Electrophotocatalytic Undirected C?H Trifluoromethylations of (Het)Arenes

Article abstract of DOI:10.1002/chem.201905774

Electrophotochemistry has enabled arene C?H trifluoromethylation with the Langlois reagent CF₃SO₂Na under mild reaction conditions. The merger of electrosynthesis and photoredox catalysis provided a chemical oxidant-free approach for the generation of the CF₃ radical. The electrophotochemistry was carried out in an operationally simple manner, setting the stage for challenging C?H trifluoromethylations of unactivated arenes and heteroarenes. The robust nature of the electrophotochemical manifold was reflected by a wide scope, including electron-rich and electron-deficient benzenes, as well as naturally occurring heteroarenes. Electrophotochemical C?H trifluoromethylation was further achieved in flow with a modular electro-flow-cell equipped with an in-operando monitoring unit for on-line flow-NMR spectroscopy, providing support for the single electron transfer processes.

Full text of DOI:10.1002/chem.201905774

A Journal of
Accepted Article
Title: Electrophotocatalytic Undirected C–H Trifluoromethylations of
(Het)Arenes
Authors: Youai Qiu, Alexej Scheremetjew, Lars H. Finger, and Lutz
Ackermann
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201905774
Link to VoR: http://dx.doi.org/10.1002/chem.201905774
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Electrophotocatalytic Undirected C–H Trifluoromethylations of
(Het)Arenes
Youai Qiu, Alexej Scheremetjew, Lars H. Finger, and Lutz Ackermann*[a]
Abstract: Electrophotochemistry has enabled arene C–H
trifluoromethylation with the Langlois reagent CF3SO2Na under mild
reaction conditions. The merger of electrosynthesis and photoredox
sustainable C–H activation[18] induced by photocatalysis,[19] we
have now developed the first electrophotochemical C–H
trifluoromethylation through single electron transfer (SET) with the
inexpensive, solid, and stable Langlois reagent (CF3SO2Na)[20]
(Figure 1). Hence, our strategy set the stage for the merger of
sustainable electrochemical and photochemical transformations
towards trifluoromethylation. Notable features of our approach
catalysis provided
a chemical oxidant-free approach for the
generation of the CF3 radical. The electrophotochemistry was carried
out in an operationally simple manner, setting the stage for
challenging C–H trifluoromethylations of unactivated arenes and
heteroarenes. The robust nature of the electrophotochemical manifold
was reflected by an ample scope, including electron-rich and electron-
deficient benzenes, as well as naturally occurring heteroarenes.
Electrophotochemical C–H trifluoromethylation was further achieved
in flow with a modular electro-flow-cell equipped with an in-operando
monitoring unit for on-line flow-NMR spectroscopy, providing support
for the single electron transfer processes.
include
(a)
unprecedented
electrophotochemical
C–H
trifluoromethylations with electricity as the sustainable sole
oxidant, (b) electrophotochemical C–H activation in a flow setup,
and (c) in-operando flow-NMR monitoring.
In the past decade, electrosynthesis has been identified as an
increasingly powerful tool for replacing stoichiometric chemical
redox reagents.[1] Based on recent contributions by Baran,[2]
Waldvogel,[3] Ackermann,[4] Yoshida,[5] and Xu,[6] among others,[7]
this strategy has recently gained momentum by alkene
functionalizations,[8] directed C–H oxygenations,[9] as well as C–H
activations[10] by transition metal catalysis.[11] Meanwhile, visible
light photoredox catalysis has emerged as a transformative
technique for molecular syntheses,[12] proving particularly
effective for single electron transfer cross-coupling-type
reactions. Despite these indisputable advances in the respective
arenas, the merger of electrochemistry with photochemistry
continues to be underdeveloped.
Figure 1. Electrophotochemical undirected C–H trifluoromethylation.
Our
studies
were
initiated
by
exploring
the
electrophotochemical nondirected C–H trifluoromethylation of
readily accessible mesitylene (1a)[21] with the Langlois reagent
(CF3SO2Na, 2) in an operationally-simple, user-friendly undivided
cell set-up. These orienting studies utilized a platinum plate
cathode and
a
graphite felt (GF) anode, employing
[Mes-Acr+]ClO4− as a photocatalyst (PC) and cost-effective KOAc
as a conductive additive in CH3CN at a room temperature of 23 °C
(Scheme 1).
Trifluoromethylated compounds display unique bioactivity and
lipophilicity, and are hence in particularly high demand in
medicinal chemistry and pharmaceutical industries.[13] Very
recently, aromatic trifluoromethylations have made the transition
from more traditional processes[14] to photoredox catalysis [15] and
electro-synthesis.[16] In the meantime, we became intrigued by the
prospect of combining[17] electrochemistry and photochemistry for
C–H trifluoromethylations of non-activated arenes under mild
reaction conditions. In this context, Moutet and Reverdy[17i]
reported the electrophotocatalytic oxidation of benzylic alcohol,
albeit with limited scope. Further, Scheffold[17h] demonstrated the
nucleophilic acylation of Michael olefins using vitamin B12 as an
electrophotocatalyst. Very recently, elegant examples of
electrophotochemical transformations were achieved by Xu,[17d]
Stahl,[17f] Hu,[17c] and Lambert.[17a,b] Within our program on
Scheme 1. Preliminary electrophotochemical C–H trifluoromethylation.
With these preliminary results in hand, we further interrogated
the electrophotochemical C–H trifluoromethylation regime (Table
1). After considerable experimentation, we were pleased to
observe that the desired product 3a was best obtained with LiClO4
as additive, and CH3CN as the solvent in an operationally simple
undivided cell (Table 1, entries 1-6). Notably, further catalyst
optimization showed that [Ru(bpy)3](PF6)2 efficiently furnished the
corresponding product 3a at lower catalyst loading (Table 1, entry
7). Control experiments verified the indispensable role of
electricity and light, while confirming the key importance of the
photocatalyst (Table 1, entries 9-13). The use of further additives,
such as water or TFA, fell short in improving the efficiency of the
[a]
Dr. Y. Qiu, A. Scheremetjew, Dr. L. H. Finger, Prof. Dr. L.
Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
Supporting information for this article is given via a link at the end of
the document.
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desired transformation (Table 1, entries 14-15), whereas a less
expensive nickel foam cathode gave the corresponding products
with comparable levels of efficiency under otherwise identical
reaction conditions (Table 1, entry 16). Thus, two optimized
conditions were identified featuring a metal-free photocatalyst
groups, such as ester and chloro substituents, or sterically-
encumbered substituents (3c), were fully tolerated. The
synergistic electrophotochemistry was hence characterized by
high levels of chemo-selectivity control. Some inert examples
were also exploited for this transformation.[22]
−
(condition A: [Mes-Acr+]ClO4 ) or alternatively a ruthenium
photocatalyst (condition B: [Ru(bpy)3](PF6)2).
Table 1. Optimization of the electrophotochemical C–H trifluoromethylation.[a]
Yield
(%)[b]
Ratio
(%)[b]
Entry
Photo-catalyst
Additive
Solvent
−
−
1
[Mes-Acr+]ClO4
KOAc
TBAPF6
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
---
CH3CN
CH3CN
CH3CN
DCE
48
10
85
38
45
68
88
75
5
93/7
---
2
[Mes-Acr+]ClO4
−
3
[Mes-Acr+]ClO4
93/7
94/6
80/20
62/38
78/22
83/17
---[c]
−
4
[Mes-Acr+]ClO4
−
5
[Mes-Acr+]ClO4
TFE
−
6
[Mes-Acr+]ClO4
HFIP
7
[Ru(bpy)3](PF6)2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Scheme 2. Electrophotochemical C–H trifluoromethylation of arenes 1.
8
Eosin Y
−
9
[Mes-Acr+]ClO4
Thereafter, we turned our attention towards probing the
scope of viable heteroarenes 4 (Scheme 3). A wide range of
heteroarenes 4 proved to be compatible with the optimized
electrophotochemical transformation, including furan, thiophene,
benzofuran, benzo[b]thiophene, indole, quinoline, and pyrimidine,
furnishing the desired trifluoromethylated products 5 with high
selectivity and good efficiency. Notably, synthetically useful ester,
amide, and acetyl substituents were well tolerated, which should
prove valuable for further late-stage modifications.
−
10
11
12
13
14
15
16
[Mes-Acr+]ClO4
4
---[d]
−
[Mes-Acr+]ClO4
8
---[e]
---
9
---
−
[Mes-Acr+]ClO4
55
70
23
52
92/8
92/8[f]
---[g]
−
[Mes-Acr+]ClO4
LiClO4
LiClO4
LiClO4
−
[Mes-Acr+]ClO4
−
[Mes-Acr+]ClO4
87/13[h]
[a] Undivided cell, graphite felt anode, Pt cathode, constant current = 4.0 mA, 1
(0.25 mmol), 2 (0.50 mmol), photocatalyst (2.0 or 5.0 mol %), additive (0.1 M),
solvent (4.0 mL), 23 °C, blue LED, under N2, 8 h. [b] Yields determined by 1H
NMR with CH2Br2 as internal standard, and ratio is mono-/bis- CF3 substituents.
[c] Without electricity under N2 in degassed solvent. [d] Without electricity under
air. [e] Without blue light. [f] Additive: H2O (2.0 equiv). [g] Additive: TFA (2.0
equiv). [h] Nickel foam as cathode. Standard condition A: [Mes-Acr+]ClO4− (5.0
mol %) as catalyst (Faradaic yield: 36%); standard condition B: [Ru(bpy)3](PF6)2
(2.0 mol %) as catalyst (Faradaic yield: 37%).
With the thus optimized reaction conditions for the
electrophotochemical C–H trifluoromethylation in hand, we
explored their versatility with a set of representative arenes 1
(Scheme 2). We were delighted to observe that substrates 1
bearing either electron-donating or electron-withdrawing
substituents underwent the C–H transformations efficiently with
high regioselectivity to afford the corresponding products 3a-3g
and 3h, respectively. Even sensitive electrophilic functional
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Scheme 4. Electrophotochemical late-stage diversification of bioactive and
natural products.
Based on the results of the electrophotochemical C–H
trifluoromethylation in batch, we became intrigued by probing the
C–H trifluoromethylation in flow.[24] To our delight, a modular
electro-flow-cell equipped with a GF anode and a nickel cathode
followed by a looped transparent tube delivered under irradiation
the desired product 3a with high efficiency, when using the PC A
(Scheme 5).[25] Notably, these findings show that the electro-
oxidation and the photo-catalysis steps can occur with spatial and
temporal separation, for the organic photocatalyst.
Scheme 3. Electrophotochemical C–H trifluoromethylation of heteroarenes 4.
The power of direct C–H functionalizations is arguably best
represented by late-stage diversification of structurally complex
molecules.[23] Remarkably, the unique robustness of the
synergistic electrophotochemical C–H trifluoromethylation
allowed for the efficient conversion of naturally occurring motifs,
such as caffeine, pentoxifylline, doxofylline, theobromine, methyl
estrone, and tryptophan derivatives, thereby highlighting the utility
of the electrophotochemical C–H transformation strategy for late-
stage trifluoromethylations (Scheme 4).
Scheme 5. Electrophotochemical C–H trifluoromethylation in a flow setup, flow
rate: 1.0 mL/min, residence time in the electrochemical flow reactor: 6 min.
Considering the remarkable performance of the
electrophotochemical C–H activation, we became intrigued to
delineate its mode of action. To this end, we first conducted typical
radical trap experiments (Scheme 6). Hence, the desired product
3a was not formed in the presence of 2.0 equivalents of TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxide). Further, the C–H
trifluoromethylation was significantly suppressed upon the
addition of stoichiometric BHT, the observations being suggestive
of a single electron transfer process. In the latter case, the
products 12 and 13 were obtained instead, providing further
support for a SET manifold.
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Scheme 6. Mechanistic studies.
Moreover,
we
performed
fluorescence
quenching
experiments towards a Stern-Volmer plot analyses (see the
Supporting Information), and monitored the conversion profile of
the electrophotochemical C–H trifluoromethylation. Thus, a Stern-
Volmer plot analysis provided strong support for an effective
quenching of the photo-excited MesAcr* PC, occurring
preferentially by the reagent 2 (Figure 2a).[22] These studies
revealed the transformations being suppressed in the absence of
light (Figure S-7), thus demonstrating the key influence of
continuous irradiation. We further conducted electricity on/off
experiments (Figure S-8), and the transformations were fully
suppressed in the absence of electricity. These findings highlight
the importance of visible-light irradiation and electricity for the
success of the C–H trifluoromethylation.[26]
Figure 2. a) Stern-Volmer plot analysis: Fluorescence quenching of
−
[Mes-Acr+]ClO4 with reagent 2. b) On-line reaction monitoring in flow by 19F
NMR spectroscopy.
At the same time, we conducted cyclic voltammetry (CV)
studies in acetonitrile with LiClO4 (0.1 M) as the electrolyte (Figure
3). The onset of the irreversible sodium trifluoromethanesulfinate
2 oxidation was observed at Eonset = +1.02 V vs. SCE. In this
process, a species is generated, which exhibits a reductive
current that initiates at Eonset = −0.57 V vs. SCE. We attribute this
event to the formation of SO2.[20] In the presence of the
photocatalyst (PC) this behavior remained unaltered. However,
upon blue light irradiation,
a
consumption of sodium
In order to rationalize the reactions’ profile in more detail we
additionally monitored the reactions’ progress by 1H and 19F NMR
spectroscopy in flow. The 19F NMR monitoring flow-experiment
depicted in Figure 2b features the readily formed reaction product
3a and remarkably the emergence and decomposition of a long-
lived intermediate. To our delight, the intermediate could also be
observed during 1H NMR monitoring (refer to the Supporting
Information) indicating the intermediate to possess two equivalent
protons with a resonance at 5.80 ppm. Thereby, the intermediate
is tentatively assigned as Int-B – a Wheland type arenium
trifluoromethanesulfinate 2 was observed. These findings are
suggestive of the formation of the CF3 radical, which occurs by
oxidation with the excited state of the PC (Ered = +2.06 V vs. SCE
in MeCN).[28] The PC can be regenerated in the ground state by
anodic oxidation, which was indicated by the reversible redox
event at E1/2 = −0.62 V vs. SCE. At the counter electrode,
molecular hydrogen is generated through cathodic reduction, as
was evidenced by headspace gas chromatographic analysis.[22]
a)
27]
cation,[ for which related resonances have been observed.[27a]
a)
20
PC
2
PC + 2
1.8
1.6
1.4
10
0
-10
-20
1.2
I0/I = (75.5 .7) [2a](mol/L)-1 + 1
1.0
0
2
4
6
8
10
[2a] (mmol/L)
b)
-2
-1
0
1
2
Potential vs. SCE (V)
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b)
In
conclusion,
we
have
developed
the
first
electrophotochemical C–H trifluoromethylation enabled by the
cooperative action of electrochemistry and photochemistry. This
strategy avoids the use of expensive and toxic chemical oxidants.
Under the electrophotochemical conditions, trifluoromethyl
radicals are efficiently generated, which readily participate in
intermolecular oxidative C–H transformations. The reaction
features a broad substrate scope and a high tolerance of
20
PC + 2
PC + 2 after 10 min
blue light irradiation
10
0
-10
-20
synthetically
electrophotochemical C–H trifluoromethylations were further
achieved in flow setup. The practical utility of the
meaningful
functional
groups.
The
a
electrophotochemical C–H trifluoromethylation in flow was
reflected by operationally simple on-line NMR-monitoring.
Mechanistic studies provided strong support for key SET
processes, overall indicating the synthetic potential of
electrophotochemical transformations.
-2
-1
0
1
2
Potential vs. SCE
Acknowledgements
Figure 3. Cyclic voltammetry. Conditions: (a) and (b) substrates (5 mmol/L),
LiClO4 (100 mmol/L), MeCN, 100 mV/s. (a) PC (black), 2 (red), PC + 2 (blue).
(b) PC + 2 (black), PC + 2 after being irradiated for 10 minutes with blue light
(red).
Generous support by the DFG (Gottfried-Wilhelm-Leibniz award
to LA) is acknowledged.
On the basis of our mechanistic findings, we propose a
plausible mechanism as depicted in Scheme 7.[25] Initial irradiation
of the organic dye Mes-Acr+ generates its oxidized excited state
Mes-Acr+*. A SET process between Mes-Acr+* and the sulfinate
anion results in the generation of the acridinyl radical and the
CF3SO2 radical. Anodic electrooxidation of the acridinyl radical
subsequently regenerates the ground state catalyst Mes-Acr+.
Simultaneously, attack of the trifluoromethyl radical on the
substrate 1a forms the Int-A radical, which undergoes SET
oxidation to form the cationic Wheland complex Int-B. In the
meantime, Int-A could also be directly oxidized at the anode.
Finally, proton abstraction delivers the desired product 3a, while
protons are reduced to generate H2 at the cathode.
Conflict of interest
The authors declare no conflict of interest.
Keywords: electrophotochemistry • C−H trifluoromethylation •
electrochemistry • oxidant-free • photoredox catalysis
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Youai Qiu, Alexej Scheremetjew, Lars H.
Finger, and Lutz Ackermann*
Page No. – Page No.
Electrophotocatalytic Undirected C–H
Trifluoromethylations of (Het)Arenes
Cooperation: Electrophotochemical C–H trifluoromethylations of unbiased arenes
were accomplished by the cooperative action of electricity and light under mild
reaction conditions.
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