Metal-free electrochemical fluorodecarboxylation of aryloxyacetic acids to fluoromethyl aryl ethers

Article abstract of DOI:10.1039/d0sc02417a

Electrochemical decarboxylation of aryloxyacetic acids followed by fluorination provides easy access to fluoromethyl aryl ethers. This electrochemical fluorodecarboxylation offers a sustainable approach with electric current as traceless oxidant. Using Et3N·5HF as fluoride source and as supporting electrolyte, this simple electrosynthesis affords various fluoromethoxyarenes in yields up to 85%.

Full text of DOI:10.1039/d0sc02417a

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Metal-free electrochemical fluorodecarboxylation
of aryloxyacetic acids to fluoromethyl aryl ethers†
Cite this: DOI: 10.1039/d0sc02417a
Michael Berger,‡a John D. Herszman,‡a Yuji Kurimoto,ab Goswinus H. M. de Kruijff,a
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
a
Aaron Schull,ac Sven Rufc and Siegfried R. Waldvogel
*
¨
Electrochemical decarboxylation of aryloxyacetic acids followed by fluorination provides easy access to
fluoromethyl aryl ethers. This electrochemical fluorodecarboxylation offers a sustainable approach with
electric current as traceless oxidant. Using Et3N$5HF as fluoride source and as supporting electrolyte,
this simple electrosynthesis affords various fluoromethoxyarenes in yields up to 85%.
Received 29th April 2020
Accepted 24th May 2020
DOI: 10.1039/d0sc02417a
rsc.li/chemical-science
this reagent is expensive and difficult to handle due to its enor-
mous reactivity. In the recent years, several methods for decar-
Introduction
Fluoromethyl aryl ethers have intriguing properties1 and show
emerging importance in agrochemical and pharmaceutical
applications.2 Replacing a hydrogen atom by uorine as a bio-
isostere for example in methyl groups has advanced to
a common method in molecular editing of drugs. The incor-
poration of uorine can improve the metabolic stability of
a drug and increase its potency.3 Furthermore, uoromethyl aryl
ethers feature a striking shi in volatility and scent compared to
their non-uorinated analogues, making them possible candi-
dates for pheromones or fragrances.4 Therefore, widely appli-
cable methods installing uorine selectively into a molecule are
of high interest.
The rst synthetic method for the formation of uoromethyl
aryl ethers involves an electrophilic monouoromethylation of
a phenol under basic conditions using FCH2Cl with chloride as
leaving group.5 Furthermore, direct nucleophilic monouoro-
methylation of phenols and thiophenes with monouoro-
methyl-substituted sulfonium ylides has been reported.6
Although their scope shows wide applicability, rstly, the
monouoromethylating agent is considered as an impactful
green-house gas (CH2FCl) and secondly the reagent has to be
prepared by a tedious synthesis including several steps.7
In a much less troublesome approach, phenoxyacetic acids are
used in decarboxylation reactions followed by the introduction of
uorine. One of the earliest methods for this reaction type
involves the use of XeF2 for a radical uorodecarboxylation,8,9 but
boxylative uorinations have been reported. For example,
MacMillan showed the decarboxylative uorination of aliphatic
carboxylic acids using photoredox catalysis in combination with
Selectuor™.10 Furthermore, Sammis and Hartwig reported on
Hunsdiecker-type uorodecarboxylation reactions11,12 using AgF2
starting either from phenoxyacetic acids, a-uoro- or a,a-
diuorocarboxylates to obtain the corresponding mono-, di- and
triuoromethyl aryl ethers. Additionally, Tang showed the
decarboxylative uorination of electron-rich heteroaromatic
carboxylic acids using Selectuor™ in combination with KF in
dichloroethane/H2O mixtures.13 However, these methods require
either a photocatalyst or an excess of oxidizing and uorinating
agents like Selectuor/NFSI,11,14 XeF2 or AgF2 which can be very
powerful,8,12 but have many drawbacks like their hazardousness
and high costs for the reagents and in particular the ruthenium
based catalyst.
Thus, an electrochemical approach for uorodecarbox-
ylation reactions could tweak these ndings, since electric
current can be used as a green oxidant to generate reactive
intermediates in situ, like the rst electrosynthetic decarboxyl-
ation reaction shown by Kolbe in 1849.15 The well-known Kolbe-
electrolysis gives the dimer of two aliphatic carboxylic acids by
decarboxylation.15,16
Organic electrochemistry offers many advantages over
traditional, reagent-based reactions, because usual reagents are
oen toxic, costly and generate a lot of reagent waste. It solely
depends on electric current as a renewable, inexpensive and
inherently safe reagent.17
Therefore, organic electrochemistry attracted a lot of atten-
tion in the recent years,18 and especially electrochemical uo-
rination reactions proved to be powerful tools for
organouorine synthesis.19
aDepartment of Chemistry, Johannes Gutenberg University, Duesbergweg 10–14, 55128
Mainz, Germany. E-mail: waldvogel@uni-mainz.de; Web: http://www.chemie.uni-
mainz.de/OC/AK-Waldvogel/
bGraduate School of Natural Science and Technology, Okayama University, 700–8530
Okayama, Japan
cSano-Aventis Deutschland GmbH, 65926 Frankfurt am Main, Germany
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0sc02417a
Recently, we worked on the electrochemical synthesis of aryl
methoxymethyl ethers by electrochemical decarboxylation of
phenoxyacetic acids (Scheme 1).20 Furthermore, Baran could
‡ Contributed equally.
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Table 1 Parameter screening for optimisation of the electrochemical
fluorodecarboxylationa
demonstrate trapping carbocations generated by electro-
chemical decarboxylation of tertiary carboxylic acids. This way,
uorine has been introduced in few examples using KF/18-
crown-6 and AgClO4 as sacricial oxidant.21 That uo-
rodecarboxylation relies on silver(I) salts, which are known for
Hunsdiecker-type decarboxylations (see Scheme 1).12 In
contrast, we present a novel metal-free electrochemical uo-
rodecarboxylation of simply accessible aryloxyacetic acids22 to
uoromethyl aryl ethers by a pseudo-Kolbe pathway.
Entry
Fluoride source
1ab (%)
2ab (%)
1
2
3
KF + 18-crown-6 (3.0 equiv.)
KF + 18-crown-6 (5.0 equiv.)
CH2Cl2/Py$9HF (4 : 1)
0
0
0
30
26
7
Results and discussion
4
5
6
7
CH2Cl2/Et3N$3HF (4 : 1)
CH2Cl2/Et3N$5HF (4 : 1)
CH2Cl2/Et3N$5HF (3 : 2)
CH2Cl2/Et3N$5HF (9 : 1)
5 + KF + 18-crown-6 (1.0 equiv.)
CH2Cl2/Et3N$5HF (4 : 1)
CH2Cl2/Et3N$5HF (4 : 1)
CH2Cl2/Et3N$5HF (4 : 1)
CH2Cl2/Et3N$5HF (4 : 1)
CH2Cl2/Et3N$5HF (4 : 1)
CH2Cl2/Et3N$5HF (4 : 1)
32
0
26
0
4
6
33
25
46
45
0
0
58
0
52
53
50
7
4
0
0
54
The screening experiments were conducted in undivided cells
equipped with a simple two-electrode arrangement using
constant current conditions.23 Electrolyses were performed at
isostatic graphite electrodes (Cgr), a common anode material for
pseudo-Kolbe electrolyses. The conversion of 4-tert-butyl-
phenoxyacetic acid (1a) in dichloromethane with a substrate
concentration of 0.1 mol Lꢀ1 served as benchmark reaction for
optimisation studies. Various parameters and their inuence
on the reaction outcome like current density, applied charge,
different uoride sources and electrode materials were investi-
gated. Since the electrolyte system turned out to be the most
critical parameter, a selection of screening experiments is
shown in Table 1, additional screening experiments are
summarized in the ESI.† The yield of the optimisation experi-
ments was determined by 1H NMR using 1,3,5-trimethox-
ybenzene as internal standard (Table 1). With an applied charge
of 3 F, a current density of 5.5 mA cmꢀ2, potassium uoride (3.0
equiv.), 18-crown-6 (3.0 equiv.), 2,4,6-collidine (3.0 equiv.) in
a 0.1 M NBu4PF6 in dichloromethane (5 mL) it was possible to
generate the desired uorinated product 2a in 30% yield
(Table 1, entry 1). The control experiment without applied
current (no conversion of starting material) indicated, that the
anodic oxidation of the carboxylic acid is crucial for the
conversion of 1a. Furthermore, a control experiment without
adding a base demonstrated its signicance (no product
8
9c
10d
11e
12f
13g
14h
a
Reaction conditions: undivided cell, graphite electrodes, 4-tert-
butylphenoxy-acetic acid (0.5 mmol, 104 mg), CH2Cl2 (5 mL), 2,4,6-
collidine (3.0 equiv.), NBu4PF6 (0.1 M) as supporting electrolyte, j ¼
5.5 mA cmꢀ2, Q ¼ 3 F, T ¼ rt. Determined by 1H NMR using 1,3,5-
b
c
trimethoxybenzene (1.0 equiv.) as internal standard. Q ¼ 2.5 F.
d
e
f
g
2,4,6-Collidine (1.5 equiv.). Anode material: Pt. BDD. Glassy
h
carbon. Graphite foil. No supporting electrolyte necessary with
amine-HF as uoride source.
formation observed) for the reaction. Higher quantities of KF
did not increase the yield (Table 1, entry 2). Replacing 2,4,6-
collidine with DBU as base resulted in no product formation,
while the starting material was consumed during electrolysis.
However, the formation of Kolbe-type products was observed as
side reaction when KF was used as uoride source. Therefore,
other uoride sources such as amine uorides were tested.
Using Py$9HF (Table 1, entry 3) as uoride source, the Kolbe
reaction was completely suppressed, but the yield of 2a dropped
as well. With the use of triethylamine trihydrouoride (Et3-
N$3HF) also no product formation was observed. Yet, with
triethylamine pentahydrouoride (Et3N$5HF) as uoride
source, uoromethyl aryl ether 2a was obtained in 58% yield
with the starting material being completely consumed (Table 1,
entry 5). Therefore, the following experiments were conducted
with Et3N$5HF as uoride source. Neither higher Et3N$5HF
(CH2Cl2/Et3N$5HF, 3 : 2) nor lower amounts (9 : 1) increased
the yield of 2a. When the amount of amine-HF was raised even
higher (CH2Cl2/Et3N$5HF, 2 : 3), the graphite anode degraded
during electrolysis. Raising the uoride concentration by add-
ing KF also did not improve the yield, indicating that larger
quantities of uoride do not benet the reaction outcome
(Table 1, entry 8). In further optimisation studies, different
current densities, amounts of charge and anode materials were
tested. Both, with lower (2.8 mA cmꢀ2) and higher current
densities (11 mA cmꢀ2) the yield of the uorinated product 2a
(47% and 0%) decreased. For the oxidation of the carboxylic
Scheme 1 Conventional vs. electrochemical fluorodecarboxylation of
aryloxyacetic acids.
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acid 1a a theoretical charge of 2.0 F is needed, but lowering
the applied charge from 3.0 F to 2.5 F led to lower yields
(Table 1, entry 9). Lower quantities of 2,4,6-collidine decreased
the yield substantially (Table 1, entry 10). The use of platinum or
boron-doped diamond (BDD) as anode material lead to almost
no formation of product 2a (Table 1, entries 11 and 12). Also
using glassy carbon, another carbon allotrope close to graphite,
as anode did not give the desired product with almost half of the
starting material remaining non-converted upon electrolysis
(Table 1, entry 13). In contrast to that, graphite foil as anode
afforded the uorinated product 2a in 54% yield but did not
exceed previous results (Table 1, entry 14).
Finally, with an optimised electrolysis protocol, we explored
the scope of this reaction with various aryl moieties (Scheme 2).
The electrochemical uorodecarboxylation of phenoxyacetic
acid 1a at optimised conditions gave product 2a in 50% isolated
yield. An experiment with the a,a-dimethylated homologue of
2a did not provide the tertiary uoride, though it was antici-
pated that the resulting tertiary carbocation would stabilize the
oxocarbenium ion. Tertiary uorides might not be electro-
chemically stable (too ionizable) or undergo elimination reac-
tions. An additional methyl substituent in ortho-position
afforded the uorinated product 2b in 61% yield. Starting from
the para-nitro-substituted substrate gave uoromethoxy-
benzene 2c in 35% yield although nitro groups oen tend to
cathodic side reactions. With another methyl group in ortho-
position to the nitro group product 2d was obtained in 31%
yield.
Furthermore, the 4-bromo-substituted phenoxyacetic acid
gave the uorinated product 2e in 42%. The corresponding
thiophenoxyacetic acid gave an even higher yield with 59% of
uoromethyl aryl thioether 2f. With 4-cyano-phenoxyacetic acid
only 24% of the uorinated product 2g was obtained under
standard conditions. However, using graphite foil the yield of
uoromethyl aryl ether 2g could be increased to 32%. In
contrast, 4-methoxyphenoxyacetic acid did not show any
product formation either with isostatic graphite (Cgr) or with
graphite foil as electrodes. For the mechanism of this uo-
rodecarboxylation process we postulate
a pseudo-Kolbe
pathway24 (see ESI† for more information). Electron rich deriv-
atives are therefore prone to possible side reactions at acces-
sible ortho-positions. Blocking these positions should therefore
prevent side reactions. Accordingly, with an additional sterically
demanding tert-butyl-substituent in ortho-position, the uo-
rodecarboxylation gave 59% yield of derivative 2h. Further,
a phenoxyacetic acid bearing two tert-butyl substituents in meta-
position was tested giving 72% yield of uoromethyl aryl ether
2i. To demonstrate the scalability of our method, that electro-
synthesis was also performed on a 2.5 mmol scale and gave the
uorinated product 2i in 85% yield. Moreover, derivatives based
on natural products like chloro-substituted thymol and d-
tocopherol (vitamin E) were tested. In both cases, the electrol-
ysis with graphite foil was superior to isostatic graphite, giving
the uorinated thymol derivative 2j in 48% and the uorinated
d-tocopherol 2n in 21% yield. Even with nitrogen heterocycles
the uorodecarboxylation was successful. The uoromethoxy
pyrimidine 2l was afforded in 44% and pyrimidine 2m with a 2-
Scheme 2 Synthesis of monofluoromethoxy arene derivatives by
electrochemical fluorodecarboxylation. Standard reaction conditions:
undivided cell, graphite electrodes, aryloxyacetic acid (0.5 mmol),
CH2Cl2 (4 mL), Et3N$5HF (1 mL), 2,4,6-collidine (3.0 equiv), Q ¼ 3 F, j ¼
5.5 mA cmꢀ2, T ¼ rt. Yields refer to isolated product. a Yield determined
by 1H NMR using 1,3,5-trimethoxybenzene (1.0 equiv.) as internal
b
standard.
Electrolysis conducted with graphite foil as electrode
material. c Electrolysis conducted on 2.5 mmol scale.
uoromethoxy group in 34% yield, respectively. It was also
possible to generate uoro-ethoxypyridine 2n from the corre-
sponding propionic acid in 53% yield.
In addition to that, for uoromethoxyarenes 2o–2t NMR
yields up to 70% were achieved. However, due to their enhanced
volatility, these products are difficult to isolate, something that
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has been reported previously11 (see ESI† for more detailed
information).
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Conclusions
In summary, we established the rst synthesis of uoromethoxy
aryl ethers by electrochemical uorodecarboxylation of aryloxy-
acetic acids using electric current as traceless oxidant. It
enabled access towards a variety of uoromethoxyarenes. This
electrochemical protocol is very easy to conduct with a simple
9 Q. Lu, T. Benneche, J. Nielsen, C. Christophersen,
¨
R. Gawinecki, G. Hafelinger, M. N. Homsi, F. K. H. Kuske,
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patterns in yields up to 85%. The successful uorodecarbox-
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with an increase in yield expected in the distillative solvent
removal from the volatile uoromethyl ethers.
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Conflicts of interest
There are no conicts to declare.
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