Anodic coupling of guaiacol derivatives on boron-doped diamond electrodes

Article abstract of DOI:10.1021/ol201030g

The anodic treatment of guaiacol derivatives on boron-doped diamond electrodes (BDD) provides a direct access to nonsymmetrical biphenols, which would require a multistep sequence by conventional methods. Despite the destructive nature of BDD anodes they

Full text of DOI:10.1021/ol201030g

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3126–3129
Anodic Coupling of Guaiacol Derivatives
on Boron-Doped Diamond Electrodes
Axel Kirste,† Gregor Schnakenburg,§ and Siegfried R. Waldvogel*,†,‡
ꢀ
Kekule Institute for Organic Chemistry and Biochemistry, Bonn University,
Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany, Institute for Organic Chemistry,
Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany,
and X-ray Analysis Department, Institute for Inorganic Chemistry, Bonn University,
Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany
waldvogel@uni-mainz.de
Received April 18, 2011
ABSTRACT
The anodic treatment of guaiacol derivatives on boron-doped diamond electrodes (BDD) provides a direct access to nonsymmetrical biphenols,
which would require a multistep sequence by conventional methods. Despite the destructive nature of BDD anodes they can be exploited for
chemical synthesis.
The cross-coupling reaction to nonsymmetrical biaryls
represents a very versatile and synthetically useful trans-
formation.1 This method for C,C bond formation belongs
to the standard repertoire in natural product synthesis,2
molecular catalysis,3 and material science.4 In general,
such conversions rely on traditional leaving groups, and
toxic transition metal catalysts based, e.g., on palladium.5ꢀ10
More recent approaches exploit that a catalytically active
transition metal species allows C,H activation on one
reaction partner and accomplishes the C,C bond forma-
tion by a common cross-coupling step.11 Activation of the
reaction partner can also be performed by an organo-
catalytic protocol.12 A direct oxidative cross-coupling of
arenes without the use of leaving functionalities is a cutting
edge concept and is very attractive in terms of atom
economy.13 Electrochemical transformations exhibit an
†
ꢀ
Kekule Institute for Organic Chemistry and Biochemistry, Bonn
University.
§ X-ray Analysis Department, Institute for Inorganic Chemistry, Bonn
University.
‡ Johannes Gutenberg University Mainz.
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Transition metals for organic synthesis: Building blocks and fine chemicals,
2nd rev. and enl. ed.; Wiley-VCH: Weinheim, Chichester, 2004. (d) Zapf, A.;
Beller, M. Top. Catal. 2002, 19, 101–109. (e) Hassan, J.; Sevignon, M.;
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10.1021/ol201030g
Published on Web 05/24/2011
2011 American Chemical Society

chemoselectivity of this unusual coupling reaction is based
on the preferential formation of oxyl spin centers on BDD
electrodes (Figure 1).22
Guaiacol derivatives occur abundantly in nature. Many
plants, e.g. the guaiac tree, contain these phenolic compounds
such as vanillin, syringic aldehyde, eugenol, or syringol (6) in
significant amounts. The biopolymer lignin represents the
largest renewable source for aromatic compounds and pro-
vides these guaiacol derivatives in huge quantities upon
oxidative treatment.23 They represent the future feedstock
for a sustainable arene chemistry. Consequently, the chem-
istry of these phenols will be of particular interest for future
applications.
Figure 1. Mode of action for BDD anodes in aqueous or
alcoholic media.
outstanding ecological and economical attractiveness
since only electrons are employed as reagents. Conse-
quently, reagent waste is avoided.14 Oxidative synthesis of
biphenols often results in the formation of the homocou-
pling product.15 Recently, we found that the boron-doped
diamond (BDD) as a very appealing innovative electrode
material which can be used for the conversion of a broad
scope of phenolic substrates to symmetrical biphenols.16,17
The addition of fluorinated alcohols significantly reduces
the oxidative degradation of the substrates and products.
Furthermore, the additive allows the conversion of solid
substrates18 and suppresses the formation of complex
molecular architectures.19 The best results were obtained
with 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as an ad-
ditive. This created the basis for the first anodic phenol-
arene cross-coupling reaction and gave an indication for
the electrochemical generation of nonsymmetrical biphe-
nol coupling products.20,21
Table 1. Electrochemical Oxidation of Guaiacol Derivatives on
BDDa
yield (%) of biphenols
guaiacol derivative
entry
R =
2
3
1b
2
CH3 (1a)
33% (2a)
21% (2b)
5% (2c)
ꢀ
ꢀ
ꢀ
C3H7 (1b)
CH(CH3)2 (1c)
C(CH3)3 (1d)
Cl (1e)
3
5% (3c)
4
18% (3d)
5
4% (2e)
8% (2f)
ꢀ
6
Br (1f)
ꢀ
a Electrolysis conditions: constant current; undivided cell; BDD
anode on silicon; nickel net cathode; j = 4.7 mA/cm2; 1 F per mol
phenol (1930 C); 0.02 mol of phenol; 30 mL of HFIP; 0.7 g of
[MeNEt3]O3SOCH3; 50 °C. b This entry is taken from ref 16.
A direct oxidation of guaiacol derivatives by transition
metal ions with a high oxidation potential, such as Mn7þ or
Fe3þ, leads to the formation of corresponding ortho-ortho-
coupled biphenols. The naturally occurring dehydrodieu-
genol is available in this way.24,25 By serendipity we found
that 4-methylguaiacol (1a) gave the ortho-meta coupled 2a
upon anodic treatment on boron-doped diamond electro-
des and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as sol-
vent. This nonsymmetrical biphenol 2a was formed
exclusively (Table 1, entry 1). Since the remaining starting
material was recovered by short-path distillation the sub-
sequent workup was easy. Although the yield is moderate,
fast access without requiring prior installation of leaving
functionalities on the respective positions made this ap-
proach interesting.20,26 Therefore, we studied the scope
of the BDD/HFIP protocol in more detail. A variety of
differently substituted guaiacol derivatives was sub-
jected to this electrochemical oxidation.
Here, we report the direct anodic dehydrodimerization
to nonsymmetrical biphenols using BDD electrodes. The
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Depending on the steric demand of the substituent in
position 4 of phenol 1 either a symmetrical or nonsymme-
trical biphenol was obtained (Scheme 1, Table 1). An
elongation of an alkyl chain from 4-methyl to 4-propyl
Waldvogel, S. R. Eur. J. Org. Chem. 2006, 241–245. (b) Barjau, J.;
Koenigs, P.; Kataeva, O.; Waldvogel, S. R. Synlett 2008, 2309–2312.
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S. R. WO 2010 139687 A1, 2010.
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S.; Hiramatsu, K.; Endo, T. Biol. Pharm. Bull. 2005, 28, 1120–1122.
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Org. Lett., Vol. 13, No. 12, 2011
3127

Scheme 1. Electrochemical Oxidation of 4-Substituted Guaiacol
Derivatives on BDD in Hexafluoroisopropanol (HFIP)
guaiacol (1b) resulted in the corresponding nonsymmetri-
cal biphenol 2b as the sole product (entry 2).
Increasing steric demand at that position promotes
the formation of the symmetrical product 3 since in 2
the arylꢀaryl linkage is adjacent to this bulky sub-
stituent. An isopropyl moiety led to an equimolar
mixture of the symmetrical 3c and nonsymmetrical
biphenol 2c.
Figure 2. Molecular structures of 2e (top) and 2f (middle) and
5 (bottom) by X-ray analysis.
Because isopropyl groups on arenes are prone to oxida-
tion, an anodic degradation of the biphenols resulted in
low yields (entry 3). The enhanced bulkiness and stability
of a tert-butyl moiety caused the regioselective formation
of the symmetrical biphenol 3d (entry 4). The less sensitive
nature for overoxidation resulted also in a higher yield for
3d. Additionally, guaiacol, eugenol, vanillin, and dihydro-
ferulic acid were examined on BDD by this protocol, but
no signficant amount of corresponding biphenols were
detected.
Scheme 2. Electrosynthesis of meta-meta Coupled Symmetrical
Biphenol 5 Using BDD Anode
The halogenated guaiacols are more difficult to be
oxidized, and the corresponding nonsymmetrical bi-
phenols 2e and 2f were obtained by the conversion of
4-chloroguaiacol (1e) and 4-bromoguaiacol (1f), re-
spectively (entries 5 and 6). The steric demand of a
chloro and bromo substituent in position 4 did not
affect the regioselectivity. The formation of symmetri-
cal or nonsymmetrical biphenols from guaiacols can be
controlled by the steric influence of a substituent in
position 4.
Switching the methoxy substituent from position 4
to 6 provides the naturally occurring syringol (6) as a
substrate. Standard oxidation methods of 2,6-disub-
stituted phenols are well-known to form the para-para
coupled dehydrodimers.27,28 Incontrast, the electrolysis on
BDD of 6 revealed the exclusive formation of the non-
symmetrical meta-para coupled biphenol 7 in 44% isolated
yield (Scheme 3). The product was completely character-
ized by spectrometric and spectroscopic means.
Suitable single crystals for X-ray analysis of 2e and 2f were
obtained, and the structures could be elucidated (Figure 2).
In the course of our investigations 4-methoxyguaia-
col (4) was oxidized on BDD in 1,1,1,3,3,3-hexafluoro-
isopropanol (Scheme 2). Surprisingly, the symmetrical
dehydrodimer 5 was exclusively obtained and isolated
in 45% yield. The electron rich nature of this substrate led
to a meta-meta coupling product. Interestingly, 5 was not
known before. The molecular structure was confirmed by
consistent spectroscopic and spectrometric data as well as
X-ray analysis of a suitable single crystal (Figure 2).
Scheme 3. Electrochemical Homo-Cross-Coupling Reaction of
Syringol (6)
When 2,5-dimethoxyphenol (8) was electrolyzed by our
protocol only the biphenol 9 was observed with an
isolated yield of 83%. Interestingly, despite the poten-
tial stabilization by the methoxy substituents an
(26) Kirste, A.; Fischer, A.; Malkowsky, I. M.; Stecker, F.; Waldvogel,
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3128
Org. Lett., Vol. 13, No. 12, 2011

overoxidation to the quinoide structure was not de-
tected (Scheme 4).
Scheme 5. Mechanistic Concept for the Oxidative Coupling
Process of Guaiacol Derivatives on BDD
Scheme 4. Electrosynthesis of para-para Coupled Symmetrical
Biphenol 9 on BDD
The formation of homo-cross-coupling products such as
7 indicates that it might not be generated by radical
recombination. Otherwise, only symmetrical biphenols
would be formed. A possible explanation is given by a
mechanistic concept for phenol oxidation ona BDD anode
(Scheme 5). This rationale commences with the anodic
oxidation of the phenolic substrate. The radical cation I
exhibits a dramatically enhanced acidity compared to the
starting material. Consequently, an extrusion of a proton
spontaneously occurs forming a phenoxyl radical with its
mesomeric structures II and III, respectively. This part of
the sequence can be considered as an anodic Umpolung
reaction.29 Subsequently, the electrophile III is trapped
by another nucleophilic phenol, generating the tauto-
meric intermediates IV and V. A second oxidation step
could follow directly or indirectly. A final rearomatization
will result in the biphenol as a product of the electrolysis.
The results are in complete accordance with the
rationale. When the steric demand in position 4 is
low enough, the electrophile (II/III) will attack the
guaiacol in position 5 forming a nonsymmetrical pro-
duct. This is obviously the case for the generation of 2a,
2b, and 7. If the steric demand in the vicinity increases,
e.g. guaiacol 1d, the C,C coupling occurs preferably in
position ortho to the hydroxy group leading to a symme-
trical product.
product was observed and isolated. The isolated yields
go up to 83%. Furthermore, the anodic coupling does
not require prior installation of leaving functionalities
and can therefore be performed with very simple sub-
strates. Known tether strategies provide higher yields
in the coupling step compared to our protocol but
require in contrast high loadings of palladium catalyst,
ligands, and significant quantities of base. In addition,
those approaches rely on prior installation of the tether
and subsequent removal.30 Despite the quite mode-
rate yields our approach provides a fast access to
the reported molecules. The 2,30,4,50-tetramethoxy-3,
40-biphenol (7) represents directly the biaryl moiety of
eupomatilone 231 and indicates the potential use of this
method for natural products synthesis.
Acknowledgment. The support by the SFB 813 Chem-
istry at Spin Centers (DFG) is highly appreciated. G.S.
thanks Prof. Dr. A. C. Filippou for support.
For the electrosynthesis of biphenol 5 this concept has to
be slightly altered, because the positions for the spin center
(species II/III) as well as the nucleophilic attack are domi-
nated by the two methoxy groups, which are in a meta ar-
rangement. With such electron rich substrates an alternative
pathway via further oxidation of the spin centers II and III to
corresponding cationic species cannot be excluded.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new compounds;
complementary data to literature for substrates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we established the selective anodic cou-
pling of guaiacol derivatives on BDD electrodes. Despite
the destructive nature of boron-doped anodes this new
electrode material can be employed for electrosynthesis
when 1,1,1,3,3,3-hexafluoroisopropanol is used as a sol-
vent. The regioselectivity is strongly dependent on the
steric demand close to the coupling position and additional
electron releasing groups. In most cases a single
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