A Readily Available Trifluoromethylation Reagent and Its Difunctionalization of Alkenes

Article abstract of DOI:10.1021/acs.orglett.1c02146

Trifluoromethyl substitution is notably popular in pharmaceuticals and agrochemicals; however, trifluoromethylated compounds normally rely on the use of cost-prohibitive or gaseous trifluoromethylating reagents, which diminishes the general applicability of these methods. Herein an efficient trifluoromethylation reagent trifluoromethylsulfonyl-pyridinium salt (TFSP) was reported, which can be readily prepared from cheap and easily available bulk industrial feedstocks. TFSP can generate a trifluoromethyl radical under photocatalysis and realize the effective azido- or cyano-trifluoromethylation reactions of alkenes.

Full text of DOI:10.1021/acs.orglett.1c02146

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Letter
A Readily Available Trifluoromethylation Reagent and Its
Difunctionalization of Alkenes
Min Zhang, Jin-Hong Lin, and Ji-Chang Xiao*
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ABSTRACT: Trifluoromethyl substitution is notably popular in
pharmaceuticals and agrochemicals; however, trifluoromethylated
compounds normally rely on the use of cost-prohibitive or gaseous
trifluoromethylating reagents, which diminishes the general
applicability of these methods. Herein an efficient trifluoromethy-
lation reagent trifluoromethylsulfonyl−pyridinium salt (TFSP) was
reported, which can be readily prepared from cheap and easily
available bulk industrial feedstocks. TFSP can generate a trifluoromethyl radical under photocatalysis and realize the effective azido-
or cyano-trifluoromethylation reactions of alkenes.
Scheme 1. Trifluoromethylation Derived from
(CF3SO2)2O
he trifluoromethyl group (CF3) has found widespread
application in pharmaceutical chemistry and agrochem-
a
T
istry owing to its strong electron-withdrawing nature, high
lipophilicity, and metabolic stability.1 During the past several
decades, many CF3-containing pharmaceuticals and agro-
chemicals, such as Prevacid, Prozac, fluazinam, and norflur-
azon, have been developed. So far, many trifluoromethylation
reagents and methods have been developed to introduce a CF3
group into organic molecules.2 From the perspective of
industrial application, it will be of great practical value if the
trifluoromethylation is directly achieved from cheap industrial
materials such as trifluoroacetic anhydride,3 trifluoroacetic
acid,4 trifluoromethanesulfonic anhydride,5 and so on.
Trifluoromethanesulfonic anhydride (Tf2O) is usually used
in the synthesis of trifluoromethanesulfonate to improve the
leaving ability of the hydroxyl group.6 In 2018, Qing’s group
first reported that the combination of Tf2O and pyridine could
release a trifluoromethyl radical under the photoredox
conditions, thus realizing an elegant trifluoromethylation and
triflation of alkynes (Scheme 1).5b Then, Hong’s group
disclosed an efficient visible-light-enabled site-selective tri-
fluoromethylative pyridylation of unactivated alkenes with
pyridines and Tf2O.5d Both Qing and Hong proposed that the
reaction may proceed through a trifluoromethylsulfonyl−
pyridinium salt intermediate. Perhaps because of the instability
of this intermediate, they did not isolate and characterize it.
Considering the volatility, hygroscopicity, and corrosiveness of
Tf2O, Pan’s group transformed Tf2O into trifluoromethylsul-
fonyl−benzimidazolium (IMDN−SO2CF3) through a two-step
synthesis and realized an efficient trifluoromethylation−
boration of inert olefins and alkynes.5c
a
Molecular structure of TFSP with thermal ellipsoids at the 30%
probability level.
Received: June 26, 2021
Published: July 23, 2021
From literature reports7 and our preliminary experiments,
we found that Tf2O could easily react with 4-(dimethylamino)-
pyridine (DMAP) to give the trifluoromethylsulfonyl−
pyridinium salt (TFSP) as a white solid, which is air stable.
https://doi.org/10.1021/acs.orglett.1c02146
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6079−6083
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Our previous work showed that the difluoromethylphos-
phonium salt (Ph3P+CF2H X−) is easy to reduce by
photocatalysis to realize the difunctionalization of olefins.14
Table 1. Optimization of Photocatalyzed Azido-
trifluoromethylation of Styrene
a
red
The redox potential of TFSP (Ep = −0.830 V vs SCE; see the
SI) measured by cyclic voltammetry showed that it may have
similar photoredox properties as Ph3P+CF2H X−. Then, we
investigated the photocatalyzed azido-trifluoromethylation of
TFSP with alkenes. Among the photocatalysts tested, Ir(ppy)3
showed the best catalytic activity (Table 1, entries 1−6).
Under the catalysis of Ir(ppy)3, various metal salts were
extensively examined, and FeCl2 was found to be the most
appropriate additive (entries 7−12). Lowering the amount of
FeCl2 to 5 mol % can slightly increase the yield (entry 13).
The reaction was further optimized by increasing the
concentration and temperature (entries 14 and 15). The
control experiments revealed that Ir(ppy)3 and blue light-
emitting diodes (LEDs) were essential for the reaction,
whereas FeCl2 was not (entries 16−18).
b
entry
photocatalyst
Ir(ppy)3
Ir(dtbpy)(ppy)2PF6
Ru(bpy)3Cl2
Ru(phen)3(PF6)2
eosin Y
fluorescein
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
additive
yield (%)
1
2
3
4
5
6
7
8
35
16
8
9
ND
ND
11
19
10
49
57
40
59
62
82
20
ND
ND
AgOTf
CuCl
CuCl2
Fe
FeCl2
Fe(OTf)2
FeCl2
FeCl2
FeCl2
9
Under the optimal reaction conditions, we investigated the
substrate scope of the photocatalyzed azido-trifluoromethyla-
tion (Scheme 2). The reaction is compatible with various
10
11
12
13
14
15
16
17
18
c
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
c d
,
Scheme 2. Substrate Scope of the Azido-
a
c de
,
,
trifluoromethylation
de
,
c de
,
,
FeCl2
FeCl2
c df
,
,
Ir(ppy)3
a
Reaction conditions: Substrate 2a (0.2 mmol), 1 (2 equiv), TMSN3
(2 equiv), photocatalyst (1 mol %), and additive (10 mol %) in DCM
(2 mL) were irradiated under 11.5 W of blue LEDs at r.t. under a N2
b
atmosphere for 24 h. Yields were determined by 19F NMR
c
spectroscopy with PhOCF3 as the internal standard. Additive (5
d
e
f
mol %). DCM (1 mL). 35 °C. Without blue LEDs. ND = not
detected.
Surprisingly, no one has ever explored the possibility of TFSP
as a trifluoromethylation reagent. Because of our interest in
fluorine-containing organic salts,8 we investigated the reactivity
of TFSP and developed a visible-light-induced azido- or cyano-
trifluoromethylation of olefins. Compared with previous
studies on the trifluoromethylative difunctionalization of
alkenes promoted by visible light,9−13 this protocol is quite
attractive due to the easy accessibility of TFSP.
At the beginning, we carefully investigated the synthesis of
trifluoromethylsulfonyl-pyridinium salt. We thought that the
stability of pyridinium salt may be improved by changing the
electron cloud density of the pyridine nucleus. Therefore,
pyridines with electron-donating substituents or conjugated
groups were subjected to the reaction with Tf2O. It was found
that the expected product could be detected by 19F NMR after
the reaction of 4-methoxy- or 4-phenyl-pyridine with Tf2O.
However, the crude products were hydrolyzed immediately
when they were filtered in the air. So the pure trifluor-
omethylsulfonyl-pyridinium salt could not be obtained. Only
the reaction of DMAP with Tf2O could efficiently give the
bench-stable product, TFSP, which could be purified simply by
filtration and washing with CH2Cl2 (Scheme 1). The reaction
could be easily scaled up to 100 mmol (36.4 g), and the yield
remained at 90%. No decomposition was observed after
keeping TFSP in the refrigerator for 4 months. Thermogravi-
metric analysis (TGA) showed that TFSP began to decompose
at its melting point, 188−191 °C.
a
Yields of isolated products are shown. Reaction conditions: Substrate
2 (0.5 mmol), 1 (1.0 mmol), TMSN3 (1.0 mmol), Ir(ppy)3 (1 mol
%), and FeCl2 (5 mol %) in DCM (2.5 mL) were irradiated with blue
LEDs at 35 °C under a N2 atmosphere for 24 h. 65% yield was
obtained for a 1 mmol-scale reaction (1 mmol of 2a).
b
styrenes bearing electron-donating or -withdrawing substitu-
ents in the ortho, meta, or para position, giving the
corresponding products in good to moderate yields (3a−3r).
A series of functional groups, such as alkyl (−CH3, -tBu),
halogen (−F, −Cl, −Br), nitrile, ester, and trifluoromethyl,
were tolerated (3a−3n). The reaction also works for the
alkenes with a fused or heterocyclic ring (3o, 3p), and it can be
applied for the late-stage functionalization of biologically
relevant molecules such as estrone and fenofibrate (3q, 3r).
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The reaction was optimized by using trimethylsilyl cyanide
(TMSCN) as the cyano source. (See the SI.) Under the
optimal reaction conditions, the reaction proceeded smoothly
and showed a wide substrate scope (Scheme 3). Alkenes with a
Scheme 4. Proposed Reaction Mechanism
Scheme 3. Substrate Scope of the Cyano-
a
trifluoromethylation
to give the corresponding higher valency metal cation. Its
subsequent reaction with intermediate B affords the final
product and regenerates the low-valency metal. In path (b),
the radical intermediated B is directly oxidized by the IrIV
complex to form the cation intermediate C. Then, the
nucleophilic attack of N3 or CN− on the cation gives the
−
final product.
Control experiments were performed to find out the path
through which the reaction proceeded. Under the optimal
conditions without FeCl2, the azido-trifluoromethylation gives
only 20% of the desired products and 40% of the olefin
byproduct (Scheme 5). This demonstrates that FeCl2 is not
a
Yields of isolated products are shown. Reaction conditions: Substrate
2 (0.5 mmol), 1 (0.75 mmol), TMSCN (1.0 mmol), Ir(ppy)3 (1 mol
%), and Cu2O (10 mol %) in CHCl3 (5.0 mL) were irradiated with
blue LEDs at room temperature under a N2 atmosphere for 60 h.
a
−CHO (4y) or −OAc (4m) group can also tolerate the
reaction conditions. It should be noted that the reaction
worked for internal alkene (4x). In the case of estrone
derivative (4q), it can also give the desired product in
moderate yield.
Scheme 5. Experimental Evidence
Taking the azido-trifluoromethylation as an example, the
reaction mechanism was explored. The fluorescence quenching
experiment showed that TFSP was the main species to quench
the excited photocatalyst, Ir(ppy)3*. The cyclic voltammetry
studies (see the SI for experimental details) further proved that
a
Yield was determined by 19F NMR spectroscopy.
red
TFSP (Ep = −0.830 V vs SCE; see the SI) could be readily
essential for the formation of the desired product, but it does
play an important role. Therefore, the reaction may proceed
mainly through path (a) (Scheme 5). Nevertheless, path (b)
may also exist in the reaction process.
reduced by the photoexcited complex [Ir(ppy)3*]
(E1/2red[IrIV/IrIII*] = −1.73 V vs SCE). The existence of
oxygen almost completely inhibited the reaction (Table S2).
Other radical scavengers such as 2,2,6,6-tetramethylpiperidine-
1-oxyl (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (buty-
lated hydroxytoluene (BHT)) could dramatically decrease the
yield, and a TEMPO adduct, TEMPO−CF3, was detected in
10% yield (determined by 19F NMR spectroscopy), indicating
the generation of a trifluoromethyl radical (Table S2).
On the basis of the above experimental evidence, a plausible
reaction mechanism was proposed as follows (Scheme 4).
After absorbing the blue light, the photocatalyst (Ir(ppy)3)
transits to its excited state, Ir(ppy)3*, which then undergoes a
single-electron transfer (SET) to the pyridinium salt TFSP to
give the intermediate A. Its homolysis delivers DMAP and the
CF3SO2· radical, which further gives the CF3· radical after the
extrusion of SO2. The capture of the CF3· radical by an alkene
substrate forms the radical intermediate B. Then, there are two
possible pathways to produce the final product. In path (a), the
IrIV complex oxidizes FeII (E1/2ox[FeIII/FeII] = +0.155 V vs
SCE; see the SI) or CuI (E1/2ox[CuII/CuI] = +0.71 V vs SCE)
In summary, we developed the trifluoromethylsulfonyl-
pyridinium salt (TFSP) into an efficient trifluoromethylation
reagent that can be readily prepared from cheap and easily
available bulk industrial materials. This solid reagent is
thermodynamically stable and easy to prepare on the large
scale. It is much more convenient than using volatile,
hygroscopic, and corrosive trifluoromethanesulfonic anhydride.
TFSP was found to be an effective trifluoromethyl radical
source for azido- or cyano-trifluoromethylation reaction of
alkenes. Further investigations on the reactivity of TFSP are
currently under way.
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Materials and methods, experimental procedures, useful
information, optimization studies,1H NMR spectra,13C
NMR spectra, and MS data (PDF)
Accession Codes
CCDC 2061716 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Ji-Chang Xiao − Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China; orcid.org/0000-0001-8881-
1796; Email: jchxiao@sioc.ac.cn
Authors
Min Zhang − Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China
Jin-Hong Lin − Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China; orcid.org/0000-0002-7000-
9540
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation
(21971252, 21991122), the Key Research Program of Frontier
Sciences, Chinese Academy of Sciences (CAS)
(QYZDJSSWSLH049), and the Youth Innovation Promotion
Association CAS (2019256) for financial support.
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