Metal-Free Direct Trifluoromethylthiolation of Aromatic Compounds Using Triptycenyl Sulfide Catalyst

Article abstract of DOI:10.1021/acs.orglett.1c00727

Herein we report an efficient synthetic method for the electrophilic trifluoromethylthiolation of aromatic compounds. The key is to use triptycenyl sulfide (Trip-SMe) and TfOH to enhance the electrophilicity of SCF3 fragment through the formation of sulfonium intermediates. This method enables direct installation of an SCF3 group onto unactivated aromatics at room temperature, adopting a commercially available saccharin-based reagent. Preliminary DFT calculation was carried out to investigate the substitution effect on the catalytic activity.

Full text of DOI:10.1021/acs.orglett.1c00727

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Letter
Metal-Free Direct Trifluoromethylthiolation of Aromatic Compounds
Using Triptycenyl Sulfide Catalyst
Ryo Kurose, Yuji Nishii,* and Masahiro Miura*
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ABSTRACT: Herein we report an efficient synthetic method for
the electrophilic trifluoromethylthiolation of aromatic compounds.
The key is to use triptycenyl sulfide (Trip-SMe) and TfOH to
enhance the electrophilicity of SCF3 fragment through the
formation of sulfonium intermediates. This method enables direct
installation of an SCF3 group onto unactivated aromatics at room temperature, adopting a commercially available saccharin-based
reagent. Preliminary DFT calculation was carried out to investigate the substitution effect on the catalytic activity.
ver the past few decades, the characteristic effect of
incorporating fluorine and fluorinated substituents
Langlois,11 Lu and Shen,12 Shibata,13 Buchwald,14 Zhang,15
Procter,16 Iskra,17 and others by introducing a series of new
electrophilic SCF3 transfer agents. These reagents are generally
used in combination with Brønsted or Lewis acids to enhance
the electrophilicity of SCF3 fragment.18 The direct substitution
of aromatic compounds are, however, generally limited to
highly nucleophilic (activated) aromatics like phenols, anilines,
pyrroles, and indoles, whereas reactions involving unactivated
substrates have been scarce.16−20 In order to meet the growing
demand for accomplishing late stage functionalization of
complex molecules, development of an efficient trifluorome-
thylthiolation strategy is still a challenging and urgent task.
Recently, we developed a triptycene-based Lewis base
catalyst Trip-SMe for electrophilic aromatic halogenation
using N-halosuccinimides under mild reaction conditions
(Scheme 2a).21 Trip-SMe forms a relevant sulfonium complex
[Trip-S(Me)Br]+ as an active species, whose charge-separated
character contributes the significantly high catalytic activity. As
part of our continuous research interest in this field, we
envisioned utilizing this catalytic system for the activation of
electrophilic SCF3 reagents.22 Herein, we report a Trip-SMe-
catalyzed direct electrophilic trifluoromethylthiolation of
unactivated aromatic compounds adopting commercially
available starting materials (Scheme 2b). Preliminary DFT
calculations suggested that the inductive effect of the
triptycene moiety considerably increases the electrophilicity
of SCF3 fragment within the sulfonium intermediate.
O
within the organic compounds has been highlighted in various
research fields. In particular, strategic synthesis of functional
molecules bearing trifluoromethylthio (SCF3) group has
recently attracted significant attention.1 A notable feature of
SCF3 functionality is an extremely high lipophilicity parameter
(Hansch constant 1.44, as being the highest among common
functional groups),2 which is valuable for the design and
development of new medicines and agrochemicals. Indeed,
several trifluoromethylthiolated compounds3 with potent
pharmacological activity have already been marketed, involving
cefazaflur,4 tiflorex,5 and toltrazuril,6 among others.
An attractive synthetic method for installing SCF3 groups to
the interested molecule is the direct functionalization of C−H
bonds using electrophilic reagents (Scheme 1).7
Scheme 1. Representative Examples of Electrophilic SCF3
Reagents
At first, we conducted an optimization study adopting p-
xylene (1a) as a model substrate for the catalytic
In the early stage of this approach, Cl-SCF3 and CF3CO2−
SCF3 have been utilized as the SCF3 source.8 These classical
reagents have been superseded by readily available, shelf-stable,
and user-friendly alternatives because of their toxicity and
handling difficulty. The rapid progress in this direction has
been achieved in virtue of pioneering researchers and recent
contributors such as Haas,9 Munavalli,10 Billard and
Received: March 2, 2021
Published: March 11, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00727
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2380−2385
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results clearly highlight the exceptional activity of the Trip-
SMe catalyst for the electrophilic trifluoromethylthiolation.
With the optimized combination of Trip-SMe and TfOH in
hand, we examined the scope of aromatic substrates (Scheme
3). The reaction of mesitylene gave 2b quantitatively. Less
Scheme 2. Trip-SMe Catalyst for Aromatic Electrophilic
Substitution Reactions
a
Scheme 3. Substrate Scope
trifluoromethylthiolation with SCF3-saccharin VII (Table 1).
This reagent is commercially available as a stable crystalline
solid.
a
Table 1. Optimization Study
b
entry
catalyst
Trip-SMe
Trip-SMe
--
additive
yield
1
2
3
4
TfOH (10 mol %)
TfOH (50 mol %)
TfOH (50 mol %)
--
TfOH (50 mol %)
TfOH (50 mol %)
TfOH (50 mol %)
TfOH (50 mol %)
TfOH (50 mol %)
TfOH (50 mol %)
21%
>95%
n.d.
Trip-SMe
Trip-SMe
n-Oct-SMe
1-Ad-SMe
SPPh3
n.d.
n.d.
n.d.
n.d.
c
5
6
7
8
9
n.d.
(4-OMe-C6H4)2Se
Trip-SeMe
trace
trace
d
10
a
Standard conditions: 1a (0.2 mmol), VII (0.24 mmol), catalyst (5.0
b
mol %), additive, DCE (1.0 mL), RT, 3 h. Determined by GC
analysis. SCF3-phthalimide VI (see Scheme 1) was used as the SCF3
source. Conducted at 0.1 mmol scale. n.d. = not detected.
c
d
a
Reaction conditions: 1 (0.2 mmol), VII (0.24 mmol), Trip-SMe (5.0
mol %), TfOH, DCE (1.0 mL). Isolated yields are shown, excepting
The desired product 2a was obtained in 21% yield in the
presence of Trip-SMe catalyst (5.0 mol %) and TfOH additive
(10 mol %) at room temperature in DCE solvent (entry 1).
This reaction was significantly accelerated with an increased
amount of TfOH (50 mol %) to afford 2a quantitatively (entry
2). Both Trip-SMe and TfOH were essential to trigger the
reaction, indicating the occurrence of a sulfonium salt consists
of Trip-S(Me)SCF3 and OTf counteranion as an active species
(entries 3, 4). In contrast, SCF3-phthalimide VI was not a
suitable reagent for this transformation (entry 5). Other
Brønsted acids (CF3CO2H, MeSO3H, TfNH2, and HBF4·
OEt2), Lewis acids (TMSOTf, Zn(OTf)2, Sc(OTf)3, and
In(OTf)3), and AgSbF6 were not effective activators (see the
Supporting Information). Interestingly, replacement of the
triptycenyl group with an alkyl group (n-octyl or 1-adamantyl)
resulted in the loss of its catalytic activity (entries 6 and 7).
Triphenylphosphine sulfide was also not an active catalyst
(entry 8). A selenide catalyst, which was adopted for aromatic
sulfenylation by Gustafson,20 yielded a negligible amount of
the product (entry 9). Moreover, Trip-SeMe failed to trigger
the reaction under the identical conditions (entry 1). These
b
c
2a and 2b due to the volatility. TfOH (100 mol %). TfOH (10 mol
d
e
f
%). TfOH (200 mol %). 1.0 equiv of VII was used. 2.0 equiv of VII
was used.
reactive monoalkylbenzenes 1c and 1d were also smoothly
converted to the corresponding products with high para-
selectivity. The reaction of biphenyl (1e) preferentially
produced a monosubstituted compound 2e, and double
substitution was not observed even with an excess amount of
the reagent VII. This is probably because of the strong negative
inductive effect of SCF3 group. In contrast, tetralin (1f)
afforded a mixture of isomers in almost 1:1 ratio. For the
reaction of di- and trisubstituted haloarenes (1g−1j), the
corresponding products were obtained as single isomers in
54−84% yield, respectively. Naphthalene and naphthol
derivatives (1k−1r) underwent selective monosubstitution at
the most nucleophilic position. The reaction of 1k could be
conducted in 1.0 mmol scale to afford 2k in 87% yield.
Benzo[b]thiophene (1s) and 5-bromobenzo[b]thiophene (1t)
were also applicable to this protocol. Similarly, the reaction of
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anthracene (1u), phenanthrene (1v), and pyrene (1w)
resulted in the formation of single regioisomers in high yield.
Double substitution was possible for p-terphenyl to give the
4,4″-substituted isomer 2x as a major product. [2.2]-
Paracyclophane was converted to 2y in 74% yield. Unfortu-
nately, the present method was not readily applicable to
aromatic compounds bearing strong electron-withdrawing
(ester, nitrile, pyridine ring, etc.) and acid-sensitive (terminal
epoxide, Boc, furan derivatives, etc.) functional groups (not
shown).
Scheme 5. Proposed Reaction Mechanism
The developed catalytic system was highly useful for the
trifluoromethylthiolation of aryl ethers. Particular examples are
showcased in Scheme 4.
when Trip-SMe was mixed with an equimolar amount of VII in
DCM-d2 solvent. Addition of TfOH to this mixture resulted in
immediate disappearance of a peak at 2.5 ppm (SMe), and
broad signals at around 3.0 ppm appeared. A similar trend was
observed in our previous study on sulfonium intermediates.17
Notably, in case the reagent VI is used instead of VII, such a
spectral change was not observed upon treatment with TfOH.
This is consistent with the result in Table 1 (entry 2 vs 5). The
reaction sequence then proceeds to an arenium ion
intermediate via electrophilic addition of the SCF3 fragment.
Subsequent deprotonation liberates the corresponding product
and regenerates TfOH.
Scheme 4. Synthetic Application
In order to elucidate the electrophilicity of the SCF3
fragment of key intermediates, we conducted a computational
study to acquire a trifluoromethylthio cation-donating ability
(Tt+DA). This parameter has been introduced by Xue and
Cheng as a quantitative descriptor for the reactivity of SCF3
transfer reagents.27 This is a relative free energy value (ΔG) to
that of a reference molecule CF3CO2SCF3, and accordingly,
lower Tt+DA values correspond to higher electrophilicity of
reagents (Figure 1, top) (for details, see the Supporting
A diaryl ether 3 was successfully converted to the
corresponding product 4 in 82% yield with high para-
selectivity. This compound is a synthetic precursor of
toltrazuril,23 a potent anticoccidial agent (Scheme 4a).
Notably, this reaction did not proceed in the absence of
Trip-SMe catalyst even at 80 °C and resulted in ca. 30%
decomposition of 3. A phenoxypiperidine derivative 5 was also
applicable to the reaction, giving 6 in 70% yield. The para
isomer can be used for the synthesis of a sulfur analogue of
delamanid,24 which is a medicine for tuberculosis (Scheme
4b). In addition, the direct trifluoromethylthiolation gemfi-
brozil methyl ester produced 7 in 80% yield as a single isomer
(Scheme 4c). These examples highlight a potential application
of this protocol for the efficient screening of new SCF3-
containing drug candidates.
Figure 1. Tt+DA values of electrophilic SCF3 species calculated at the
M06-2X/6-311++G(2df,2p)/PCM(DCE) level.
Information). The Tt+DA value of SCF3-saccharin VII was
17.0 kcal/mol in DCE solvent, whereas a considerably lower
value of −2.3 kcal/mol was obtained for its TfOH adduct.28
The proposed “active species” derived from Trip-SMe is
suggested to be much more electrophilic, considering the value
of −7.0 kcal/mol. In sharp contrast, replacement of the sulfur
atom with selenium considerably reduced the donating ability
to −1.1 kcal/mol. This is consistent with the result in Table 1
(entry 2 vs 19).
Subsequently, we have examined the donating ability of
several sulfonium complexes A−E to elucidate the effect of
substituents on the sulfur atom (Figure 1, bottom). Here the
OTf anion is omitted to clarify the effect.29 In accordance with
According to the literature,21,25,26 we propose a reaction
mechanism as shown in Scheme 5. Initial protonation of the
reagent VII with TfOH reinforces its electrophilicity, thus
facilitating the formation of a catalytically active sulfonium
complex. Controlled NMR experiments support this SCF3
group transfer event (for details, see the Supporting
1
Information). H NMR spectra showed no obvious change
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the exceptionally high activity of the Trip-SMe catalyst, the
lowest Tt+DA value was given to E (−17.1 kcal/mol).
Additionally, NPA charges on the sulfur atom of SCF3 groups,
which would directly reflect their electrophilic nature,
considerably correlate to the Tt+DA values (see the Supporting
Information). It is notable that a barrelene-based complex D
exhibited a relatively lower value (−10.2 kcal/mol) than alkyl-
substituted sulfonium salts A−C; however, no obvious spatial
interaction was found between the sulfonium moiety and π
bonds within D by an NBO analysis. We thus focused on the
inductive effect of these substituents.
AUTHOR INFORMATION
Corresponding Authors
■
Masahiro Miura − Department of Applied Chemistry,
Graduate School of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan; orcid.org/0000-0001-8288-
6439; Email: miura@chem.eng.osaka-u.ac.jp
Yuji Nishii − Department of Applied Chemistry, Graduate
School of Engineering, Osaka University, Suita, Osaka 565-
0871, Japan; orcid.org/0000-0002-6824-0639;
Email: y_nishii@chem.eng.osaka-u.ac.jp
Considering the change in NPA charge distribution before
and after the formation of sulfonium complexes A−E, the
positive charge on the central sulfur atom is somewhat
delocalized over the three substituents (for details, see the
Supporting Information). Accordingly, three minor contrib-
utors can be considered as shown in Figure 2.
Author
Ryo Kurose − Department of Applied Chemistry, Graduate
School of Engineering, Osaka University, Suita, Osaka 565-
0871, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00727
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant No. JP
19K15586 (Grant-in-Aid for Young Scientists) and the
Foundation for the Promotion of Ion Engineering to Y.N.
and JSPS KAKENHI Grant No. JP 17H06092 (Grant-in-Aid
for Specially Promoted Research) to M.M.
Figure 2. Schematic representation of possible contributors within the
sulfonium complexes.
REFERENCES
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complexation with SCF3 cation, and the longest S−SCF3
bond length was given to E among the calculated structures.
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within the sulfonium complex.
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Detailed experimental procedures, computational meth-
od, products’ identification data, and copy of NMR
spectra (PDF)
Atomic coordinates of all calculated molecules (XYZ)
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kcal/mol lower energy than the SO-protonated species (see the
Supporting Information).
(29) These values are overestimated because of the omission of the
counteranion. Thus, comparison with other neutral species is not
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