Cathodic C-H Trifluoromethylation of Arenes and Heteroarenes Enabled by an in Situ-Generated Triflyltriethylammonium Complex

Article abstract of DOI:10.1021/acs.orglett.9b02948

While several trifluoromethylation reactions involving the electrochemical generation of CF₃ radicals via anodic oxidation have been reported, the alternative cathodic, reductive radical generation has remained elusive. Herein, the first cathodic trifluoromethylation of arenes and heteroarenes is reported. The method is based on the electrochemical reduction of an unstable triflyltriethylammonium complex generated in situ from inexpensive triflyl chloride and triethylamine, which produces CF₃ radicals that are trapped by the arenes on the cathode surface.

Full text of DOI:10.1021/acs.orglett.9b02948

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cathodic C−H Trifluoromethylation of Arenes and Heteroarenes
Enabled by an in Situ-Generated Triflyltriethylammonium Complex
Wolfgang Jud,†,‡ Snjezana Maljuric,†,‡ C. Oliver Kappe,*,†,‡ and David Cantillo*,†,‡
†Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
‡Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE),
Inffeldgasse 13, 8010 Graz, Austria
S
* Supporting Information
ABSTRACT: While several trifluoromethylation reactions involving the
electrochemical generation of CF3 radicals via anodic oxidation have been
reported, the alternative cathodic, reductive radical generation has remained
elusive. Herein, the first cathodic trifluoromethylation of arenes and
heteroarenes is reported. The method is based on the electrochemical
reduction of an unstable triflyltriethylammonium complex generated in situ
from inexpensive triflyl chloride and triethylamine, which produces CF3
radicals that are trapped by the arenes on the cathode surface.
ecent years have witnessed a significant resurgence of
electrochemical methods for the promotion of organic
R
reactions,1 not only as an inherently sustainable approach2 but
also as an elegant strategy for accessing high-energy
intermediates under mild conditions.3 Radical species, for
example, can be generated from relatively unreactive reagents
at room temperature,1,3 providing access to challenging organic
transformations difficult to achieve using conventional
synthetic methods.4 Radical trifluoromethylation reactions,
pivotal transformations in modern organic and medicinal
chemistry,5−7 have also been explored by means of electro-
chemical methods. Trifluoromethyl radicals have been
generated by anodic oxidation of sodium and zinc triflinate
salts and utilized for the introduction of this moiety into
unsaturated compounds.1 Arene and heteroarene trifluorome-
thylations are arguably the most pursued perfluoroalkylation
reactions.8 In fact, a majority of active pharmaceutical
ingredients decorated with trifluoromethyl groups contain
this moiety attached to an aromatic ring.9 In addition to a
range of methods for the trifluoromethylation of aromatic rings
based on chemical oxidants or photoredox catalysis (Figure
1A),10,11 electrochemical methods have also been re-
ported.12,13 These methods, as mentioned above, exclusively
rely on the anodic oxidation of triflinate salts (Figure 1B).
While the original report using the oxidation of KSO2CF3 had
a rather limited scope of aromatic hydrocarbons,12 nitrogen-
containing heteroarenes were successfully functionalized using
Zn(SO2CF3)2 in a divided cell setup.13
Figure 1. Strategies for arene trifluoromethylation.
trifluoromethylation of the aromatic ring occurs on the surface
of the cathode. It was envisioned that such reductive radical
generation, combined with an easily oxidized amine (to act as a
reductant for the anodic oxidation and a base), might enable
During our recent work on anodic oxytrifluoromethylations
involving oxidation of sodium triflinate,14 we questioned
whether the alternative cathodic generation of CF3 radicals,
not reported so far, is possible and how such an unexplored
strategy might broaden the scope of the electrochemical
procedure for the functionalization of arenes and heteroarenes.
In a reductive radical generation strategy (Figure 1C),
Received: August 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02948
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Letter
Figure 2. Development of a cathodic trifluoromethylation method for aromatic compounds via reduction of triflyl species.
electrochemical trifluoromethylation of oxidatively labile
heteroarenes (e.g., thiophenes). Furthermore, development of
a cathodic trifluoromethylation concept may unlock oppor-
tunities for other reductive perfluoroalkylation strategies of
compounds that are difficult to perform using oxidation
methods.
(∼13 mA/cm2) resulted in a cell voltage of ∼1.5 V. No
reaction was observed in the absence of electricity (entry 6).
Interestingly, product formation was also observed when Zn or
Mn was used as the stoichiometric reductant in the absence of
electricity (entry 7). However, low conversions (10−12%)
were obtained using 3 equiv of metal after 24 h (see the
Supporting Information for experimental details).
Trifluoromethanesulfonyl chloride (TfCl) was selected as
trifluoromethyl source for this investigation. TfCl is an
inexpensive, relatively easy to handle liquid.15 In addition, its
low negative reduction potential (−0.18 V vs Ag/AgCl)16
makes it particularly attractive for an electrochemical
reduction. We began our study with a series of experiments
using mesitylene as a model substrate (Figure 2A) and an
undivided cell setup (IKA ElectraSyn 2.0) using graphite as the
anode and cathode material. Although we aimed for easily
oxidized amine bases such as Et3N, several bases with different
properties were also evaluated to gain some insight into the
reaction mechanism. These bases included inorganic non-
nucleophilic (K2HPO4) and organic bases of increasing
nucleophilicity (2,6-lutidine, iPr2EtN, and Et3N). As expected,
when K2HPO4 and 2,6-lutidine were used as the base (Figure
2A, entries 1 and 2, respectively), moderate conversion of the
starting material was observed with poor selectivity. The lack
of a suitable reductant in the reaction medium for the anodic
oxidation resulted in high cell voltages (>4 V) and significant
amounts of undesired aryl oxidation side products, including
chlorination of the aromatic ring (3) and trapping of the aryl
cation (resulting from oxidation of the starting material) with
acetonitrile (4) (Figure 2B). The results improved with
When TfCl and Et3N were mixed in acetonitrile, with or
without the substrate and supporting electrolyte, a rapid color
change (from colorless to pale yellow) could be observed. As
both reagents were used in equimolar amounts in the initial set
of experiments, TfCl was most likely transformed into the
corresponding triflyltriethylammonium chloride complex 5
(Figure 2C). 19F NMR monitoring of the reaction mixture
revealed that a complex mixture of triflyl-containing species
was indeed formed upon mixing of the reagents. Signals
corresponding to diethyl sulfonamide 6 and triflinate 7 were
detected as the major side products. Formation of 6 takes place
slowly via elimination of chloroethane, while triflinate 7 is
produced when an excess of base is present. These
observations, which could be confirmed by 19F NMR
monitoring of solutions containing variable amounts of TfCl
and Et3N (see the Supporting Information), are in agreement
with those reported by Netscher and Bohrer for mixtures of
triflic anhydride and Et3N.17 The presence of both species (6
and 7) in solution was undesirable because they do not release
CF3 radicals under the reaction conditions. This hypothesis
was confirmed by preparing 6 and a mixture of sodium
triflinate and Et3N and utilizing them as reagents for the
cathodic trifluoromethylation under standard conditions in two
separate control reactions. No conversion was observed
(Figure 2C) (see the Supporting Information for details).
Identification of the triflyl species occurring in solution
proved to be very valuable for understanding the reaction
behavior and boosting further optimization. When an excess of
Hunig’s base (entry 3). Remarkably, using Et3N as an additive,
̈
the side products were fully suppressed. After the application
of 1 F/mol, 32% conversion of the starting material and 99%
selectivity toward the desired trifloromethylated arene were
observed (Figure 2A, entry 4). The cell voltage was also
significantly lower than for the non-nucleophilic bases; 20 mA
B
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Scheme 1. Reaction Scope and Limitations
a
b
Yields were determined by 19F NMR using fluorobenzene as the internal standard. Values in parentheses refer to isolated yields. Method A: 0.3
c
d
mmol scale, 3 equiv of TfCl, 3 mL of acetonitrile. Method B: 0.6 mmol scale, 3 mL of acetonitrile, 5 equiv of TfCl. Obtained as a mixture of
isomers (see the Supporting Information for details). Bis-trifluoromethylation product also obtained.
e
Et3N over TfCl was used (Figure 2A, entry 8), low conversion
and selectivity were achieved, as expected due to the faster
generation of compound 7, which inhibits the reaction.
Moreover, reactions in nonpolar solvents such as THF and
acetone (entries 9 and 10, respectively) failed; when Et3N was
added to the reaction mixture in these solvents, a white
precipitate rapidly formed (most likely ionic complex 5). The
lack of reagents in solution generated exceedingly high cell
voltages (>5 V) and no conversion to the desired product. To
minimize degradation of the active species 5 to 6 and 7, a rapid
reaction was expected to be beneficial. Thus, the current was
increased to 40 mA (∼26 mA/cm2) [for sensitive substrates,
the current was reduced to 20 or 10 mA (vide infra)]. A
gradual increase in the amount of TfCl to 4 equiv and charge
to 5 F/mol led to high conversion and selectivity (Figure 2A,
entries 11 and 12, respectively). Ultimately, excellent results
were achieved using a substrate concentration of 0.1 M (entry
13). As expected, at high conversions certain amounts (∼10%)
of the bis-trifluoromethylated product were also detected for
this relatively active substrate (GC-FID monitoring of a typical
reaction mixture is shown in Figure S2).
omethylation strategy (Scheme 1A,B). An excess of current
ranging from 2 to 8 F/mol was utilized depending on the
substrate. The method tolerated several functional groups,
including alkyl, halogen, ether, ester, nitrile, or ketone moieties.
As expected, the reaction performed best for electron-rich
substrates (e.g., 2a and 2b). Electron-withdrawing groups such
as halogens (2m−o), esters (2q), or ketones (2r) decreased
the efficiency of the reaction, and modest yields were achieved.
The strongly deactivated nitrobenzene resulted in only traces
of the target product (2s). Importantly, low conversions but no
side reactions were observed for the low-yielding examples.
Most likely, the poor radical trapping character of electron-
poor aromatics led to dimerization of the CF3 radicals to
hexafluoroethane (F3C−CF3), an effect probably enhanced by
the fact that the radicals are formed on the electrode surface
(probably leading to high local concentrations of CF3 radicals).
Gratifyingly, thioanisole, containing an oxidatively labile sulfur
atom, could also be successfully functionalized (2p). Yields
reported in panels A and B of Scheme 1 were obtained under
analogous conditions. Method A (0.3 mmol scale, 3 equiv of
TfCl) was used for electron-rich substrates. In method B,
utilized for electron-poor substrates, the scale was increased to
0.6 mmol and the excess of TfCl to 5 equiv.
With the optimal conditions in hand, a series of arenes and
heteroarenes were functionalized using this cathodic trifluor-
C
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Importantly, this method could also be utilized for the
trifluoromethylation of heteroaromatics containing nitrogen,
oxygen, and sulfur atoms (Scheme 1B). While nitrogen-
containing heteroaromatics had been previously trifluorome-
thylated using an oxidative approach and a divided cell by
Baran and Blackmond,13 the latter two had not been reported
so far using electrochemical approaches. N-Phenyl and N-
methyl pyrrole were successfully trifluoromethylated (2v and
2w, respectively). Trifluoromethylated heteroaromatics deco-
rated with N and S atoms were also prepared in synthetically
useful yields as well as thiophene (2y and 2z) and furane (2ab
and 2ae) derivatives. More complex heteroarenes such as
caffeine (2af) or the drug pentoxifylline (2ag) were also
successfully derivatized.
The proposed reaction mechanism involves a transformation
that would mainly take place on the cathode surface (Figure
3A). One-electron reduction of triflylammonium complex 5
results in neutral radical 8. Although satisfactory cyclic
voltammetry measurements of compound 5 could not be
obtained, DFT calculations showed that the reduction of the
complex should be significantly favored compared to TfCl
(Figure 3B), with a reduction potential that was ∼0.5 V lower
(less negative) (see the Supporting Information for calculation
details). This indicates that even with the two species existing
in equilibrium (particularly when TfCl is in excess over Et3N),
5 most likely is the species being reduced and the radical
source. DFT calculations also confirmed that compound 6 has
a very negative reduction potential and cannot be involved in
the electrochemical process (Figure 3B), as demonstrated by
the control experiments [Figure 2C (vide supra)]. Decom-
position of 8 recovers the amine (Et3N), releasing SO2 and the
CF3 radical. Trapping of the latter by the aromatic ring
generates the new radical 9, which then rearomatizes via
hydrogen abstraction or a SET process followed by
deprotonation. Such rearomatization after radical additions to
aromatics in the absence of oxidants has often been reported in
the literature.18 The Et3N released during the reduction of 5 is
oxidized on the anode. As oxidation of the amine is a two-
electron process, only 0.5 equiv of amine is required for the
anodic oxidation. Several plausible products for the oxidation
of triethylamine have been proposed. Most often, N,N-diethyl
ethenamine has been suggested.19 Anodic dealkylation of
tertiary aliphatic amines has also been previously reported.20
To assess the fate of triethylamine during the anodic oxidation
in our procedure, electrolysis experiments were carried out in
MeCN-d3 as the solvent under the typical reaction conditions
(see the Supporting Information for details). 1H and 13C NMR
analysis of the crude reaction mixture ruled out the formation
of an alkene and pointed to the generation of diethylamine via
electrochemical dealkylation. This secondary amine is probably
partially present in its hydrochloride form if the rear-
omatization of 9 releases a proton. The intermediacy of the
trifluoromethylsulfonyl (CF3SO2) radical could be confirmed
by its trapping with styrene (Figure 3B). Furthermore, the
presence of TEMPO as an additive (1 equiv) inhibited the
reaction, most likely by trapping most of the CF3SO2 radical
(no TEMPO-CF3 was detected by GC analysis).
In summary, we have developed a method for the cathodic
trifluoromethylation of arenes and heteroarenes based on the
reduction of a trifluoromethyltriethylammonium complex (5),
generated in situ from triflyl chloride and triethylamine. The
method has shown a good functional group tolerance, and as
the trifluoromethylation takes place at the cathode surface,
oxidatively labile sulfur-containing aromatics could be
successfully functionalized. Further extension of this concept
to other perfluoroalkynation reactions is currently in progress.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02948.
Experimental details, supplementary figures and tables,
characterization data, and copies of NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: david.cantillo@uni-graz.at.
*E-mail: oliver.kappe@uni-graz.at.
Figure 3. Proposed reaction mechanisms, control experiments, and
reduction potentials of TfCl and compounds 5 and 6 calculated at the
M06-2X/6-311G++(d,p) level and referenced to the experimental
value of TfCl.
ORCID
C. Oliver Kappe: 0000-0003-2983-6007
David Cantillo: 0000-0001-7604-8711
D
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98−105. (j) Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett. 2011, 13,
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The CC FLOW Project (Austrian Research Promotion Agency
FFG Grant 862766) is funded through the Austrian COMET
Program by the Austrian Federal Ministry of Transport,
Innovation and Technology (BMVIT), the Austrian Federal
Ministry of Science, Research and Economy (BMWFW), and
the State of Styria (Styrian Funding Agency SFG).
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Visible-Light Photoredox Decarboxylation of Perfluoroarene Iodine-
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