. [a] Reaction performed on
3 mmol scale.
Table 2. Reaction of lithium amides with reagent 1.
[a] Reaction conditions: Thiol 5 (0.3 mmol) and 1 (0.36 mmol) in PhCF3
(4 mL) were heated at 808C for 0.25–1 h. Yields of the isolated products
after column chromatography; [b] reaction performed on 3 mmol scale.
(Table 3). However, unlike in the case of amines, oxygen had to
be excluded, as formation of significant amounts of symmetri-
cal disulfides was observed due to oxidation with molecular
oxygen. The reaction conditions allowed the preparation of
various aliphatic disulfides with good yields. Aromatic thiol 5g
works also under these reaction conditions however with
lower yield and even higher loadings of reagent 1 could not
improve it.
amides, which are oxidized further to trifluoromethanesulfon-
amides. In the presence of fluoride and iodide ions, decompo-
sition was not observed. Additionally, we did not observe de-
composition of 3a in the presence of tributyltin hydride (tolu-
ene, 1008C, 20 min) and sodium borohydride (methanol, 258C,
1 h). These experiments show the generally high stability of tri-
fluoromethanesulfenamides and together with the high lipo-
philicity demonstrate their value for use as bioactive com-
pounds.
In addition, to show the efficiency and practicability of our
approach, we performed the reactions with amines 2m and
2u and thiol 5d on a 3 mmol scale. The corresponding prod-
ucts were obtained without a significant change in the yield.
To summarize, we have developed a practical method for
the synthesis of trifluoromethanesulfenamides and mixed tri-
fluoromethyl-containing disulfides. The electrophilic and shelf-
stable N-(trifluoromethylthio)phthalimide was efficiently ap-
plied for the selective synthesis of trifluoromethanesulfena-
mides starting from primary and secondary aliphatic and aro-
matic amines. Similarly, both aliphatic and aromatic thiols were
converted into the corresponding disulfides. Sulfenamides and
disulfides belong to promising classes of organic molecules
and as such the corresponding trifluoromethylated analogs
will be of interest for medicinal, agrochemical, and materials
chemistry.
Many drugs with different applications contain free thio
groups, which are essential for the pharmacological effect due
to their high reactivity.[21] Protection of these groups in pro-
drugs is of particular interest as it leads to improved pharma-
cokinetic properties, as well as stability of molecules. Methods
for protection of the thiol moiety include acylation, alkylation,
and preparation of mixed disulfides. Preparation of unsymmet-
rical fluorinated disulfides is an interesting challenge in syn-
thetic organic chemistry. To date, disulfides bearing an SCF3
Keywords: fluorine · SÀN bond formation · sulfenamides ·
synthetic methods · trifluoromethanesulfenylation
[22]
group were prepared exclusively from CF3SCl or CF3SSCF3
and thus research and potential applications were strongly lim-
ited. Simultaneously to our research, Shen described the prep-
aration of such disulfides in a similar approach.[20]
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Received: October 15, 2014
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COMMUNICATION
&
Synthetic Methods
R. Pluta, M. Rueping*
&& – &&
Selective and Scalable Synthesis of
Trifluoromethanesulfenamides and
Fluorinated Unsymmetrical Disulfides
using a Shelf-Stable Electrophilic SCF3
Reagent
SÀN-tial: The selective trifluorome-
thylthiolation of nitrogen nucleophiles
and thiols using N-(trifluoromethylth-
io)phthalimide under mild, metal-free
conditions is described. A series of ali-
phatic and aromatic amines and thiols
was transformed into the corresponding
trifluoromethanesulfenamides and disul-
fides. The reactions are operationally
simple and tolerate a wide variety of
functional groups.
Chem. Eur. J. 2014, 20, 1 – 5
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These are not the final page numbers! ÞÞ