2,2′-Biaryldicarboxylate Synthesis via Electrocatalytic Dehydrogenative C-H/C-H Coupling of Benzoic Acids

Article abstract of DOI:10.1021/acscatal.1c01127

2,2′-Biaryldicarboxylates are important functionalities in bioactive compounds, functional materials, and chiral catalysts. These compounds have been found to be conveniently accessible from benzoic acids via Rh-catalyzed electrooxidative C-H/C-H couplings, giving valuable dihydrogen as the byproduct. In an undivided cell with Pt electrodes, RhCl3·3H2O catalyzes the oxidative carboxylate-directed ortho-homocoupling of various aromatic acids with a current efficiency of 67%. The protocol is operationally simple, tolerates a wide variety of functional groups, and does not require the exclusion of air and moisture. Heterodimerizations via cross-dehydrogenative couplings of naphthyl-1-carboxylic acids with acrylic or benzoic acids were also shown to work.

Full text of DOI:10.1021/acscatal.1c01127

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Letter
2,2′-Biaryldicarboxylate Synthesis via Electrocatalytic
Dehydrogenative C−H/C−H Coupling of Benzoic Acids
Zhongyi Zeng, Jonas F. Goebel, Xianming Liu, and Lukas J. Gooßen*
Cite This: ACS Catal. 2021, 11, 6626−6632
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ABSTRACT: 2,2′-Biaryldicarboxylates are important functional-
ities in bioactive compounds, functional materials, and chiral
catalysts. These compounds have been found to be conveniently
accessible from benzoic acids via Rh-catalyzed electrooxidative C−
H/C−H couplings, giving valuable dihydrogen as the byproduct.
In an undivided cell with Pt electrodes, RhCl3·3H2O catalyzes the
oxidative carboxylate-directed ortho-homocoupling of various
aromatic acids with a current efficiency of 67%. The protocol is
operationally simple, tolerates a wide variety of functional groups, and does not require the exclusion of air and moisture.
Heterodimerizations via cross-dehydrogenative couplings of naphthyl-1-carboxylic acids with acrylic or benzoic acids were also
shown to work.
KEYWORDS: electrooxidation, rhodium catalysis, C−H/C−H coupling, carboxylic acids, biaryl synthesis
Scheme 2. Mechanistic Blueprint for the Target Reaction
ross-dehydrogenative couplings involving the activation
Cof two aromatic C−H bonds with release of dihydrogen
Scheme 1. Biaryl Syntheses by C−H/C−H Coupling
electronic or steric factors alone are possible for only few
(hetero)aromatic substrates.2 Alternatively, strongly coordinat-
are arguably the most desirable synthetic entries to biaryl
moieties because no prefunctionalization of aromatic feed-
stocks is required.1 However, the high atom and step economy
of the coupling step is often offset by a stoichiometric use of
metal oxidants, usually Ag, Cu, or Mn salts in combination
with elaborate transition metal catalysts. Thus, stoichiometric
metal hydroxide waste is released rather than valuable
hydrogen. Moreover, regioselective couplings based on
Received: March 11, 2021
Revised: April 16, 2021
Published: May 21, 2021
https://doi.org/10.1021/acscatal.1c01127
© 2021 American Chemical Society
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Letter
a
Table 1. Optimization of the C−H/C−H Homocoupling
no.
catalyst
solvent
electrode
conv. (%)
2a (%)
1
2
3
4
5
6
7
8
[Cp*IrCl2]2
Pd(OAc)2
[RuCl2(p-cym)]2
[Rh(cod)Cl]2
Rh2(OAc)4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMAc
DMSO
nBuOH
Pt(+)||Pt(−)
Pt(+)||Pt(−)
Pt(+)||Pt(−)
Pt(+)||Pt(−)
Pt(+)||Pt(−)
Pt(+)||Pt(−)
Pt(+)||Pt(−)
Pt(+)||Pt(−)
Ni(+)||Pt(−)
graphite(+)||Pt(−)
RVC(+)||Pt(−)
Pt(+)||steel(−)
Pt(+)||Pt(−)
Pt(+)||Pt(−)
Pt(+)||Pt(−)
46
35
60
>95
83
<5
<5
39
81
71
69
71
87 (77)
6
26
Rh(OAc)3
75
[Cp*RhCl2]2
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
RhCl3·3H2O
>95
>95
70
>95
49
>95
77
33
9
10
11
12
13
14
15
38
78
72
18
42
24
further variation from optimal condition (entry 8)
16
17
18
19
20
21
22
23
24
25
26
27
28
3 mol % RhCl3·3H2O
91
9
74
trace
86
78
86
n
nBu4NPF6 instead of Bu4NOAc
n
KOAc instead of Bu4NOAc
>95
>95
>95
89
18
<5
36
42
>95
>95
53
electrolysis at 3.0 mA
electrolysis at 0.5 mA
run at 60 °C
no electricity
66
<5
trace
15
19
65
no RhCl3·3H2O
O2 (balloon) instead of electricity
NaClO2 (2 equiv) instead of electricity
Ag2CO3 (2 equiv) instead of electricity
MnO2 (2 equiv) instead of electricity
CuO (2 equiv) instead of electricity
60
39
a
Conditions: 0.50 mmol 1a, 7 mol % catalyst, 0.5 mmol electrolyte, 8.0 mL solvent, undivided cell with 1 cm × 2 cm electrodes, constant current of
1.0 mA (ca. 1.5 F·mol−1), 80 °C, 20 h. Conversions and yields were determined by GC after esterification with methyl iodide using n-tetradecane as
an internal standard. Isolated yield of the free acid 2a in parentheses. Cp*, 1,2,3,4,5-pentamethylcyclopenta-1,3-diene; DMF, N,N-
dimethylformamide; DMAc, dimethylacetamide; DMSO, dimethyl sulfoxide; RVC, reticulated vitreous carbon.
ing mono- or bidentate functional groups are often required to
direct transition-metal mediated C−H/C−H coupling into
specific positions, usually ortho to the directing groups
(Scheme 1A).3
acting as directing groups, they can be removed tracelessly by
protodecarboxylation or serve as leaving groups in decarbox-
ylative cross-couplings.6 However, in comparison to pyridyl
groups, they coordinate only weakly, which makes the
development of catalytic reactions based on directed C−H
metalations more difficult. Their use in electrochemical
reactions is further complicated by their electrostatic attraction
to the anode and tendency to undergo electrodecarboxylative
couplings of the Kolbe or Hofer-Moest type.7 Nevertheless,
several ortho-C−H functionalizations of carboxylates have been
transferred successfully from metallic oxidants to electro-
oxidative protocols, for example, oxidative annulations8 and
Heck-type reactions.9 In this context, Ackermann et al. showed
that benzoic acids undergo electrochemical alkenylations in the
presence of alkyl acrylates.9
The use of an electric current as an inexpensive and waste-
free oxidant has opened up a window of opportunities for the
development of sustainable C−H functionalization reactions.4
On the basis of pioneering work by Amatore and Jutand, Mei,
and others,5 Kakiuchi et al. showcased the feasibility of
electrooxidative biaryl synthesis with a palladium-catalyzed
homocoupling of arylpyridines. However, this innovative
reaction could be conducted only within a divided cell setup
in the presence of stoichiometric iodine (Scheme 1B).5f The
necessity of using strongly coordinating pyridyl directing
groups, which are hard to install and remove, further limits its
practical utility.
Our plan was to develop a biaryl synthesis based on a
carboxylate-directed electrocatalytic dehydrogenative coupling
(Scheme 1C). This reaction is of considerable preparative
utility, since 2,2′-biaryldicarboxylates are valuable synthetic
Carboxylate groups represent some of the most desirable
directing groups for C−H functionalization, since carboxylic
acids are widely accessible in great structural variety. After
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a
Table 2. Scope of the C−H/C−H Homocoupling
a
n
Conditions: 0.50 mmol 1, 7 mol % RhCl3·3H2O, 0.5 mmol Bu4NOAc, 8.0 mL DMF, undivided cell with two Pt electrodes (each 1 × 2 cm2),
constant current of 1.0 mA (ca. 1.5 F·mol−1), 80 °C, 20 h under air; isolated yields of methyl esters 2′ after esterification with methyl iodide.
b
c
d
e
f
Isolated as free acid. 10 mol % RhCl3·3H2O. 15 mol % RhCl3·3H2O. GC yield with n-tetradecane as an internal standard. <5% of double
g
arylation. 10 mol % RhCl3·3H2O at 90 °C.
documented, for example, for Pd, Ir, and Rh complexes.13
A
Scheme 3. Scale-up Reaction
follow-up C−H activation of a second carboxylate leading to a
diaryl species such as C is not unprecedented3k−n but still a
major challenge, since the first metal−carbon bond reduces its
electrophilic reactivity. One possible pathway consists of
protonolysis of the M−O bond in the metallacycle by a
second carboxylate, followed by its chelation-controlled C−H
activation. Alternatively, dinuclear pathways in which carbox-
ylate-bridged complexes exchange bridging carboxylate ligands
with formation of C also seemed possible.14 Reductive
elimination would liberate the biaryl product from C.
Reoxidation of the catalyst D to A would take place at the
anode, while at the cathode, the hydrogen byproduct is
generated.
hubs en route to bioactive compounds and natural products,10
functional materials,11 as well as C2-symmetric chiral ligands/
catalysts.12 Our mechanistic blueprint for such a reaction is
shown in Scheme 2.
In our search for an effective catalyst system for the outlined
electrooxidative coupling, we chose the homocoupling of 2-
toluic acid (1a) as a model reaction (Table 1). Various catalyst
In the first step, one of the carboxylates directs an
electrophilic metal catalyst A toward its ortho-C−H bond,
which breaks with formation of metallacycle B. This step is
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a
Table 3. Scope of the Cross-Dehydrogenative Coupling
Scheme 4. Mechanistic Investigations
a
Conditions: see Table 2 with 2.0 equiv of nBu4NOAc; isolated yields
n
solvents such as DMSO, BuOH, HFIP, water, or acetonitrile
gave only unsatisfactory yields (entries 13−15 and Table S1).
The presence of acetate in the electrolyte is essential (entries
17, 18). This is in line with findings by Ackermann et al., who
propose a base-assisted electrophilic process for carboxylate-
directed C−H rhodation.9a The reaction proceeds best at a
temperature of 80 °C and current densities between 0.5 and
3.0 mA (entries 19−21). Exclusion of air and moisture is not
required. Control experiments confirmed that a Rh catalyst is
necessary and that oxygen and overstoichiometric oxidants are
less effective than electrochemical oxidation. The electro-
oxidative process has an excellent current efficiency of 67%,
which underlines the sustainability of the overall process.
We next investigated the scope of the optimized protocol. As
can be seen from the examples in Table 2, it is widely
applicable to both electron-rich and electron-deficient benzoic
acids, bearing substituents in the ortho, meta, or para position.
The products were isolated after conversion into their esters to
simplify chromatographic purification. The functional group
of the corresponding methyl esters 4′ or 5′ after esterification with
b
methyl iodide. 1.0 equiv of nBu4NOAc; yields in parentheses
obtained with 5 mol % [Cp*RhCl2]2.
metals were investigated in an undivided cell equipped with Pt
electrodes. With Ir, Ru, and Pd complexes, unsatisfactory yields
were obtained (entries 1−3), while Rh complexes gave
promising results (entries 4−8). We were pleased to find
that simple RhCl3·3H2O was effective even at a loading of 3
mol % (entry 16). This is remarkable, as its use in
electrochemical couplings has not yet been reported.15 Several
anode materials, for example, nickel, graphite, and reticulated
vitreous carbon (RVC), were investigated, and the best results
were obtained with Pt (entries 9−11). As the cathode, Pt and
stainless steel worked similarly well (entries 8, 12), while other
materials were less effective. Amides, in particular DMF, were
found to be the optimal solvents, whereas other common
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To probe the viability of our mechanistic blueprint, we
performed a series of mechanistic studies. Conducting the
reaction in the presence of D2O led to deuterated products,
which point toward a rapid, reversible C−H metalation step
(Scheme 4A). This was not observed for acrylic acids, which
support a C−H alkenylation/oxa-Michael addition sequence,
and rules out a cross-dehydrogenative coupling route for the
acrylate cross-couplings. A negligible isotope effect for
deuterated substrate confirmed that neither of the two C−H
activation steps is rate determining (Scheme 4B). This explains
why it is so difficult to achieve selectivity in cross-couplings.
The reaction rates correlate with the electric current densities,
showing that the regeneration of the RhIII catalyst is rate-
determining (Scheme 4D).
When conducting the reaction in the absence of electricity,
the amount of product corresponded to the amount of Rh
catalyst (entry 22, Table 1). With Rh(OAc)3, the stoichio-
metric reaction gave 51% yield (Scheme 4C). This suggests
that the reaction starts from RhIII without an upfront oxidation
step. In cyclic voltammetry, two reduction peaks of RhCl3·
3H2O were observed at −0.50 and −1.10 V (curve c), which
confirms that the RhIII salt is easily reduced to RhII and/or RhI,
but that an oxidation to RhIV and/or RhV is difficult under the
Figure 1. Cyclic voltammograms using glassy carbon electrode, scan
rate: 100 mV/s, 10 mM 1a, 0.1 M Bu4NPF6, 0.1 M Bu4NOAc, 5
mM RhCl3·3H2O.
n
n
tolerance of the process is remarkable. It includes ether (2g,
2h, 2y), ester (2l, 2q, 2ad, 2ai), keto (2j, 2k, 2ab), cyano
(2ag), sulfonyl (2ae), amino (2o), fluoroalkyl (2m),
fluoroalkoxy (2i, 2z, 2aa), and fluoroalkylthio groups (2p).
Oxidation-sensitive formyl groups (2ac) and easily reduced
nitro groups (2r, 2af) are tolerated. Compounds bearing
chloro (2e), bromo (2f), iodo (2x), and even SO2F (2s)
groups were selectively coupled, demonstrating the orthogon-
ality of this process to traditional cross-couplings.
Competing double arylation was observed in significant
amounts only for unsubstituted benzoic acid (product 3t). Any
substituent seems to effectively suppress unwanted double
arylation (2n−2ag). 3-Substituted benzoic acids as well as 2-
naphthoic acid underwent selective coupling in the less-
hindered position. Multisubstituted and fused benzoic acids
were also successfully coupled (2ah−2at), as were several
heterocyclic acids (2au−2ax). In some cases, for example, 2h,
2r, and 2ag, less than 5% yields of final ortho-C−H
methoxylated products were observed, which probably result
from the ortho-C−H hydroxylation16 of benzoic acids with air
and subsequent etherification by reaction with methyl iodide.
The electrooxidative coupling was successfully performed on
multigram scale with 3% catalyst loading (Scheme 3). The
diacid 2a was obtained in high purity after recrystallization,
which underlines the scalability of the reaction.
We went on to investigate whether selective electrocatalytic
dehydrogenative cross-coupling could be achieved for mixtures
of two different aromatic carboxylates (Table 3). Since 1-
naphthoic acids had reacted rather slowly in homodimeriza-
tions, we investigated their cross-coupling with more reactive
acids. Indeed, moderate yields and reasonable selectivities were
achieved in cross-dimerizations with benzoic acids (4a−4h).
Attempts to achieve selectivity in the coupling of electron-rich
with electron-deficient benzoic acids gave close to statistical
product mixtures (4i). Cross-couplings with vinylcarboxylates
resulted in the formation of lactones. The lactonization is a
typical follow-up reaction in α-vinylations of benzoic acids
(5a−5c), which itself could result from a C−H alkenylation/
oxa-Michael addition sequence, or a cross-dehydrogenative
coupling. In this reaction, [Cp*RhCl2]2 gave higher yields than
RhCl3·3H2O, which points toward a shift in the mechanistic
pathway.
n
reaction conditions (Figure 1). Adding Bu4NOAc to RhCl3·
3H2O showed a broad reduction peak, which may result from
carboxylate-bridged oligonuclear species (curve d). This
system displayed a large oxidation peak at +1.35 V, which
may be explained with the oxidation of the acetate (curve b).
All findings support the pathway proposed in Scheme 2.
In conclusion, the newly developed electrocatalytic dehy-
drogenative C−H/C−H coupling allows generating various
biaryl dicarboxylates under mild conditions. The reaction is
operationally simple and easily scalable, has an excellent
functional group compatibility, and is orthogonal to common
cross-coupling strategies.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c01127.
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General information, experimental details, spectra data,
copies of NMR spectra for all final products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Lukas J. Gooßen − Fakultät Chemie und Biochemie, Ruhr
Universität Bochum, 44801 Bochum, Germany;
orcid.org/0000-0002-2547-3037;
Email: lukas.goossen@rub.de
Authors
Zhongyi Zeng − Fakultät Chemie und Biochemie, Ruhr
Universität Bochum, 44801 Bochum, Germany
Jonas F. Goebel − Fakultät Chemie und Biochemie, Ruhr
Universität Bochum, 44801 Bochum, Germany
Xianming Liu − Fakultät Chemie und Biochemie, Ruhr
Universität Bochum, 44801 Bochum, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c01127
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Funded by the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation) under Germany’s Excellence
Strategy − EXC-2033−390677874 − RESOLV, SFB TRR88
“3MET”, and FOR 982/1 “UNODE”. We thank BMBF and
the state of NRW (Center of Solvation Science “ZEMOS”).
We thank UMICORE for donating chemicals; Z. Hu, T. van
́
Lingen, A. M. Martínez, M. Dyga, and N. Sivendran for helpful
discussions; and M. Wustefeld for HRMS measurements.
̈
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