Synthesis of 1,2-Bis(trifluoromethylthio)arenes via Aryne Intermediates

Article abstract of DOI:10.1021/acs.orglett.7b01901

A general method for synthesis of 1,2-bis-trifluoromethylthioarenes has been developed. Arynes generated from silyl aryl triflates or halides react with bis(trifluoromethyl)disulfide to afford 1,2-bis-trifluoromethylthioarenes. Aryl, alkyl, ester, halide,

Full text of DOI:10.1021/acs.orglett.7b01901

Letter
pubs.acs.org/OrgLett
Synthesis of 1,2-Bis(trifluoromethylthio)arenes via Aryne
Intermediates
Milad Mesgar and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204, United States
S
* Supporting Information
ABSTRACT: A general method for synthesis of 1,2-bis-
trifluoromethylthioarenes has been developed. Arynes gen-
erated from silyl aryl triflates or halides react with bis(trifluoro-
methyl)disulfide to afford 1,2-bis-trifluoromethylthioarenes.
Aryl, alkyl, ester, halide, and methoxy functionalities are
compatible with reaction conditions. Use of bis(perfluoroaryl)-
disulfides gave moderate yields of aryne disulfenylation or
cyclization to fluorinated dibenzothiophenes.
luorine-containing organic substances are important in
of trifluoromethylthiocopper with aromatic halides.8d Unfortu-
nately, trifluoromethylthiocopper is not commercially available.
We report here a convenient method for the preparation of 1,2-
bis(trifluoromethylthio)arenes from silyl aryl triflates or halides
and commercially available bis(trifluoromethyl)disulfide.
A few examples of aryne reactions with trifluoromethylthio-
containing nucleophiles have been reported in the literature.9 In
2008, Kolomeitsev reported one example of trifluoromethyl-
thiobenzene synthesis in the reaction between trimethylsilyl-
phenyl triflate, fluoride, and trifluoromethylsulfide anion.9a In
2013, Lee and co-workers disclosed silver-mediated trifluoro-
methylthiolation via hexadehydro Diels−Alder reaction where a
trifluoromethylthio substituent is introduced by employing
excess AgSCF3 reagent.9b Recently, Hu reported the reaction of
in situ generated arynes with excess AgSCF3, affording aryl
trifluoromethylsulfides in good yields.9c In all these examples,
the source of trifluoromethylthio substituent is not commer-
cially available, and synthesis of bis-1,2-(trifluoromethylthio)-
arenes was not reported.
Aryne insertion in disufide S−S bonds, which is a potential
route to 1,2-bis(trifluoromethylthio)arenes, has not been
extensively studied.10 Aryne generation by employing strong
bases is not compatible with electrophilic bis(trifluoromethyl)-
disulfide.11 Consequently, the mildest conditions of aryne
generation from silyl aryl triflates and silyl aryl halides were
employed.12 Three different conditions of aryne generation
from silyl aryl triflates or halides were explored based on our
previous work.12b
F
medicine, agriculture, and as materials.1 Among fluorinated
organics, aryl trifluoromethyl sulfides (ArSCF3) are particularly
interesting because they are present in many biologically active
substances (Figure 1).2 Furthermore, trifluoromethylthiolation
Figure 1. Bioactive molecules possessing trifluoromethylthioarene
functionality.
of organic compounds is less studied than fluorination and
trifluoromethylation.3 For many years, the trifluoromethylthio
moiety was generated either by halogen−fluorine exchange in
chloro- or bromomethyl sulfides or by trifluoromethylation of
thiols.3g,h Trifluoromethylthiolation by nucleophilic substitu-
tion usually requires harsh reaction conditions and stoichio-
metric amounts of transition metals.4 Recently, however,
efficient methods utilizing milder protocols have been
developed for trifluoromethylthiolation of aryl halides, boronic
acids, and sp2 C−H bonds under transition metal catalysis.5−7
Synthesis of 1,2-bis(trifluoromethylthio)arenes has been
reported in a very limited number of publications, and the
reactions appear to lack generality.8 For example, electrophilic
aromatic substitution affords low yields of 1,2-bis(trifluoro-
methylthio)benzene.8a Multistep reactions involving cyclo-
addition of bis(trifluoro-methylthio)acetylene have also been
reported.8b Perhaps the most general method involves reaction
Aryne insertion in the bis(trifluormethyl)disulfide S−S bond
proceeds with best yields at relatively high temperatures. Use of
cesium fluoride in dimethoxyethane afforded the highest yields.
Other fluoride sources, such as tetramethylammonium fluoride,
and solvents such as acetonitrile gave lower yields.13 The scope
of the reaction with respect to silyl aryl triflates is presented in
Received: June 21, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01901
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Organic Letters
Letter
a
Table 1. Bis(trifluoromethylthiolation) of Silyl Aryl Triflates
a
Reaction conditions: Aryne precursor (0.3 or 0.5 mmol), CsF (3 equiv), CF3SSCF3 (3.5 equiv), DME (2 mL), 24−48 h, 85 or 110 °C. Yields are
b
c
isolated yields. Yield determined by NMR with PhCF3 as an internal standard. DME is dimethoxyethane. Scale: 1.0 mmol. Please see Supporting
Information for details.
Table 1. Substrates possessing both electron-withdrawing and
electron-releasing substituents are reactive. A methoxy
substituent is tolerated affording products in good yields
(entries 1−3). Phenyl-substituted silyl aryl triflate is reactive as
well, giving bis(trifluoromethylthio)biphenyl in 78% yield
(entry 4). Alkyl-substituted substrates afford products in 64−
74% yields (entries 5, 8, 10, and 12). A fluorinated substrate
gives bis(trifluoromethylthio)fluorobenzene in an acceptable
yield (entry 7). Chlorinated substrates provide products in 44%
and 65% yields (entries 11 and 13). An ester substituent is
tolerated as well, and product is obtained in 41% yield (entry
14). Several of the products are very volatile, and their NMR
yields were determined (entries 5−7, 10, 13). Silyl aryl triflate 4
derived from estrone was converted to bis(trifluoromethylthio)
derivative 5 in 83% yield, showing relevance of the method-
ology to the modification of biologically active compounds
(Scheme 1).
Scheme 1. Bis(trifluoromethylthiolation) of Estrone
Derivative
available starting materials. Arynes can be generated from these
compounds under conditions similar to those employed for
silyl aryl triflates.12b Consequently, bis(trifluoromethyl-
thiolation) of silyl aryl halides would be practical and
convenient. A potential issue that could interfere with the
desired reaction pathway is the trapping of arylcesium
intermediate 7 by the highly electrophilic bis(trifluoromethyl)-
disulfide affording monotrifluoromethylthiolation product 9
(Scheme 2). The ease of aryne formation from ortho-metalated
species 7 is related to the strength of the leaving group (X−)
conjugate acid. Examination of hydrogen iodide and triflic acid
Unfortunately, only a few silyl aryl triflates are commercially
available. In addition, their preparation requires lengthy
synthetic procedures starting from ortho-bromophenols, which
are of limited availability as well. In contrast, silyl aryl bromides
and iodides can be prepared in one step from commercially
B
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Organic Letters
Letter
a
Scheme 2. Reactivity of Arylmetal Intermediate
Table 2. Silyl Aryl Iodide Reactions
DMSO pKa values shows that the acidity of HI is close to that
of CF3SO3H.14
As expected, use of silyl aryl bromides was problematic due
to 2-bromoarylcesium trapping with bis(trifluoromethyl)-
disulfide (Scheme 3). Out of many silyl aryl bromide substrates
Scheme 3. Silyl Aryl Bromide Reactions
subjected to the reaction conditions, only two gave modest
yields of the desired products. Compounds 10 and 13 were
reacted with bis(trifluoromethyl)disulfide to afford 61% and
53% isolated yields of 11 and 14, respectively. Crude reaction
mixture NMR spectra showed that, in addition to the desired
11 and 14, substantial amounts of monotrifluoromethyl-
sulfenylation products 12 and 15 were formed.
Considering the above results, silyl aryl iodides were used as
aryne precursors. Silyl aryl iodide reactions with bis(trifluoro-
methyl)disulfide are summarized in Table 2. 1-Iodo-3-methoxy-
2-(dimethylsilyl)benzene reacts with bis(trifluoromethyl)-
disulfide to afford the product in 74% isolated yield (entry
1). 3,6-Dimethoxy-1,2-bis(trifluoromethylthio)benzene was
synthesized in 71% yield (entry 2). 1,2-Bis(trifluoro-
methylthio)benzene was prepared in 58% yield (entry 3).
Entries 4 and 5 show the formation of symmetric alkoxy-
substituted products in 63% and 58% isolated yields,
respectively. 1-Iodo-3,4,5-trimethoxy-2-(dimethylsilyl)benzene
reacts with bis(trifluoromethyl)disulfide to afford the product
in 82% isolated yield (entry 6). While the reactions appear to
be more general than those of corresponding silyl aryl
bromides, substantial amounts of monotrifluoromethyl-
sulfenylation products are observed in all reaction mixtures.
The bis-/monofunctionalized product crude ratios range from
2.4/1.0 (entry 3) to 4.5/1.0 (entry 6) showing the high
electrophilicity of bis(trifluoromethyl)disulfide.
a
Reaction conditions: Aryne precursor (0.3 mmol), CsF (3 equiv),
CF3SSCF3 (3.5 equiv), DME (2 mL), 37−46 h. Yields are isolated
yields. 3,6-Dimethoxy-2-trifluoromethylthioiodobenzene (23%) also
isolated. Yield determined by NMR with PhCF3 as an internal
standard. Please see Supporting Information for details.
b
c
Scheme 4. Reactions with Bis(pentafluoroaryl)disulfides
Scheme 5. Reaction with Bis(perfluorotolyl)disulfide
Next, silyl aryl triflate reactions with bis(perfluoroaryl)-
disulfides were examined. 4-tert-Butyl and 3-chlorobenzynes
generated from the corresponding silyl aryl triflates were
reacted with bis(pentafluorophenyl)disulfide (Scheme 4).
Isolated yields of the products were 26% and 21%, respectively.
Attempts to improve reaction efficiency were not successful.
Interestingly, when bis(perfluoro-p-tolyl)disulfide was re-
acted with trimethylsilylphenyl triflate, a different pathway was
followed (Scheme 5). Instead of aryne formal insertion into the
disulfide S−S bond, a single addition of sulfide followed by
intramolecular nucleophilic substitution of fluoride on the
C
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Organic Letters
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In summary, a general method for synthesis of 1,2-bis-
trifluoromethylthioarenes has been developed. Arynes gener-
ated from silyl aryl triflates and silyl aryl halides react with
bis(trifluoromethyl)disulfide to afford 1,2-bis(trifluoro-
methylthio)arenes. Aryl, alkyl, ester, halide, and methoxy
functionalities are compatible with reaction conditions. Use of
bis(perfluoroaryl)disulfide reagents gave moderate yields of
disulfenylation products or, in the case of bis(perfluoro-p-
tolyl)disulfide, cyclization to fluorinated dibenzothiophenes.
Silyl aryl bromides and iodides gave substantial amounts of
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electrophilicity of bis(trifluoromethyl)disulfide.
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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.7b01901.
Detailed experimental procedures and characterization
data for new compounds (PDF)
(15) Travieso-Puente, R.; Budzak, S.; Chen, J.; Stacko, P.; Jastrzebski,
J. T. B. H.; Jacquemin, D.; Otten, E. J. Am. Chem. Soc. 2017, 139, 3328.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: olafs@uh.edu.
ORCID
Olafs Daugulis: 0000-0003-2642-2992
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Welch Foundation (Chair No. E-0044) and
NIGMS (Grant No. R01GM077635) for supporting this
research.
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