Synthesis of Aryl Sulfides: Metal-Free C-H Sulfenylation of Electron-Rich Arenes

Article abstract of DOI:10.1021/acs.orglett.5b01889

A simple, efficient, and practical metal-free C-H sulfenylation of substituted electron-rich arenes has been developed. This method is highly regioselective, and the corresponding aryl sulfides were obtained in moderate to excellent yields from stable and

Full text of DOI:10.1021/acs.orglett.5b01889

Letter
pubs.acs.org/OrgLett
Synthesis of Aryl Sulfides: Metal-Free C−H Sulfenylation of Electron-
Rich Arenes
Thomas Hostier, Vincent Ferey,† Gino Ricci,‡ Domingo Gomez Pardo, and Janine Cossy*
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI), UMR 8231, ESPCI ParisTech/CNRS/PSL
Research University 10 rue Vauquelin, Paris 75231 Cedex 05, France
S
* Supporting Information
ABSTRACT: A simple, efficient, and practical metal-free C−H
sulfenylation of substituted electron-rich arenes has been developed.
This method is highly regioselective, and the corresponding aryl sulfides
were obtained in moderate to excellent yields from stable and readily
accessible N-(alkylthio)- and N-(arylthio)succinimides at room temper-
ature in the presence of TFA.
sulfoxide17 under oxidative conditions. A copper-catalyzed
ryl sulfides are important building blocks in organic
Asynthesis and can be used in material science as well as arylthiolation of acidic C−H bonds of heterocycles such as
in the pharmaceutical industry.1 For example, these scaffolds
are found in bioactive natural products such as lissoclibadin 6,
benzoxazoles, benzothiazoles, and indoles has also been
achieved with diaryl disulfides or aryl thiols.18 Recently, the
an antimicrobial agent,2 and in bioactive non-natural
direct arylthiolation of nonacidic arenes was reported with
transition-metal catalysts (Fe,19a Pd,19b or Cu19c) using diaryl
disulfides19a,c or arylsulfonyl cyanides19b as sulfenylating
reagents. In addition, the C−H sulfenylation of electron-rich
arenes was realized under metal-free conditions20 using aryl
thiols or diaryl disulfides in the presence of an oxidizing
agent.21 Recently, Daugulis et al. reported a Cu(II)-catalyzed
directed thioetherification of aromatics by C−H activation
utilizing a 8-acetamidoquinoline moiety as a chelating group.22
This bidentate directing group was also used by Shi et al. to
perform a nickel-catalyzed sulfenylation of sp2 and sp3 C−H
bonds.23 2-Pyridine, 2-pyrimidine, pyrazole, and oxime ether
were also reported as directing groups in rhodium-catalyzed
C−H thiolation of arenes with aryl and alkyl disulfides.24 In
the past few years, electrophilic sulfenylating reagents, such as
N‑thiosuccinimides, N-thiophthalimides, or trifluoromethane-
sulfenamides, were utilized to perform the arylthiolation and
the trifluoromethylthiolation of (hetero)aromatic C−H bonds.
For example, the direct trifluoromethylthiolation of N-
heteroarenes and aromatics was achieved using N-[(trifluoro-
methyl)thio]phthalimide25a and N-methyl-N-tosyltrifluorome-
thanesulfenamide25b under metal-free and acidic conditions,
respectively. Very recently, palladium-catalyzed and Lewis acid
catalyzed C−H sulfenylation of unactivated arenes26a and
phenols26b was realized with N-(arylthio)succinimides as
sulfenylating reagents. Despite some advantages, these
established methods suffer from the use of prefunctionalized
reagents, harsh reaction conditions, or toxic metal salts as
catalysts. As a consequence, the development of efficient and
attractive protocols for the formation of CAr−S bonds,
avoiding aryl halides, organometallic reagents, or transition-
compounds such as AZD4407, a 5-lipoxygenase inhibitor,3
or KRP-203, an immunomodulator (Figure 1).4
Figure 1. Representative examples of biologically active compounds
incorporating an aryl sulfide moiety.
One of the most powerful reactions to introduce a sulfenyl
group on an arene is the cross-coupling of thiols or disulfides
with aryl halides or pseudohalides, catalyzed by transition
metals1b,5 such as palladium,6 copper,7 cobalt,8 indium,9
nickel,10 iron,11 rhodium,12 and gold.13 In addition, aryl
sulfides were also prepared by using cross-couplings of
arylmagnesium halides14 or arylboronic acid derivatives15
with arylsulfur reagents in the presence of suitable catalysts.
In the past few years, the development of mild and selective
methods for the direct functionalization of C−H bonds has
received great attention from organic chemists. Therefore,
various methods of direct C−H thiolation, employing an
appropriate sulfenylating reagent, have been developed to
produce aryl sulfides including copper-mediated alkylthiolation
of 2-phenylpyridine with dimethyl disulfide16 or dimethyl
Received: July 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01889
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Organic Letters
Letter
metal catalysts, is of great interest from a viewpoint of atom
economy and waste treatment of halide salts and metals.
Herein, we report an efficient metal-free regioselective C−H
sulfenylation of electron-rich arenes from N-(arylthio)-
succinimides using trifluoroacetic acid (TFA) at room
temperature.
The direct phenylthiolation of anisole 1a was chosen as a
model reaction, and various electrophilic sulfenylating
reagents, 3−5a, were employed in the presence of TFA
(Table 1). By using diphenyl disulfide 3 in neat TFA (30
equiv) at room temperature, the expected sulfide 2a was not
observed (Table 1, entry 1). On the contrary, when 1a was
treated with S-phenyl benzenethiosulfonate 4, compound 2a
was obtained in 39% yield (Table 1, entry 2), and the yield
was increased to 85% by using 1 equiv of N‑(phenylthio)-
succinimide 5a in neat TFA (Table 1, entry 3). The best yield
in 2a was obtained when anisole was treated with 5a in the
presence of 15 equiv of TFA in CH2Cl2 (97%) (Table 1,
entry 4). We have to point out that when the reaction was
performed with 10 and 5 equiv of TFA, the yield of 2a
decreased slightly (91% and 87% respectively, Table 1, entries
5 and 6). It is worth noting that sulfide 2a was not formed
when a stoichiometric amount of TFA was used (Table 1,
entry 7). From the optimization studies, the following
conditions were chosen to study the scope of the reaction:
arene 1 (1 equiv), N‑(thio)succinimide 5 (1 equiv), TFA (15
equiv), CH2Cl2 (0.5 M) at rt for 6 h.
To test the general scope of the arylthiolation, various
arenes were subjected to the optimized conditions (Scheme
Table 2. Metal-Free Aryl(alkyl)sulfenylation of Arenes:
Scope and Limitation
Table 1. Evaluation of Reaction Conditions
a
entry
R-SPh
TFA (equiv)
solvent
yield (%)
1
2
3
4
5
6
7
3
30
30
30
15
10
5
TFA
0
39
85
4
TFA
5a
5a
5a
5a
5a
TFA
b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
97 (76)
91
87
0
1
a
1
Yields were determined by H NMR using 1,3,5-trimethoxybenzene
b
as the internal standard. Isolated yield given in parentheses.
Difference between the isolated and the NMR yields may be due to
an overestimation of the NMR yield as well as a loss during the
workup/purification process.
Scheme 1. Metal-Free Phenylsulfenylation of Arenes: Scope
and Limitation
B
DOI: 10.1021/acs.orglett.5b01889
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Organic Letters
Letter
1). The sulfenylation of substituted arenes was regioselective
in accord with Holleman’s rules.27 The arylthiolation of
anisole 1a provided the corresponding methoxyphenyl sulfide
2a in 76% yield. When the arenes were substituted with two
electron-donating groups in a relative meta position, the yields
in the corresponding sulfenylated arenes 2b and 2c were
obtained in modest yields, 37% and 49%, respectively.28
3‑Bromoanisole 1d gave o-(phenylthio)anisole 2d with a good
yield of 86%. When anisole was substituted by a methyl group
at the ortho position as in 1e, the corresponding sulfenylated
compound 2e was isolated in 78% yield. The arylthiolation of
arenes enriched by three electron-donating groups afforded
the thiolated products 2f, 2g, and 2h in 81%, 60%, and 98%
yield, respectively. In the case of phenol 1i, the presence of an
electron-withdrawing group at the ortho position is
detrimental to the yield, as the sulfenylated arene 2i was
isolated in a low yield of 26%. Interestingly, 2-naphthol 1j was
sulfenylated at the C1 position leading to diaryl sulfide 2j in
high isolated yield (89%). However, naphthalene furnished
the corresponding diarylthiolated compound 2k in a poor
yield of 17%. We have to point out that no product was
formed when acetanilide 2l was subjected to the optimized
conditions.
In addition to the sulfenylation of electron-rich arenes with
5a, we have examined the reactivity of various N-(arylthio)-
succinimides 5b−5f using mesitylene 1f and 1,3,5-trimethoxy-
benzene 1g as the substrates (Table 2). When N-(tolylthio)-
succinimide 5b was used, sulfenylated arenes 2m and 2n were
obtained in 91% and 65% yield, respectively (Table 2, entries
1 and 2). Both electron-donating, such as a methoxy, and
moderate electron-withdrawing groups, such as a bromine, on
the arylthio moiety were tolerated and afforded the
corresponding diaryl sulfides (2o, 2p and 2q, 2r) in good
yields (Table 2, entries 3−6). Furthermore, when a strong
electron-withdrawing group was present on the arylthio
moiety, such as a nitro group (5e), mesitylene 1f did not
react under the optimized conditions (Table 2, entry 7), but
on the contrary, 1,3,5-trimethoxybenzene 1g afforded the
corresponding sufenylated derivative 2t in a moderate yield
(47%) (Table 2, entry 8). The low yields obtained for the
diaryl sulfides 2s and 2t could be explained by the short
lifetime of the N-(arylthio)succinimide 5e under strong acidic
conditions. The reaction was also performed with
N‑(ethylthio)succinimide 5f, which led to aryl alkyl sulfides
2u and 2v in 41% and 71%, respectively (Table 2, entries 9
and 10).
Scheme 2. Possible Mechanism for the Sulfenylation of
Arenes
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01889.
1
Experimental procedures, characterization, and H and
13C NMR spectra of isolated compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: janine.cossy@espci.fr.
Present Addresses
†Chemistry and Biotechnology Development, SANOFI, 371
rue du Professeur Blayac, 34184 Montpellier Cedex 04,
France.
‡Sanofi Process Development, 45 chemin de Met
́
eline BP15,
04210 Sisteron Cedex, France.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Sanofi is gratefully acknowledged for financial support and for
a Ph.D. grant (T.H.).
■
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To rationalize the observed results, a mechanism can be
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DOI: 10.1021/acs.orglett.5b01889
Org. Lett. XXXX, XXX, XXX−XXX