Metal- and reagent-free highly selective anodic cross-coupling reaction of phenols

Article abstract of DOI:10.1002/anie.201400627

The direct oxidative cross-coupling of phenols is a very challenging transformation, as homo-coupling is usually strongly preferred. Electrochemical methods circumvent the use of oxidizing reagents or metal catalysts and are therefore highly attractive. Employing electrolytes with a high capacity for hydrogen bonding, such as methanol with formic acid or 1,1,1,3,3,3-hexafluoro-2- propanol, a direct electrolysis in an undivided cell provides mixed 2,2'-biphenols with high selectivity. This mild method tolerates a variety of moieties, for example, tert-butyl groups, which are not compatible with other strong electrophilic media but vital for later catalytic applications of the formed products. Current synthesis: In a highly sustainable access to mixed biphenols, electric current makes the use of reagents, catalysts, and leaving groups obsolete. Solvents with a strong tendency to act as hydrogen-bond donors lead to a unique selectivity for the cross-coupling product.

Full text of DOI:10.1002/anie.201400627

Angewandte
Chemie
DOI: 10.1002/anie.201400627
Oxidative Phenol Cross-Coupling Very Important Paper
Metal- and Reagent-Free Highly Selective Anodic Cross-Coupling
Reaction of Phenols
Bernd Elsler, Dieter Schollmeyer, Katrin Marie Dyballa, Robert Franke, and
Siegfried R. Waldvogel*
Abstract: The direct oxidative cross-coupling of phenols is
a very challenging transformation, as homo-coupling is usually
strongly preferred. Electrochemical methods circumvent the
use of oxidizing reagents or metal catalysts and are therefore
highly attractive. Employing electrolytes with a high capacity
for hydrogen bonding, such as methanol with formic acid or
1,1,1,3,3,3-hexafluoro-2-propanol, a direct electrolysis in an
undivided cell provides mixed 2,2’-biphenols with high selec-
tivity. This mild method tolerates a variety of moieties, for
example, tert-butyl groups, which are not compatible with other
strong electrophilic media but vital for later catalytic applica-
tions of the formed products.
on the nature of the substituents.[10] Therefore, universal
synthetic protocols for the coupling of substituted phenols are
highly significant.
A considerably improved atom economy results from the
direct oxidative coupling of arenes.[6,11] This excludes the
necessity of leaving functionalities and thus represents an
important breakthrough. A prior oxidation of one component
and subsequent coupling under strongly electrophilic con-
ditions provides access to a variety of biaryl derivatives.[12]
Unfortunately, most of the currently known and established
methods require very costly catalyst systems and produce
large quantities of reagent waste.
Electroorganic synthesis is an attractive method for the
formation of organic compounds,[13] including C C coupling
À
N
onsymmetrical biaryls are important structural units in
organic chemistry,[1] natural product synthesis,[2,3] molecular
reactions.[14] Because only electrons serve as reagent and the
employed carbon electrodes are of sustainable origin, electro-
chemistry complies with the conditions of “green chemis-
try”.[15] Direct electrochemical cross-coupling faces the chal-
lenge that the individual oxidation potential of the compo-
nents usually directs the selectivity. This results in a strong
predominance of homo-coupling products, whereas only
traces of the desired cross-coupling products are generated.
Recently, Yoshida et al. circumvented this dilemma with the
cation-pool method and established an elegant electroorganic
access to biaryls.[14d,16] So far, this method cannot be extended
to biphenols and is not scalable. Consequently, a direct
electrolysis to selectively afford the cross-coupled 2,2’-biphe-
nols is highly desirable. Here, we report the first cross-
coupling of phenol and naphthol derivatives without using
leaving functions, protecting groups, or reagents in an
undivided electrolysis cell (Scheme 1).
catalysis,[4] and material science.[5] C C cross-coupling reac-
À
tions provide highly versatile and applicable transformations
for their synthesis.[3,6] Typically, such coupling reactions
require leaving groups and complex catalysts that are often
based on toxic transition metals, for example, palladium.[7]
À
Selective functionalization of arenes by direct C H activation
is consequently one of the hot topics in contemporary organic
synthesis. A variety of efficient protocols for this modern
strategy have recently been developed, allowing a catalytic
approach to the active transition-metal species in the
presence of only one activated coupling partner.[8] C H
À
activation of one reaction partner can also be achieved by an
organocatalytic pathway.[9] In particular, 2,2’-dihydroxybiaryls
play an important role in ligand development for transition-
metal catalysis. They are widely employed as structural units
of sterically hindered diphosphate ligands for rhodium-
catalyzed hydroformylation, one of the largest homogene-
ously catalyzed reactions in industry. In general, these
phosphorous acid triesters are manufactured from substituted
biphenols. Their catalytic properties are strongly dependent
Boron-doped diamond (BDD) has recently attracted
considerable attention as a novel electrode material and is
readily available by chemical vapor deposition methods.[17]
Because of its unique electrochemical properties,[18] BDD
electrodes enable new synthetic strategies in electroorganic
synthesis.[19] Owing to the unusually high over-potentials for
oxygen evolution in protic media, the oxyl radicals are
directly generated with high efficiency.[20] These outstandingly
reactive spin centers are exploited in wastewater treatment or
constructive synthesis.[21] Fluorinated alcohols such as
[*] B. Elsler, Dr. D. Schollmeyer, Prof. Dr. S. R. Waldvogel
Institut fꢀr Organische Chemie
Johannes Gutenberg-Universitꢁt Mainz
Duesbergweg 10–14, 55128 Mainz (Germany)
E-mail: waldvogel@uni-mainz.de
Homepage: http//www.chemie.uni-mainz.de/OC/AK-Waldvogel/
Dr. K. M. Dyballa, Prof. Dr. R. Franke
Evonik Industries AG
Paul-Baumann-Straße 1, 45772 Marl (Germany)
Prof. Dr. R. Franke
Lehrstuhl fꢀr Theoretische Chemie, Ruhr-Universitꢁt Bochum
44780 Bochum (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400627.
Scheme 1. Direct anodic cross-coupling of phenols.
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1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) seem to have an
extraordinary stabilizing effect onto these intermediates,
avoiding mineralization of employed substrates.[22,23]
Recently, we found the first direct anodic phenol–arene
cross-coupling.[24] Both yields and selectivity were dramati-
cally enhanced when water or methanol were added to the
electrolyte.[25] Although an electrolyte-dominated process, the
best performance was achieved at BDD anodes. The
employed HFIP can be quantitatively recovered as this
alcohol exhibits outstanding electrochemical stability.[26]
Despite the fact that simple phenols tend to form wide
polycyclic scaffolds upon anodic treatment,[27] we were
pleased to find that this concept can be extended to the
cross-coupling of phenols.
In the previously studied phenol–arene cross-coupling,
guaiacol derivatives turned out to be suitable phenolic
components,[24,26] which form nonsymmetric homo-dehydro-
dimers in the absence of another coupling partner.[28] 4-
Methylguaiacol exhibits a lower oxidation potential and
therefore represents component A, which initiates the cross-
coupling sequence (see the Supporting Information). The
electrolysis was performed in an undivided cell with a BDD
anode and a nickel cathode. As an electrolyte, either HFIP or
HFIP/methanol were used in which methyltriethylammonium
methylsulfate was dissolved as a supporting electrolyte. The
scope of desired 2,2’-biphenols obtained through cross-
coupling of 4-methylguaiacol with simple phenols and the
variation in substitution patterns are displayed in Table 1. In
all examples except entry 10, no homo-coupling products of
Table 1: (Continued)
Entry
Cond.[c]
Product(s)
Yield[d]
50%
8
II
8
9a
9a
9b
39%
II[e]
9b
19%
52%
10[f]
I
I
10
11
12
11
12
36%
46%
I
13a
13b
13a
13b
61%
7%
I
Table 1: Scope of direct anodic phenol cross-coupling reactions.[a,b]
Entry
Cond.[c]
Product(s)
Yield[d]
14
I
14
63%
1
I
1
2
36%
[a] Electrolysis conditions: 508C, constant current (j=2.8 mAcmÀ2),
BDD anode, nickel-net cathode, undivided cell, Q=2 F·n(phenol A),
supporting electrolyte: 0.68 g Et3NMe O3SOMe. [b] Ratio of cross-
coupling product(s) AB to homo-coupling products AA or BB (deter-
mined by GC) is >100:1, with the exception of entry 10. [c] Solvent: I:
HFIP + 18 vol% MeOH; II: HFIP. [d] Yields of isolated products.
[e] BDD anode und cathode. [f] AB/BB=9:1.
2
3
I
I
39%
34%
3
4a
4b
5
4a
4b
5
21%
23%
52%
63%
52%
the individual components were detected. The electrochem-
ical protocol does not require blocking of all activated
positions. However, p-cresol provides the mixed 2,2’-biphenol
in 36% yield, while a larger alkyl substituent in position 4 of
component B provides similar yields of isolated products
(entries 1–3). It is noteworthy, that these products exhibit
a free and activated position 3. The products are readily
isolated despite the formation of some oligomeric material.
Using m-cresol as the phenolic component, B leads exclu-
sively to two different cross-coupling products (entry 4).
Because positions 4 and 6 of m-cresol are the more easily
accessible and activated positions, both coupling products are
found in almost equal amounts. The use of substrates with
sterically more demanding substituents not only enhances the
II
II
II
I
6
6
7
7
2
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yield, but exclusively provides the desired 2,2’-biphenol with
52% and 63% yield, respectively (entries 5 and 6). A 3,4-
disubstituted phenolic component B reliably provided the
cross-coupling products with yields higher than 50%
(entries 7–9). When bromo substituents were involved, the
coupling also occurred, accompanied by a partial dehaloge-
nation at the cathode. Interestingly, upon debromination 9b
was formed without any traces of the isomeric 9 (entry 9).
Consequently, bromo substituents can be removed without
a trace and can therefore be used in this transformation as
protecting groups. 2,4-Dimethylphenol also undergoes the
cross-coupling sequence with 52% yield (entry 10). Replacing
a methyl group either in ortho or para position by a tert-butyl
moiety results in the cross-coupling with lower yield, but
unique selectivity (entries 11 and 12). 2-Naphthols are also
suitable substrates for this electroorganic coupling. With 4-
methylguaiacol only cross-coupling products are found. The
desired 2,2’-dihydroxy biaryl 13a was isolated with a good
yield of 61%. From the electrolysis mixture 7% of an
isomeric structure was found (entry 13). Switching to a more
electron-rich substrate for A, led to the formation of a sole
cross-coupling product in 63% yield (entry 14). All structures
were thoroughly characterized and most of the described
compounds are new (see the Supporting Information). The
structural elucidation was verified by X-ray analysis of
suitable single crystals.
The use of formic acid instead of HFIP resulted in the
same exclusive selectivity for cross-coupling reactions, but the
yields for the respective 2,2’-dihydroxybiaryls were lower. The
reduced efficiency of the electroorganic cross-coupling can be
attributed to the significantly lower anodic stability of formic
acid. However, the low cost of this electrolyte and the direct
process still makes for a synthetically useful reaction con-
version, providing compound 13a with 45% yield (entry 3b)
and less negative environmental impact. Compared to tradi-
tional approaches to related mixed 2,2’-biphenols, the steps
for O protection and installation of leaving functionalities of
both compounds, the catalytic coupling, and the deprotection
can be cut short by a single electrolytic action.
Received: January 20, 2014
Published online: && &&, &&&&
À
Keywords: anodic biaryl synthesis · C C coupling ·
.
green chemistry · oxidative coupling · phenol cross-coupling
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36%
13%
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HCOOH +
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HFIP
HCOOH +
9 vol% MeOH
1
8
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Oxidative Phenol Cross-Coupling
B. Elsler, D. Schollmeyer, K. M. Dyballa,
R. Franke,
S. R. Waldvogel*
&&&& — &&&&
Metal- and Reagent-Free Highly Selective
Anodic Cross-Coupling Reaction of
Phenols
Current synthesis: In a highly sustainable
access to mixed biphenols, electric cur-
rent makes the use of reagents, catalysts,
and leaving functionalities obsolete. Sol-
vents with a strong tendency to act as
hydrogen-bond donors lead to a unique
selectivity for the cross-coupling product.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!