Selective and Scalable Dehydrogenative Electrochemical Synthesis of 3,3,5,5-Tetramethyl-2,2-biphenol

Article abstract of DOI:10.1055/s-0039-1690706

3,3,5,5-Tetramethyl-2,2-biphenol is a compound of high technical significance, as it exhibits superior properties as building block for ligands in the transition-metal catalysis. However, side reactions and overoxidation are challenging issues in the conventional synthesis of this particular biphenol. Here, an electrochemical method is presented as powerful and sustainable alternative to conventional chemical strategies, which gives good yields up to 51percent. Despite using inexpensive and well-available bromide-containing supporting electrolytes, the issue of bromination and general byproduct formation is effectively suppressed by adding water to the electrolyte. Additionally, the scalability of this method was demonstrated by conducting the electrolysis on a 122 g scale.

Full text of DOI:10.1055/s-0039-1690706

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
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M. Selt et al.
Letter
Synlett
Selective and Scalable Dehydrogenative Electrochemical Synthesis
of 3,3′,5,5′-Tetramethyl-2,2′-biphenol
Maximilian Selta,b
Stamo Mentizia
Dieter Schollmeyera
Robert Frankec,d
HFIP +
H2O
NR4Br
OH
OH
H
2
Siegfried R. Waldvogel*a,b
0
0
0
0-0
0
0
2-
7
9
4
9-9
6
3
8
OH
undivided cell
– 2 e–, – 2 H+
a Institut of Organic Chemistry, Johannes Gutenberg University
Mainz, Duesbergweg 10-14, 55128 Mainz, Germany
waldvogel@uni-mainz.de
no brominated product
scalable
b MAterial Science IN MainZ (MAINZ), Graduate School of Excellence,
Staudingerweg 9, 55128 Mainz, Germany
39% (122 g scale)
c Evonik Performance Materials GmbH, Paul-Baumann- Straße 1,
45772 Marl, Germany
d Lehrstuhl für Theoretische Chemie, Ruhr-Universität Bochum,
44780 Bochum, Germany
Received: 15.08.2019
Accepted after revision: 21.09.2019
Published online: 17.10.2019
obtain the biphenol 2 in yields of 72% by simply applying
sodium hypochlorite as oxidizer.9 However, it could be
proven that instead of a C–C homocoupling solely chlorinat-
ed byproducts occur (see section 7 in the Supporting Infor-
mation). The action of hypochlorite as chlorinating agent of
phenols was found also by Beifuss et al.10
DOI: 10.1055/s-0039-1690706; Art ID: st-2019-b0427-l
Abstract 3,3′,5,5′-Tetramethyl-2,2′-biphenol is a compound of high
technical significance, as it exhibits superior properties as building
block for ligands in the transition-metal catalysis. However, side reac-
tions and overoxidation are challenging issues in the conventional syn-
thesis of this particular biphenol. Here, an electrochemical method is
presented as powerful and sustainable alternative to conventional
chemical strategies, which gives good yields up to 51%. Despite using
inexpensive and well-available bromide-containing supporting electro-
lytes, the issue of bromination and general byproduct formation is ef-
fectively suppressed by adding water to the electrolyte. Additionally,
the scalability of this method was demonstrated by conducting the
electrolysis on a 122 g scale.
In contrast, electroorganic chemistry as part of green
chemistry offers a potent alternative over conventional
chemical approaches.11 Since only electrons serve as re-
agent, no terminal oxidant is required. Consequently, the
formation of reagent waste is effectively avoided. In addi-
tion, electrochemical methods are inherently safe. When
using renewable energy sources and in particular tempo-
rary electricity surplus, electrochemical methods are even
more sustainable and contribute to a stable electrical grid.12
There have been several approaches for an electrochem-
ical synthesis of 2. However, these methods either cause
low yields13,14 or need in most labs not readily available
supporting electrolytes like methyltriethylammonium
methylsulfate.15,16 Another approach is an template-direct-
ed coupling reaction via a tetraphenoxy borate derivative.17
Even though, this method is very selective, there are several
drawbacks. First, it is a multistep reaction, which is very la-
borious, time consuming, and atom inefficient. Secondly,
boron-containing intermediates are used. This leads to
problematic boron contents in wastewater. Consequently, a
scalable process for electrochemical synthesis of 2 is highly
desired.
Key words electrosynthesis, oxidation, phenol, anode, biphenol, sus-
tainable synthesis
Biphenols represent a very frequently appearing struc-
tural motif in many organic compounds. They play a signifi-
cant role in natural products,1 in technical applications,2
and most importantly in ligand systems.3 In particular,
3,3′,5,5′-tetramethyl-2,2′-biphenol (2) shows an outstand-
ing behaviour as powerful ligand building block in transi-
tion-metal catalysis.4 Therefore, an efficient and sustain-
able way of synthesizing 2 is highly desired. Most common-
ly, methods based on transition-metal catalysis,5,6 or
stoichiometric and over stoichiometric amounts of oxidants
are used.6–8 However, these strategies suffer from several
disadvantages: Many of the reagents applied are costly
and/or toxic.8 Additionally, a significant amount of reagent
waste is created, which subsequently has to be disposed or
recycled laboriously. Facing a rising need in sustainability
as one of the largest global challenges, the methods men-
tioned above are not contemporary and appropriate any-
more. An approach reported by Easwaramoorthy claims to
A general challenge in electrochemical coupling reac-
tions is overoxidation. In particular, methylated phenols
such as 2,4-dimethylphenol (1) face this issue. Consequent-
ly, usually a complex mixture of several products are
formed within the oxidation process (Scheme 1).18,19 Espe-
cially noteworthy byproducts are some pentacyclic scaf-
folds like 7–10, whereby 9 and 10 represent secondary
products of dehydrotetramer 7.14,20 Depending on the con-
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Selt et al.
Letter
Synlett
O
OH
OH
OH
H
O
O
anode
– 2 e–, – 2 H+
+
+
+
+
+
+
OH
1
2
3
4
HO
O
O
O
O
+
O
O
OH
5
6
7
O
O
O
O
O
+
+...
O
O
O
O
O
8
9
10
Scheme 1 Product variety by the electrochemical oxidation of 2,4-dimethylphenol (1)19
.
ditions of the electrolysis different products can be domi-
nant. In alkaline media with Ba(OH)2 as supporting electro-
lyte a derivative of the Pummerer ketone 3 and the spirolac-
tone 7 are the main products of the electrolysis. Whereas,
the target compound 2 appears with a yield of 3% only as
byproduct. Therefore, a further improvement of the electro-
chemical synthesis of 2 is still strongly required.
Here we describe an electroorganic method for the se-
lective synthesis of 3,3′,5,5′-tetramethyl-2,2′-biphenol (2)
by direct dehydrogenative homocoupling of 1. The method
is metal- and reagent-free, and only readily available and
inexpensive electrolyte components are employed and can
be recycled as well.
(NBnEt3Br) as low-cost organic supporting electrolyte. In a
preliminary study, a variety of different quaternary ammo-
nium salts were tested for their suitability in this electroly-
sis, with NBnEt3Br providing the best results (see section 4
in the Supporting Information). HFIP turns out to be an ide-
al solvent for electrochemical coupling reactions.23,24 This is
dedicated to its high stability under electrolytic condi-
tions,25 its outstanding radical stabilizing properties,26 and
its unique behavior of building a micro-heterogeneous
structure.27 Even though HFIP is a rather expensive solvent,
almost quantitative recycling is feasible. Contrary to expec-
tations indicated by the literature,28 NBnEt3Br as supporting
electrolyte did not lead to bromination as dominant reac-
For the development of new electrosynthetic protocols
we start with a screening and optimization of the electro-
lytic conditions. These screening experiments are conduct-
ed in small electrolysis cells with a volume up to 5 mL.21 To
keep the optimization process as less time consuming as
possible quantification of the screening results is per-
formed by gas chromatography using an internal standard
method (see section 2 in the Supporting Information).
Thus, it is possible to determine the yield of 2 directly from
the crude product without conducting complete workup.
When the optimal conditions are identified by screening
experiments, the electrolysis is performed in larger elec-
trolysis cells with a volume of 25 mL to obtain reliable isolated
yields.22 This should demonstrate that scale-up is then viable.
In the synthesis of 2, the electrolyte consists of the
starting material 1, 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP) as solvent, and benzyltriethylammonium bromide
Figure 1 Gas chromatogram of the reaction mixture after electrolysis
of 1 with NBnEt3Br as supporting electrolyte. Signal assignment via GC–
MS and authentic samples (see section 8.4 in the Supporting Information).
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F

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M. Selt et al.
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tion pathway. Brominated phenol derivatives just occur as
byproducts in small quantities, whereas the biphenol 2 is
the major product of the electrolysis (Figure 1).
As first parameter, the concentration of the supporting
electrolyte was studied (Table 1).
As expected, a slightly higher amount of applied charge
is beneficial. With an applied charge of 1.2 F per mol of 1
the yield was increased to 44% (Table 2, entry 3). Although,
the starting material is not completely converted, by a dis-
tillative recovery of the starting material, the economic effi-
ciency of the process is still warranted.16 Additionally,
when applying higher amounts of charge, overoxidation
dominates the reaction which leads to lower yields and the
co-formation of oligomers (see section 8.5 in the Support-
ing Information).
Table 1 Optimization for the Concentration of Supporting Electrolytea
Entry
Concentration of NBnEt3Br
Yield of 2 (%)b
(mol·L–1
)
Table 3 shows the influence of the current density onto
the conversion. Lower current densities as 7.2 mA·cm–2 fa-
vor the yield of 2, whereas higher current densities lead to
inferior results. In order to have the shortest electrolysis
time a current density of 6.1 mA·cm–2 (Table 3, entry 3) was
chosen for the following experiments.
1
2
3
4
5
0.04
0.08
0.12
0.16
0.20
41
41
41
42
42
a Electrolytic conditions: glassy carbon electrodes, undivided cell (5 mL),
HFIP, constant current conditions, j = 7.2 mA·cm–2, Q = 1.0 F per mol of 1,
0.44 mol·L–1 of 1, 50 °C.
Table 3 Optimization of Current Densitya
b Yield was determined from crude product by GC using an internal stan-
dard (IK1).
Entry
Current density
Yield of 2 (%)b
(mA·cm–2
)
The concentration of the supporting electrolyte has vir-
tually no influence onto the performance of the reaction.
The yields stay more or less constant. Hence, the use of
small amounts of supporting electrolyte for the electrolysis
is viable without corrosion of yield (Table 1, entry 1). This is
of benefit for a technical application of this reaction, be-
cause it minimizes the costs and facilitates downstream
processing.
The theoretically required amount of applied charge is
1 F per mol of 1. However, side reactions can cause a higher
demand of electricity. Therefore, the influence of the ap-
plied charge was investigated (Table 2).
1
2
3.9
5.6
42
45
45
44
39
39
39
40
41
36
35
36
3
6.1
4
7.2
5
7.8
6
8.3
7
8.9
8
9.4
9
10.0
12.9
19.4
25.6
10
12
13
Table 2 Optimization of Applied Chargea
a Electrolytic conditions: glassy carbon electrodes, undivided cell (5 mL),
HFIP, constant current conditions, Q = 1.2 F per mol of 1, 0.04 mol·L–1 of
NBnEt3Br, 0.44 mol·L–1 of 1, 50 °C.
Entry
Applied charge (F per
mol 1)
Yield of 2 (%)b
b Yield was determined from crude product by GC using an internal stan-
dard (IK2).
1
2
3
4
5
6
7
8
1.0
1.1
1.2
1.3
1.4
1.5
1.6
1.7
40
42
44
44
42
42
38
36
The impact of the temperature was also screened (see
section 5 in the Supporting Information). However, no im-
provement was achieved. Hence, the electrolyses were con-
ducted at a temperature of 50 °C further on.
Previous studies have indicated that adding methanol or
water by a volume fraction of 18 vol% or 9 vol% to the elec-
trolyte can have an enormously positive effect onto cross-
coupling reactions. For example, in the cross-coupling of 4-
methylguaiacol with 1,2,4-trimethoxybenzene, the yield of
the corresponding biaryl was increased from 21% in pure
HFIP to 67% in HFIP with 9 vol% water. This behaviour is at-
tributed to an interaction of the additive within the solva-
tion of the substrates.24,29 For the C–C homocoupling of 1,
addition of 18 vol% methanol lead to a slight decrease of
a Electrolytic conditions: glassy carbon electrodes, undivided cell (5 mL),
HFIP, constant current conditions, j = 7.2 mA·cm–2, 0.04 mol·L–1 of
NBnEt3Br, 0.44 mol·L–1 of 1, 50 °C.
b Yield was determined from crude product by GC using an internal stan-
dard (IK2).
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F

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M. Selt et al.
Letter
Synlett
yield (Table 4, entry 1), whereas a volume fraction of
18 vol% of water did not affect the yield (Table 4, entry 1).
However, water almost completely suppresses the forma-
tion of brominated byproducts (Figure 2). This is probably
contributed to a quenching effect of water: Anodically
formed highly reactive bromine species may be captured by
water and thus are not able to attack the substrate any-
more. This indeed, underlines the positive effect of water as
additive in electrochemical coupling reactions. Conse-
quently, the purification of the product as well as the recov-
ery of the starting material becomes significantly easier be-
cause no brominated by-products have to be separated.
This increases the chances for a later application of this
electrolysis. The suppression of the bromination reaction
might be attributed to the specific hydrogen bonding of
HFIP to anions and oxygen termini promoting the C–C bond
formation. The addition of water seems to enhance this sol-
vent control, since the protic domains are increased.27
Table 4 Influence of Methanol and Water as Additive onto the Electro-
chemical Synthesis of 2a
Figure 2 Gas chromatogram of the reaction mixture after electrolysis
of 1 with NBnEt3Br as supporting electrolyte and 18 vol% methanol (A)
or 18 vol% water (B) as additive. Signal assignment via GC–MS and au-
thentic samples (see section 8.4 in the Supporting Information).
Entry
Additive
Volume fraction (vol%) GC Yield of 2 (%)b
1
2
MeOH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
18
18
5
42
45
42
48
50
46
39
36
30
21
3
Table 5 Optimization of the Concentration of 1a
4
10
15
20
25
30
35
40
5
Entry
Concentration of 1 (mol·L–1
)
Yield of 2 (%)b
6
1
2
3
4
5
0.40
0.50
1.00
1.50
2.00
46
47
48
47
45
7
8
9
10
a Electrolytic conditions: glassy carbon electrodes, undivided cell (5 mL),
HFIP + additive, constant current conditions, j = 6.1 mA·cm–2, Q = 1.2 F per
mol of 1, 0.04 mol·L–1 of NBnEt3Br, 0.44 mol·L–1 of 1, 50 °C.
b Yield was determined from crude product by GC using an internal standard
(IK3).
a Electrolytic conditions: glassy carbon electrodes, undivided cell (5 mL),
HFIP + 15 vol% H2O, constant current conditions, j = 6.1 mA·cm–2
,
Q = 1.2 F per mol of 1, 0.04 mol·L–1 of NBnEt3Br, 50 °C.
b Yield was determined from crude product by GC using an internal stan-
dard (IK4).
Stimulated by this result, the water content in the elec-
trolyte was systematically varied from 5 vol% up to 40 vol%
(Table 4). The conductivity of the solution was increased by
this, which led to a lower applied voltage. However, this ef-
fect was marginal, since the main part of the conductivity is
dominated by the supporting electrolyte. With a yield of
50% the best result was obtained at a volume fraction of
15 vol% water (Table 4, entry 5).
yield of 48% was obtained with a concentration 1.00 mol·L–2
(Table 5, entry 3).
To validate the screening results, determination of reli-
able isolated yields on gram scale is crucial. The electrolyses
for the product isolation were conducted in 25 mL beaker-
type cells to also demonstrate a viable scale-up of this elec-
trolysis. Additionally, it was studied if other bromide-con-
taining supporting electrolytes are also suitable for this
electrolytic conversion (Table 6). Since NBnEt3Br is a com-
paratively expensive supporting electrolyte (Table 6,
entry 4), the application of less expensive supporting elec-
trolytes is advantageous.
Finally, the concentration of the starting material 2 was
optimized, by altering the concentration from 0.40 mol·L–2
to 2.00 mol·L–2 (Table 5). Within this screening, the best
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F

E
M. Selt et al.
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Synlett
It becomes apparent that the isolated yields are compa-
rable with those yields determined by the internal standard
method (Table 6, entry 4). The slightly lower value of the
isolated yield is dedicated to the purification process. Clear-
ly, that all four bromide-containing supporting electrolytes
are suitable for the electrochemical synthesis of 2. The iso-
lated yields vary from 46% for NEt4Br (Table 6, entry 1) and
NBu4Br (Table 6, entry 3) to even 51% for NPr4Br (Table 6,
entry 2), but can be considered as in the similar range. With
regards to a scale-up, the replacement of the slightly more
expensive NBnEt3Br by more inexpensive supporting elec-
trolytes is gratifyingly unproblematic.
chemical production of such components. The synthesis
was also successfully transferred into 122 g scale with a
yield of 39%. In addition, a purification strategy was devel-
oped, which is suitable for larger amounts. This, together
with the simple recycling of the starting material as well as
the solvent makes the developed method ecological and
economical attractive for a technical application.
Funding Information
The authors highly appreciate the financial support by the Graduate
School Materials Science in Mainz, Deutsche Forschungsgemeinschaft
(Grant Number GSC 266), and the support by the Bundesministerium
für Bildung und Forschung (BMBF-EPSYLON, Grant Number FKZ
Table 6 Scope of Different Bromide-Containing Supporting Electrolytesa
13XP5016D).
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e
F
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e
m
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h
aft(G
S
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2
6
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Supporting electrolyte Yield of isolated 2 (%)b Costs (€∙500 g–1
)
Supporting Information
1
2
3
4
NEt4Br
46
51
46
47
6430
9731
NPr4Br
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690706.
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a Electrolytic conditions: glassy carbon electrodes, undivided cell (25 mL),
References and Notes
HFIP + 15 vol% H2O, constant current conditions, j = 6.1 mA·cm–2
,
Q = 1.2 F per mol of 1, 1.00 mol·L–1 of 1, 0.08 mol·L–1 of supporting elec-
(1) (a) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M.
Chem. Rev. 2011, 111, 563. (b) Bringmann, G.; Price Mortimer, A.
J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew.
Chem. Int. Ed. 2005, 44, 5384. (c) Kozlowski, M. C.; Morgan, B. J.;
Linton, E. C. Chem. Soc. Rev. 2009, 38, 3193. (d) Zechmeister, L.;
Herz, W.; Bringmann, G. Progress in the Chemistry of Organic
Natural Products, Vol. 82; Springer: Wien/New York, 2001.
(2) (a) Francke, R.; Cericola, D.; Kötz, R.; Schnakenburg, G.;
Waldvogel, S. R. Chem. Eur. J. 2011, 17, 3082. (b) Grimsdale, A. C.;
Chan, K. L.; Martin, R. E.; Jokisz, P. G.; Holmes, A. B. Chem. Rev.
2009, 109, 897. (c) Kirsch, P.; Bremer, M. Angew. Chem. Int. Ed.
2000, 39, 4216. (d) Kirsch, P.; Bremer, M. Angew. Chem. 2000,
112, 4384. (e) Su, S.-J.; Tanaka, D.; Li, Y.-J.; Sasabe, H.; Takeda, T.;
Kido, J. Org. Lett. 2008, 10, 941.
(3) (a) Alexander, J. B.; La, D. S.; Cefalo, D. R.; Hoveyda, A. H.;
Schrock, R. R. J. Am. Chem. Soc. 1998, 120, 4041. (b) La, D. S.;
Sattely, E. S.; Ford, J. G.; Schrock, R. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 2001, 123, 7767. (c) Kiely, A. F.; Jernelius, J. A.;
Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 2868.
(d) Hultzsch, K. C.; Jernelius, J. A.; Hoveyda, A. H.; Schrock, R. R.
Angew. Chem. Int. Ed. 2002, 41, 589. (e) Cortez, G. A.; Schrock, R.
R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2007, 46, 4534. (f) Singh,
R.; Czekelius, C.; Schrock, R. R.; Müller, P.; Hoveyda, A. H.
Organometallics 2007, 26, 2528. (g) van Leeuwen, P. W. N. M.;
Kamer, P. C. J.; Claver, C.; Pàmies, O.; Diéguez, M. Chem. Rev.
2011, 111, 2077. (h) Franke, R.; Selent, D.; Börner, A. Chem. Rev.
2012, 112, 5675.
trolyte, 50 °C.
b Yield of isolated product.
Finally, conduction of the electrolysis in an even larger
scale was demonstrated. Therefore, an alternate polarized
arrangement of six glassy carbon electrodes (immersed an-
ode surface: 195 cm2) was placed into a large beaker-type
electrolysis cell filled with a total volume of 1 L electrolyte
(122 g starting material 1). As supporting electrolyte NEt4Br
was chosen, because of its low costs. With this setup the
desired biphenol 2 was obtained in 39% yield. An additional
advantage of this system is that workup of the reaction
mixture is very simple and allows further scale-up as well
as reasonable downstream processing. The pure product is
obtained only by extraction and evaporative crystallization.
In conclusion, we developed and optimized an electro-
chemical method for the synthesis of 3,3′5,5′-tetramethyl-
2,2′-biphenol via a simple and fast screening methodology.
By the addition of 15 vol% water to the electrolyte the for-
mation of numerous byproducts was effectively sup-
pressed. In particular, the bromination of 2,4-dimethylphe-
nol was inhibited, despite the bromide-containing support-
ing electrolytes. So far, there are only few examples for
electrochemical coupling reactions, where the addition of
water to the electrolyte was tested. However, the results of
this work could lead to a reinvestigation of other reactions
of this kind. In particular, when having technical relevance.
Additionally, it was demonstrated that even most common
quaternary ammonium salts, such as NEt4Br and NPr4Br are
suitable for this reaction and deliver good yields up to 51%.
This is an important prerequisite for the large-scale electro-
(4) (a) Hayano, S.; Kurakata, H.; Tsunogae, Y.; Nakayama, Y.; Sato,
Y.; Yasuda, H. Macromolecules 2003, 36, 7422. (b) Alexakis, A.;
Polet, D.; Benhaim, C.; Rosset, S. Tetrahedron: Asymmetry 2004,
15, 2199. (c) Alexakis, A.; Polet, D.; Rosset, S.; March, S. J. Org.
Chem. 2004, 69, 5660. (d) Li, K.; Alexakis, A. Angew. Chem. Int.
Ed. 2006, 45, 7600. (e) Falciola, C. A.; Alexakis, A. Angew. Chem.
Int. Ed. 2007, 46, 2619. (f) Li, K.; Alexakis, A. Chem. Eur. J. 2007,
13, 3765. (g) Mata, Y.; Pàmies, O.; Diéguez, M. Chem. Eur. J. 2007,
13, 3296. (h) Palais, L.; Mikhel, I. S.; Bournaud, C.; Micouin, L.;
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F

F
M. Selt et al.
Letter
Synlett
Falciola, C. A.; Vuagnoux-d’Augustin, M.; Rosset, S.;
Bernardinelli, G.; Alexakis, A. Angew. Chem. Int. Ed. 2007, 46,
7462. (i) Raluy, E.; Diéguez, M.; Pàmies, O. J. Org. Chem. 2007, 72,
2842. (j) Vuagnoux-d’Augustin, M.; Kehrli, S.; Alexakis, A.
Synlett 2007, 2057. (k) Hawner, C.; Li, K.; Cirriez, V.; Alexakis, A.
Angew. Chem. Int. Ed. 2008, 47, 8211. (l) Smith, S. E.; Rosendahl,
T.; Hofmann, P. Organometallics 2011, 30, 3643.
(20) (a) Barjau, J.; Königs, P.; Kataeva, O.; Waldvogel, S. Synlett 2008,
2309. (b) Barjau, J.; Schnakenburg, G.; Waldvogel, S. R. Angew.
Chem. Int. Ed. 2011, 50, 1415. (c) Astruc, D. Modern Arene Chem-
istry 2002.
(21) General Protocol for Screening Reactions
A solution of 2,4-dimethylphenol (1, 2–10 mmol) and the
respective supporting electrolyte (0.2–1.0 mmol) in 5 mL HFIP
or HFIP with 18 vol% methanol or HFIP with 5–40 vol% water
was transferred into a screening electrolysis cell equipped with
a glassy carbon anode and a glassy carbon cathode. A constant
current electrolysis with a current density of 3.9–25.6 mA·cm–2
was performed at 20–60 °C. After application of 1.0–1.7 F per
mol of 1, the electrolysis was stopped, and the solvent mixture
was recovered in vacuo (50 °C, 200–70 mbar). Subsequently, the
sample was prepared according to the respective internal cali-
bration (IK1–IK4, see section 2 in the Supporting Information).
(22) General Protocol for the Electrochemical Synthesis of
3,3′,5,5′-Tetramethyl-2,2′-biphenol (2)
A solution of 2,4-dimethylphenol (1, 3.05 g, 25.0 mmol) and the
respective supporting electrolyte (2.0 mmol) in 25 mL HFIP
with 15 vol% water was transferred into an undivided beaker-
type electrolysis cell equipped with a glassy carbon anode and a
glassy carbon cathode. A constant current electrolysis with a
current density of 6.1 mA·cm–2 was performed at 50 °C. After
application of 2895 C (1.2 F per mol of 1 ) the electrolysis was
stopped, and the solvent mixture was recovered in vacuo (50 °C,
200–20 mbar), and the crude product was purified by short-
path distillation (recovery of starting material 1: 60 °C, 2·10–3
mbar; sublimation of product 2: 140 °C, 2·10–3 mbar).
(23) (a) Kirste, A.; Schnakenburg, G.; Stecker, F.; Fischer, A.;
Waldvogel, S. R. Angew. Chem. Int. Ed. 2010, 49, 971. (b) Francke,
R.; Cericola, D.; Kötz, R.; Weingarth, D.; Waldvogel, S. R. Electro-
chim. Acta 2012, 62, 372. (c) Waldvogel, S. R.; Elsler, B. Electro-
chim. Acta 2012, 82, 434.
(5) (a) Bowden, K.; Reece, C. H. J. Chem. Soc. 1950, 1686. (b) Barrett,
A. G.M.; Itoh, T.; Wallace, E. M. Tetrahedron Lett. 1993, 34, 2233.
(c) Hwang, D.-R.; Chen, C.-P.; Uang, B.-J. Chem. Commun. 1999,
1207. (d) Sharma, V. B.; Jain, S. L.; Sain, B. Tetrahedron Lett. 2003,
44, 2655. (e) Yadav, J. S.; Reddy, B. V. S.; Uma Gayathri, K.;
Prasad, A. R. New J. Chem. 2003, 27, 1684. (f) Jiang, Q.; Sheng,
W.; Tian, M.; Tang, J.; Guo, C. Eur. J. Org. Chem. 2013, 1861.
(6) Kaeding, W. W. J. Org. Chem. 1963, 28, 1063.
(7) (a) Bamberger, E.; Brun, J. Ber. Dtsch. Chem. Ges. 1907, 40, 1949.
(b) Cosgrove, S. L.; Waters, W. A. J. Chem. Soc. 1951, 1726.
(c) Haynes, C. G.; Turner, A. H.; Waters, W. A. J. Chem. Soc. 1956,
2823. (d) Huddle, P. A.; Perold, G. W. J. Chem. Soc., Perkin Trans.
1 1980, 2617. (e) Elovitz, M. S.; Fish, W. Environ. Sci. Technol.
1995, 29, 1933.
(8) Quell, T.; Mirion, M.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.;
Waldvogel, S. R. ChemistryOpen 2016, 5, 115.
(9) Neelamegam, R.; Palatnik, M. T.; Fraser-Rini, J.; Slifstein, M.;
Abi-Dargham, A.; Easwaramoorthy, B. Tetrahedron Lett. 2010,
51, 2497.
(10) Constantin, M.-A.; Conrad, J.; Beifuss, U. Tetrahedron Lett. 2012,
53, 3254.
(11) (a) Sequeira, C. A. C.; Santos, D. M. F. J. Braz. Chem. Soc. 2009, 20,
387. (b) Frontana-Uribe, B. A.; Little, R. D.; Ibanez, J. G.; Palma,
A.; Vasquez-Medrano, R. Green Chem. 2010, 12, 2099.
(c) Schäfer, H. J. C. R. Chim. 2011, 14, 745. (d) Yan, M.; Kawamata,
Y.; Baran, P. S. Chem. Rev. 2017, 117, 13230. (e) Möhle, S.; Zirbes,
M.; Rodrigo, E.; Gieshoff, T.; Wiebe, A.; Waldvogel, S. R. Angew.
Chem. Int. Ed. 2018, 57, 6018. (f) Yan, M.; Kawamata, Y.; Baran,
P. S. Angew. Chem. Int. Ed. 2018, 57, 4149. (g) Waldvogel, S. R.;
Lips, S.; Selt, M.; Riehl, B.; Kampf, C. J. Chem. Rev. 2018, 118,
6706.
(24) Elsler, B.; Wiebe, A.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.;
Waldvogel, S. R. Chem. Eur. J. 2015, 21, 12321.
(25) Colomer, I.; Chamberlain, A. E. R.; Haughey, M. B.; Donohoe, T. J.
Nat. Rev. Chem. 2017, 1, 88.
(12) (a) Waldvogel, S. R.; Janza, B. Angew. Chem. Int. Ed. 2014, 53,
7122. (b) Horn, E. J.; Rosen, B. R.; Baran, P. S. ACS Cent. Sci. 2016,
2, 302. (c) Wiebe, A.; Riehl, B.; Lips, S.; Franke, R.; Waldvogel, S.
R. Sci. Adv. 2017, 3, eaao3920. (d) Wiebe, A.; Gieshoff, T.; Möhle,
S.; Rodrigo, E.; Zirbes, M.; Waldvogel, S. R. Angew. Chem. Int. Ed.
2018, 57, 5594.
(13) (a) Nilsson, A.; Ronlán, A.; Parker, V. D. J. Chem. Soc., Perkin
Trans. 1 1973, 2337. (b) Malkowsky, I. M.; Griesbach, U.; Pütter,
H.; Waldvogel, S. R. Eur. J. Org. Chem. 2006, 4569.
(14) Malkowsky, I. M.; Rommel, C. E.; Wedeking, K.; Fröhlich, R.;
Bergander, K.; Nieger, M.; Quaiser, C.; Griesbach, U.; Pütter, H.;
Waldvogel, S. R. Eur. J. Org. Chem. 2006, 241.
(15) Kirste, A.; Nieger, M.; Malkowsky, I. M.; Stecker, F.; Fischer, A.;
Waldvogel, S. R. Chem. Eur. J. 2009, 15, 2273.
(26) (a) Eberson, L.; Hartshorn, M. P.; Persson, O. J. Chem. Soc., Perkin
Trans. 2 1995, 1735. (b) Eberson, L.; Hartshorn, M. P.; Persson,
O.; Radner, F. Chem. Commun. 1996, 2105.
(27) Hollóczki, O.; Berkessel, A.; Mars, J.; Mezger, M.; Wiebe, A.;
Waldvogel, S. R.; Kirchner, B. ACS Catal. 2017, 7, 1846.
(28) (a) Millington, J. P. J. Chem. Soc. B 1969, 982. (b) Casalbore, G.;
Mastragostino, M.; Valcher, S. J. Electroanal. Chem. Interfacial
Electrochem. 1977, 77, 373. (c) Taniguchi, I.; Yano, M.;
Yamaguchi, H.; Yasukouchi, K. J. Electroanal. Chem. Interfacial
Electrochem. 1982, 132, 233. (d) Milisavljević, S. S.; Wurst, K.;
Laus, G.; Vukićević, M. D.; Vukićević, R. D. Steroids 2005, 70, 867.
(e) Lyalin, B. V.; Petrosyan, V. A. Russ. J. Electrochem. 2013, 49,
497. (f) Thasan, R.; Kumarasamy, K. Korean J. Chem. Eng. 2014,
31, 365. (g) Hammerich, O.; Speiser, B. Organic Electrochemistry,
5th ed; CRC Press: Boca Raton, 2016.
(16) Kirste, A.; Hayashi, S.; Schnakenburg, G.; Malkowsky, I. M.;
Stecker, F.; Fischer, A.; Fuchigami, T.; Waldvogel, S. R. Chem. Eur.
J. 2011, 17, 14164.
(29) Kirste, A.; Elsler, B.; Schnakenburg, G.; Waldvogel, S. R. J. Am.
Chem. Soc. 2012, 134, 3571.
(17) (a) Malkowsky, I. M.; Rommel, C. E.; Fröhlich, R.; Griesbach, U.;
Pütter, H.; Waldvogel, S. R. Chem. Eur. J. 2006, 12, 7482.
(b) Malkowsky, I. M.; Fröhlich, R.; Griesbach, U.; Pütter, H.;
Waldvogel, S. R. Eur. J. Inorg. Chem. 2006, 1690.
(18) Johnston, K. M.; Jacobson, R. E.; Williams, G. H. J. Chem. Soc. C
1969, 1424.
(30) Chemical catalogue: TCI (25.02.2019), CAS-No: 71-91-0, >98.0%.
(31) Chemical catalogue: TCI (25.02.2019), CAS-No: 1941-30-6,
>98.0%.
(32) Chemical catalogue: TCI (25.02.2019), CAS-No: 1643-19-2,
>99.0%.
(33) Chemical catalogue: TCI (25.02.2019), CAS-No: 5197-95-5,
>98.0%.
(19) Waldvogel, S. R. Pure Appl. Chem. 2010, 82, 1055.
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