Direct Electrochemical Defluorinative Carboxylation of gem-Difluoroalkenes with Carbon Dioxide

Article abstract of DOI:10.1021/acs.orglett.0c03051

We report a facile and economical synthesis of α-fluoroacrylic acids via direct electrochemical defluorinative carboxylation of gem-difluoroalkenes with CO2. By using a platinum plate as the working cathode and a cheap nickel plate as the anode in a user-friendly undivided cell under constant current conditions, the reactions proceed smoothly under room temperature, without the use of expensive transition metal catalysts, ligands, external base or reductant, affording the desired adducts in up to 83% yield and 20:1 Z/E ratio, with good functional group tolerance. A cyclic voltammetry study was conducted and suggested a novel ECEC process.

Full text of DOI:10.1021/acs.orglett.0c03051

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Letter
Direct Electrochemical Defluorinative Carboxylation of gem-
Difluoroalkenes with Carbon Dioxide
Shi-Liang Xie, Xiao-Tong Gao, Hai-Hong Wu,* Feng Zhou,* and Jian Zhou
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ABSTRACT: We report a facile and economical synthesis of α-
fluoroacrylic acids via direct electrochemical defluorinative
carboxylation of gem-difluoroalkenes with CO2. By using a
platinum plate as the working cathode and a cheap nickel plate
as the anode in a user-friendly undivided cell under constant
current conditions, the reactions proceed smoothly under room
temperature, without the use of expensive transition metal
catalysts, ligands, external base or reductant, affording the desired
adducts in up to 83% yield and 20:1 Z/E ratio, with good functional group tolerance. A cyclic voltammetry study was conducted and
suggested a novel ECEC process.
sing CO2 as an abundant and renewable C1 resource to
value-added chemicals has attracted wide attention from
borocupration of alkene and subsequent β-F elimination gave
the alkenylboronate intermediate with a perfect Z-config-
uration, the subsequent carboxylation of which with CO2
delivered the desired α-fluoroacrylic acids with excellent Z-
selectivity. However, the use of 1.5−1.8 equiv of expensive
B2Pin2 and 3.0−3.5 equiv of LiOtBu compromised the
efficiency of this protocol because of the generation of
substantial of waste (Scheme 1b). In light of this, the
development of catalyst-, base-, and reductant-free defluor-
inative carboxylation of gem-difluoroalkenes with CO2, with
broad substrate scope under mild conditions, is still very much
in demand.
Nowadays, increasing attention has been paid to organic
synthetic electrochemistry, and electrochemical carboxylation
has become one of the most sustainable and efficient methods
for fixation of CO2 into organic compounds.10 By using
electricity as a driving force, it can overcome the inherent high
thermodynamic stability of CO2, thus avoiding the utilization
of expensive reducing chemicals and enable the reaction to be
performed under mild ambient conditions.11 Along with our
continual interest in chemical fixation of CO2,12 just recently
we realized an direct electrochemical γ-carboxylation of α-CF3
alkenes with CO2 under constant current conditions, in which
an opposite regiocontrol was observed for the corresponding
copper-catalyzed transformation.13 Encouraged by this re-
search, we envisioned whether the electrochemical defluor-
U
the viewpoint of resource utilization and environmental
protection.1 Over the past decade, more than 20 chemical
transformations with CO2 as a C1 resource have been realized,
among which the carboxylation of C−hetero bonds has been a
well-established method to synthesize carboxylic acids via a
C−X bond-breaking and C−C bond-forming process.2
However, C−F bond activation and transformation have
been largely undeveloped, probably due to the following
inherent difficulties.3,4 First, the C−F bond is the strongest
covalent single bond that carbon can form, possessing high
thermodynamic stability; second, the fluoride in C−F bond is
neither a good Lewis base nor a good leaving group, the
activation of which is kinetically unfavorable. On the other
hand, fluorinated carboxylic acids, in particular α-fluoracrylic
acids, represent an important class of structural motifs widely
existing in pharmaceuticals and bioactive compounds.5
Although a number of synthetic routes to α-fluoracrylic acids
have been reported,6 the defluorinative carboxylation of gem-
difluoroalkenes with CO2 represents one of the most
straightforward strategies, but only a limited number of
processes have been developed with the current state-of-the-
art represented by the photocatalysis and metal catalysis.7−9
In 2019, Feng and co-workers pioneered a dual catalytic
system involving Ir-based photocatalyst and Pd-based co-
catalyst, enabling the selective C−F bond carboxylation of gem-
difluoroalkenes with CO2 efficiently to afford a wide range of
α-fluoroacrylic acids in good to excellent yields with the
utilization of 3.0 equiv of iPi2NEt and Cs2CO3. Of 24 examples
examined, only six gave more than a 90:10 Z/E ratio (Scheme
1a).7 Shortly thereafter, copper-catalyzed formal carboxylation
of fluorinated alkenes with CO2 was realized by Yu8 and our
group,9 independently. It was demonstrated that the
Received: September 12, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03051
© XXXX American Chemical Society
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A

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inative carboxylation of gem-difluoroalkenes with CO2 could
constitute a direct and facile entry to α-fluoroacrylic acids.
Accordingly, it could be performed free of external expensive
transition-metal catalysts, ligands, excessive reductants, or
bases, thus possessing higher atomic economy. In addition,
the milder reaction condition should enable a better functional
group compatibility. Herein, we report our preliminary results
on this research work (Scheme 1c).
Scheme 1. C−F Bond Carboxylation of gem-Difluoroalkenes
We started our research by evaluating the electrochemical
carboxylation of 2-(2,2-difluorovinyl)naphthalene (1a) with
CO2 as shown in Table 1. Initially, constant current electrolysis
(8 mA) of 1a with bubbling CO2 in an undivided cell equipped
with a Pt plate as cathode and anode at room temperature
could give α-fluoroacrylic acid (2a′) in 24% yield with
excellent Z selectivity (entry 1). Considering that the
utilization of the nonsacrificial Pt-plate anode might result
the undesired oxidation of starting material or carbonate
product, we focused our efforts on using cheap metal as the
sacrificial anode. To our delight, when the Pt-plate was
changed to Mg-, Al-, or Ni-sheet as the anode material, the
reaction yield increased gradually to 48%, 32%, and 60%,
respectively (entries 2−4). Then the influence of cathode
materials on the transformation was studied with an Ni-sheet
as anode. Graphite rod and RVC were noneffective for this
carboxylation, and glassy carbon gave an inferior result
compared to that of the Pt-plate (entries 5−7 vs 4).
Considering that the oxidized nickel might plate out into the
cathode, the utilization of a Ni-plate as cathode was also
attempted, with only 35% yield received (entry 8). Fortunately,
when the reaction time was reduced to 4.5 h, with a total
charge of 6.7 Faraday/mol, 75% NMR yield could be achieved,
with the methyl esterification product 2a obtained in 71%
a
Table 1. Optimization of Reaction Conditions.
b
entry
anode
cathode
electrolyte
solvent
Z (mA)
time (h)
yield (%)
1
Pt
Pt
Pt
Pt
Pt
C
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NBr
nBu4NBF4
nBu4NClO4
Et4NI
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
NMP
CH3CN
8
8
5.5
5.5
5.5
5.5
5.5
5.5
5.5
5.5
4.5
3.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
24
2
Mg
Al
48
3
8
32
4
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
8
60
5
8
trace
trace
53
6
RVC
GC
Ni
Pt
Pt
Pt
Pt
Pt
Pt
Pt
Pt
Pt
Pt
Pt
8
7
8
8
8
35
c
9
8
75 (71)
10
11
12
13
14
15
16
17
18
19
8
58
34
34
13
27
60
39
59
39
43
8
8
8
8
6
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
10
8
8
8
a
b
Reaction conditions: electrolyte (0.07 M), solvent (7 mL), undivided cell, rt. Determined by 19F NMR with p-MeOC6H4CF3 as internal
c
standard. Isolated yield of methyl esterification product 2a. GC (glassy carbon).
B
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isolated yield (entry 9). The choice of supporting electrolyte
reactivity to give the carboxylate products 2e−p in moderate
to high yields. The location of the substituents on the phenyl
ring also has a negligible influence on the reaction. For
instance, the reaction of isomeric substrates with an ester or
CF3 group at the para-, meta-, or ortho-position worked well to
give the corresponding products 2f,g and 2k−n in similarly
moderate to good yields. Notably, for substrates bearing
different sp2 or sp3 C−F bonds, the defluorinative carbox-
ylation occurred exclusively at the gem-difluoroalkene position,
with the Ar−F, CF3, or OCF3 moiety remaining untouched.
Apart from β-aryl-substituted gem-difluoroalkenes, substrates
possessing a β-alkenyl or alkynyl moiety were also competent
in this reaction, producing 2q−s in 35%, 58%, and 50% yield,
respectively. The reaction of tetrasubstituted alkene 1t was
further conducted, affording the corresponding product 2t in
55% yield. These results clearly demonstrated the good
tolerance of our method. Notably, the reaction could be
scaled up to gram scale, as demonstrated by the electro-
carboxylation of 6 mmol of 1a, with 62% yield obtained (for
details, see the SI).
also has a crucial influence on the reaction. When the
n
n
n
electrolyte was changed from Bu4NI to Bu4NBr, Bu4NBF4,
nBu4NClO4, or Et4NI, the reaction yield decreased in different
degrees (entries 11−14). Reducing the current to 6 mA gave a
lower 60% yield due to incomplete reaction, but increasing the
current to 10 mA led to a dramatic decrease of the reaction
yield (entries 15 and 16). The solvent effect was also evaluated,
but no better results than that of DMF were obtained (entries
17−19).
Based on the outcome of the condition screening, we
decided to evaluate the substrate scope by performing the
n
reaction in DMF containing Bu4NI using constant current of
8 mA in an undivided cell with CO2 bubbling and a Ni-sheet as
anode and a Pt-plate as cathode at room temperature. To
facilitate product isolation and analysis, the original carboxylic
acid was converted to the corresponding methyl ester.
At first, the performance of alkenes containing fused
aromatics was evaluated (Scheme 2). The reaction of 1-
a
The thus obtained α-fluoroacrylic acids could be easily
elaborated to other valuable fluorinated compounds, further
demonstrating the synthetic utility of this electrochemical
defluorinative carboxylation. For instance, the reduction of
carboxyl moiety with LiAlH4 gave alcohol 3 in 83% yield. In
addition, the TFA catalyzed [3 + 2] cycloaddition could deliver
the 3-fluoropyrrolidine derivate 4 in 82% yield (Scheme 3).
Scheme 2. Electrocarboxylation of gem-Difluoroalkenes
Scheme 3. Synthetic Elaboration of 2a
To gain more insight into the reaction mechanism, cyclic
voltammetry (CV) analysis were conducted (Figure 1).14 For
a
Isolated yield, with Z/E ratio determined by 19F NMR study of
reaction mixture.
naphthyl or 2-benzothiophene substituted gem-difluoroalkene
could deliver the desired products 2b and 2c in 74% and 60%
yield, respectively, with a Z-configuration. However, for the
carboxylation of 1d possessing a 3-benzothiophene moiety, 2d
was obtained in only 45% yield with a reversed E/Z selectivity.
The reason why for this phenomenon is still unclear.
Then the influence of the substituents on the phenyl ring of
2-aryl-1,1-difluoroalkenes was investigated. Substrates bearing
a variety of functional groups, such as phenyl, ester, amide,
sulfuryl, cyano, fluoro, CF3, or OCF3, all showed good
Figure 1. CV analysis of 1f.
the CV of gem-difluoroalkene 1f, a one-electron reduction peak
at the potential of −2.7 V and the second one at −3.0 V was
observed (blue line, c). Notably, at a potential of −2.7 V, the
reduction current of CO2 is significantly lower than that of 1f
(0.15 vs 0.6 mA), which indicated that the latter was much
easier to be reduced. When CO2 was introduced into the
C
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solution of 1f, only one reduction peak at −3.09 V was
observed with the peak current increased greatly to 1.36 mA,
indicating a fast interaction of the one-electron reduction
species with CO2. Meanwhile, the doubled peak current
suggested that the electrochemical reduction of the gem-
difluoroalkenes with CO2 at a cathode might be a two-times
one-electron reduction process.
Based on CV experiments, along with previous literature
reports,15 a putative ECEC16 reaction mechanism was
proposed as shown in Figure 2. First, a one-electron reduction
AUTHOR INFORMATION
Corresponding Authors
■
Hai-Hong Wu − Shanghai Key Laboratory of Green Chemistry
and Chemical Process and Shanghai Engineering Research
Center of Molecular Therapeutics and New Drug Development,
East China Normal University, Shanghai 200062, China;
orcid.org/0000-0001-6266-8290; Email: hhwu@
chem.ecnu.edu.cn
Feng Zhou − Shanghai Key Laboratory of Green Chemistry and
Chemical Process and Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, East
China Normal University, Shanghai 200062, China;
orcid.org/0000-0002-6729-1311; Email: fzhou@
chem.ecnu.edu.cn
Authors
Shi-Liang Xie − Shanghai Key Laboratory of Green Chemistry
and Chemical Process, East China Normal University, Shanghai
200062, China
Xiao-Tong Gao − Shanghai Key Laboratory of Green Chemistry
and Chemical Process, East China Normal University, Shanghai
200062, China
Jian Zhou − Shanghai Key Laboratory of Green Chemistry and
Chemical Process and Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, East
China Normal University, Shanghai 200062, China; State Key
Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Shanghai 200032, China; orcid.org/
0000-0003-0679-6735
Figure 2. Proposed reaction mechanism.
of gem-difluoroalkene on the cathode generated a radical anion
A, followed by a quick selective fixation of CO2 at
difluorocarbon to give intermediate B. Then a secondary
one-electron reduction of B and the subsequent defluorination
delivered the carboxylate anion C, which was developed to be
their salt forms by capturing Ni ion formed at the anode.
Finally, the acidification gave the target α-fluoroacrylic acid.
On the basis of electrochemistry, a facile and economical
direct defluorinative carboxylation of gem-difluoroalkenes with
CO2 is developed. The reaction is performed with Pt-plate as
working cathode and cheap Ni-sheet as anode, under
continuous current electrolysis. The aryl-, alkenyl-, and
alkynyl-substituted gem-difluoroalkenes are all viable substrates
to give the structurally diverse α-fluoroacrylic acids in up to
83% yield and 20/1 Z/E ratio under mild room temperature.
The synthetic utility is further demonstrated by the elaboration
to fluorinated alcohol and heterocyclic compound. CV analysis
reveals that a ECEC (single-electron reduction, reaction with
CO2, single-electron reduction, loss of fluoride) process should
be involved, which is novel and totally different from the
photoredox/Pd- and Cu-catalyzed pathway. Considering that
both CO2 and hydrofluorocarbons are recognized to be
greenhouse gases,17 this study on electrochemical defluor-
inative carboxylation should also be meaningful to green and
sustainable chemistry. Further developments of CO2-incorpo-
rating transformations with the help of electrochemistry to
value-added chemicals are in progress.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03051
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from NSFC (21871090), the Ministry of
Education (PCSIRT), and the Fundamental Research Funds
for the Central Universities is greatly appreciated.
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Experimental procedures, characterization data, and
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