Novel Use of CF3SO2Cl for the Metal-Free Electrophilic Trifluoromethylthiolation

Article abstract of DOI:10.1021/acs.orglett.6b01026

The regioselective trifluoromethylthiolation of indole derivatives was achieved under reductive conditions with trifluoromethanesulfonyl chloride as the readily available source of electrophilic SCF₃ and a phosphine as the reducing agent. It is a straightforward process free from any metal and also applicable for the trifluoromethylthiolation of other azaarenes, enamines, and enoxysilanes.

Full text of DOI:10.1021/acs.orglett.6b01026

Letter
pubs.acs.org/OrgLett
Novel Use of CF3SO2Cl for the Metal-Free Electrophilic
Trifluoromethylthiolation
Helene Chachignon,† Mayaka Maeno,†,‡ Hiroya Kondo,‡ Norio Shibata,*,‡ and Dominique Cahard*,†
́
̀
†UMR 6014 CNRS COBRA, Normandie Universite,
́ ̀
INSA Rouen, 1 rue Tesniere, 76821 Mont Saint Aignan, France
‡Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
S
* Supporting Information
ABSTRACT: The regioselective trifluoromethylthiolation of indole derivatives was achieved under reductive conditions with
trifluoromethanesulfonyl chloride as the readily available source of electrophilic SCF3 and a phosphine as the reducing agent. It is
a straightforward process free from any metal and also applicable for the trifluoromethylthiolation of other azaarenes, enamines,
and enoxysilanes.
he fluorine chemotype SCF3 is virtually absent in marketed
drugs even though it has predicted high potential in
desirable to offer simple solutions suitable for industrial use on
a larger scale. In moving toward this goal, Zhang and co-workers
reported the use of sodium triflinate for the direct trifluoro-
methylthiolation of indoles,4 sodium triflinate being otherwise
frequently used as a trifluoromethylation agent5 with extrusion
of SO2 or, to a lesser extent, as a trifluoromethanesulfonylation
agent.6 Their reaction system consists of a combination of K with
diethyl phosphite and CuCl in DMSO at 110 °C for the in situ
generation of bis(trifluoromethyl) disulfide, CF3SSCF3. With
the thought in mind to use an alternative readily available raw
material at milder temperatures and under metal-free conditions,
we selected trifluoromethanesulfonyl chloride, CF3SO2Cl, for
the synthesis of SCF3 molecules. The underlying idea was that
the highly reactive CF3SCl could be generated in situ under
reductive conditions (Scheme 1).
T
medicinal chemistry, attributable to the exceptional lipophilicity
imparted to SCF3 molecules.1 And yet, we are aware of the
strong interest in recent years for the chemical positioning
of this fluorinated motif in a wide variety of substrates. In the
early stage of the direct electrophilic trifluoromethylthiolation,
trifluoromethanesulfenyl chloride, CF3SCl, was the only reagent
available, but its gaseous and toxic nature precluded a wider
development. Recently, what motivated a revival in the field is
the design of a collection of stable and easy to handle reagents
to perform efficient trifluoromethylthiolations (Figure 1).2
Scheme 1. New Strategy in Trifluoromethylthiolation
Figure 1. Classes of electrophilic trifluoromethylthiolation reagents.
CF3SO2Cl is typically employed in the formation of sulfona-
mides and sulfonic esters7 but also in electrophilic chlorination,8
radical desulfinative trifluoromethylation,9 or trifluoromethyl-
chlorosulfonylation with retention of the SO2 moiety.10 Herein,
we present a new utilization of CF3SO2Cl that retains the C−S
bond in transferring the whole SCF3 motif.
Although high efficiency was demonstrated in the trifluoro-
methylthiolation of several substrates,3 these reagents suffer from
a common drawback which is that their preparation requires
diverse fluorinated raw materials. Indeed, N-SCF3 reagents
A−C necessitate a primary source of SCF3, either CF3SCl or
AgSCF3; trifluoromethanesulfenamides D−F are prepared using
(diethylamino)sulfur trifluoride (DAST) and the Ruppert−
Prakash reagent (CF3SiMe3); O-SCF3 reagents G and H need
AgSCF3 directly or through C; whereas SO2CF3 reagents I and J
ultimately require sodium triflinate (CF3SO2Na, K). Faced with
the increasing level of sophistication of reagents A−J, it is highly
We selected indole 1a as substrate to evaluate our working
hypothesis because indole is a structural unit found in many
Received: April 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01026
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
biologically active compounds and is frequently functionalized
at the C-3 position by electrophiles including the SCF3 group.3,4
As a reducing agent, we first evaluated a trimethylphosphine
solution 1.0 M in toluene for the deoxygenation of trifluoro-
methylsulfonyl chloride to produce in situ the active CF3SCl.
The higher nucleophilicity of alkyl- versus arylphosphines and
the water solubility of alkylphosphine oxide byproducts were
essential elements in choosing a reducing agent. A combination
of indole/CF3SO2Cl/PMe3 in a ratio 1:1.5:3 was placed at low
temperature and slowly warmed to ambient temperature in
order to deliver progressively the reactive CF3SCl species. This
way, the trifluoromethylthiolation is regioselective at C-3
producing the 3-(trifluoromethylthio) indole 2a in up to 70%
yield (Table 1, runs 1−3). Two side products were identified:
adjustments to the reaction conditions. Fourteen variously
decorated indole derivatives 1a−n were submitted to our
trifluoromethylthiolation protocol (Scheme 2).
Both electron-withdrawing and electron-donating substitu-
ents were well tolerated in positions 4, 5, 6, and 7 of the benzo-
fused ring (products 2a−h). The use of a phosphine in this
reaction is compatible with other reducible functional groups
such as halogens, nitro groups, and esters. 2-Methyl- and
2-phenyl-substituted indoles were converted into the expected
products 2i,j; however, 2-carbethoxyindole 1k failed to react,
probably because of the duality of functions enamine/conjugated
ester. Importantly, no protecting group at the nitrogen atom was
required; nevertheless, N-methylindole derivatives reacted very
well, providing better yields for the desired SCF3 products 2l,m.
When 3-methylindole 1n was subjected to the trifluoromethylth-
iolation, only a trace amount of C-2 SCF3 product was observed.
The reaction mechanism of this reductive deoxygenation−
trifluoromethylthiolation starts with the heterolytic cleavage
of the S−Cl covalent bonds triggered by the halogen bond
between the positive electrostatic potential on the outer side of
the chlorine atom in CF3SO2Cl and the lone pair of phosphorus
atom in the phosphine. The resulting chlorophosphonium
sulfinate is converted into the O-sulfinatophosphonium chloride,
which undergo Arbuzov collapse to trimethylphosphine oxide,
confirmed by 31P NMR of the reaction mixture, and tri-
fluoromethanesulfinyl chloride, CF3SOCl. A second similar
sequence affords the trifluoromethanesulfenyl chloride, CF3SCl,
as the desired reactive electrophilic species (Scheme 3). In two
recent papers on the use of sodium triflinate as SCF3 donor, the
authors demonstrated that CF3SSCF3 is an intermediate react-
ing with CuCl to generate either an electrophilic4 or a nucleo-
philic SCF3 species.11 Because CF3SSCF3 was identified when
our reaction was monitored by 19F NMR spectroscopy, we
wondered if this disulfide plays a role in the trifluoromethylth-
iolation. Accordingly, we performed a reaction in the absence
of indole and observed the reductive coupling of CF3SO2Cl
yielding the symmetrical disulfide (Scheme 4). The disulfide was
collected and engaged in the reaction with indole 1a under our
reaction conditions in the presence or not of trimethylphos-
phine. Product 2a was not obtained, attesting that in the
absence of metal salt CF3SSCF3 does not act as an electrophilic
trifluoromethylthiolation agent,12 and therefore, CF3SCl is
the metal-free generated reactive species in our experimental
conditions. Compared with the combination CF3SO2Na/diethyl
phosphite/CuCl described by Zhang that generates CF3SSCF3
as a reactive intermediate,4 our method presents a clear mec-
hanistic difference. In addition, we conducted a similar reaction
with methanesulfonyl chloride MeSO2Cl in order to highlight
the specific effect of fluorine.13 Indeed, MeSO2Cl failed in the
sulfenylation of indole because its deoxygenation by phosphine
does not occur. The surface electrostatic potential of the
chlorine atom is no longer positive to allow the halogen bonding
interaction with the phosphine.
Table 1. Optimization of the Reaction Parameters
a
b
run
reducing agent
solvent
temp (°C)
yield (%)
Variation of the Temperature
1
2
3
PMe3 (1:1.5:3)
PMe3 (1:1.5:3)
PMe3 (1:1.5:3)
toluene
toluene
toluene
−78 to rt
−4 to rt
−20 to rt
70
62
40
Variation of the Amount of CF3SO2Cl and of the Ratio CF3SO2Cl/Reducing
Agent
4
5
6
7
8
PMe3 (1:1.5:1.5)
PMe3 (1:1.5:3)
toluene
toluene
toluene
toluene
toluene
−78 to rt
−78 to rt
−78 to rt
−78 to rt
−78 to rt
41
70
77
78
73
PMe3 (1:1.5:3.75)
PMe3 (1:1.8:3.6)
PMe3 (1:1.8:4.5)
Screening of the Reducing Agent and Solvent
9
PMe3 (1:1.8:3.6)
PPh3 (1:1.5:3)
PPh3 (1:1.5:3)
PPh3 (1:1.5:3)
P(OMe)3 (1:1.8:3.6)
P(OMe)3 (1:1.8:3.6)
(EtO)2P(O)H
TMSCl + NaI
Me2S
THF
−78 to rt
−78 to rt
−78 to rt
−78 to rt
−78 to rt
−78 to rt
−78 to rt
−78 to rt
−78 to rt
89
35
51
21
21
46
0
10
11
12
13
14
15
16
17
toluene
DCM
CHCl3
toluene
DCM
toluene
toluene
toluene
0
0
a
b
Ratio indole/CF3SO2Cl/reducing agent. Yields were determined by
19F NMR using trifluorotoluene as an internal standard.
3-(trifluoromethyl sulfoxide)indole and bis(trifluoromethyl)
disulfide, CF3SSCF3; the former results from an incomplete
deoxygenation of CF3SO2Cl, whereas the latter results from the
disproportionation of CF3SCl. In order to maximize the yield
of the desired SCF3 indole by suppressing the side reactions,
we studied variations of the amount of CF3SO2Cl and of the
ratio CF3SO2Cl/PMe3 (Table 1, runs 4−8). It was found that
a ratio of indole/CF3SO2Cl/PMe3 1:1.8:3.6 led to an improved
yield of 78% and even up to 89% when toluene was replaced
by THF (Table 1, run 9). Next, we screened other reducing
agents: triphenylphosphine and trimethyl phosphite led to the
desired SCF3 indole 2a although in lower yields than with
trimethylphosphine (Table 1, runs 10−14), whereas diethyl
phosphite (Zhang’s best reductant of K),4 trimethylsilyl
chloride/sodium iodide, and dimethyl sulfide appeared to
be unsuitable for this transformation (Table 1, runs 15−17).
We next sought to examine the substrate scope, providing some
The invention of a route to in situ formation of CF3SCl
prompted us to examine the reaction with other azaarenes that
include the synthesis of trifluoromethylthiolated pyrroles 3 and
4, imidazo[1,2-a]pyridine 5, methyl indolizine-1-carboxylate 6,
and pyrazolone 7 (Scheme 5). Interestingly, pyrroles 4 are
potent insecticidal and fungicidal agents that were initially
prepared by means of CF3SCl.14 Under the same reaction
conditions as for indoles, these azaarenes afforded the expected
SCF3 products in moderate to good yields. In addition, we
found that enamines and enoxysilanes were suitable substrates
B
DOI: 10.1021/acs.orglett.6b01026
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Letter
Scheme 2. Scope of Trifluoromethylthiolation of Indole Derivatives
a
b
c
Yields of isolated pure products. Ratio indole/CF3SO2Cl/PMe3 1:1.8:3.6. Ratio indole/CF3SO2Cl/PMe3 1:2.2:4.4. N.R.: no reaction.
Scheme 3. Proposed Deoxygenative Sulfenylation Mechanism
In conclusion, we have tamed the transient existence of
trifluoromethylsufenyl chloride in a novel phosphine-mediated
reductive deoxygenation−trifluoromethylthiolation reaction of
indoles, other azaarenes, enamines, and enoxysilanes with
trifluoromethanesulfonyl chloride. The metal-free mild protocol
is simple to implement with readily available reagents bypassing
sophisticated SCF3 reagents which are difficult to use on a larger
scale. The invention offers an alternative access to SCF3 com-
pounds and unveils a novel application of trifluoromethanesulfonyl
chloride that is otherwise frequently used in organic chemistry.
Our approach also allows a convenient preparation of CF3SSCF3.
Scheme 4. Insights into the Active Species
a
Scheme 5. Scope of Trifluoromethylthiolation
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01026.
Experimental procedures and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: nozshiba@nitech.ac.jp.
*E-mail: dominique.cahard@univ-rouen.fr.
Notes
The authors declare no competing financial interest.
a
Ratio indole/CF3SO2Cl/PMe3 1:1.8:3.6 for 3−4, 9 and 1:2.2:4.4 for
b
ACKNOWLEDGMENTS
5−8, 10. Yields of isolated pure products. Yields were determined by
■
19F NMR.
This research was partially supported by the Centre National de
la Recherche Scientifique (CNRS, PICS No. 7262), University
of Rouen, INSA Rouen, and Labex SynOrg (ANR-11-LABX-
for further development of our methodology, affording SCF3
products 8−10 in 53−65% yields (Scheme 5).
0029). H.C. thanks the French “Minister
̀
e de la Recherche et de
C
DOI: 10.1021/acs.orglett.6b01026
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
l’Enseignement Super
Letter
́
ieur” for a doctoral fellowship. M.M. is
grateful to the French ministry of foreign affairs for an Eiffel
excellence doctorate scholarship. N.S. thanks the Platform for
Drug Discovery, Informatics, and Structural Life Science from
MEXT Japan.
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DOI: 10.1021/acs.orglett.6b01026
Org. Lett. XXXX, XXX, XXX−XXX