Sequential paired electrosynthesis of a diaryl ether derivative using an electrochemical microreactor

Article abstract of DOI:10.1246/cl.140046

A paired electrosynthetic conversion of a phenol to a diaryl ether derivative by using an electrochemical microreactor has been demonstrated. Sequential anodic CO coupling reaction of phenol 1 to dienone aryl ether 2 and following reduction of 2 took place to give diaryl ether derivative 3 selectively by simply passing an electrolytic solution through the electrochemical microreactor.

Full text of DOI:10.1246/cl.140046

Received: January 20, 2014 | Accepted: February 23, 2014 | Web Released: February 28, 2014
CL-140046
Sequential Paired Electrosynthesis of a Diaryl Ether Derivative
Using an Electrochemical Microreactor
Tsuneo Kashiwagi,1 Toshio Fuchigami,1 Tsuyoshi Saito,3 Shigeru Nishiyama,2 and Mahito Atobe*1,4
1Department of Electronic Chemistry, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8502
2Department of Chemistry, Faculty of Science Technology, Keio University,
3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522
3International Institute for Integrative Sleep Medicine, Tsukuba University, Tennodai, Tsukuba, Ibaraki 305-8557
4Department of Environment and System Sciences, Yokohama National University,
79-7 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501
(E-mail: atobe@ynu.ac.jp)
A paired electrosynthetic conversion of a phenol to a diaryl
ether derivative by using an electrochemical microreactor has
been demonstrated. Sequential anodic C-O coupling reaction of
phenol 1 to dienone aryl ether 2 and following reduction of 2
took place to give diaryl ether derivative 3 selectively by simply
passing an electrolytic solution through the electrochemical
microreactor.
sequence could be performed in a manner of paired electrolysis,
the process could become more sustainable. With this consid-
eration in mind, herein we wish to demonstrate a paired
electrosynthesis of diaryl ether.
To meet this challenge, an efficient sequential oxidation of
phenol and the following reduction must be achieved in one
electrolytic cell. However, in general, efficient sequential
oxidation (or reduction) and the following reduction (or
oxidation) of a single starting material has been difficult7
because the distance between the anode and cathode is
centimeter order when the reaction is carried out in a conven-
tional batch-type reactor. In other words, electrochemically
generated intermediates need specific time to diffuse from
the electrode surface to the counter electrode surface, so that
complete conversion of the intermediates is difficult with the
theoretically required amount of electricity. This reduces the
efficiency of the electrolysis as well as utility of the synthetic
process.
In order to solve this problem, an electrochemical micro-
reactor8 was employed in this study. The short distance between
the electrodes in the microreactor enable fast molecular diffusion
from anode to cathode, offering ideal circumstances for the
desired paired electrolysis (Figure 1).
At first, the effect of anode material on the desired reaction
was examined because the total yield (yield of 2 + 3) depends
on the anodic oxidation step. On the other hand, a Zn plate was
commonly employed as a cathode material in the reduction of
2 avoiding hydrogen evolution. According to the linear sweep
voltammograms, both graphite and glassy carbon electrodes
show clear anodic peaks. In contrast, an anodic peak was not
observed in this potential region when Pt electrode was used
although the current was greater than that recorded by other
electrode materials (Figure 2). Subsequently, preparative elec-
Diaryl ethers are important structural motifs that form the
central building block in a large number of naturally occurring
compounds and pharmaceutical agents. For instance, com-
brestatin,1 aspercyclide,2 and vancomycin3 contain a diaryl
ether moiety and show interesting biological activities. The
Williamson ether synthesis is the most classical and reliable
method to construct ethers. However, diaryl ethers cannot be
synthesized by just mixing a metal phenoxide and aryl halide.
Therefore, transition-metal-catalyzed or -mediated reaction4
between phenol and aryl halide has been the most widely used
method. On the other hand, synthetic methods without need for
metal reagents, especially oxidative C-O coupling, have been
reported recently.3
One of the authors (S. Nishiyama) has developed elec-
trochemical construction of diaryl ethers and applied this
protocol to total synthesis of natural products.5 In this reaction,
anodic one electron oxidation of phenol takes place to give
a dimeric product (dienone aryl ether) and then, reduction of
dienone aryl ether with zinc yields desired diaryl ether
derivatives. If natural products containing a diaryl ether structure
become a lead compound in drug discovery, the use of oxidants
difficult to handle on a large reaction scale or expensive
transition-metal reagents should be avoided. In contrast, since
electrochemical reaction is driven by electric potential, it has
cost advantages over other methods and the reaction is easily
controlled by switching the electrical power supply on and off.
In this regard, electrochemical methods would be ideal for diaryl
ether synthesis.
cathode
+2e, +H+
-CH3O-
O
O
O
flow
O
O
O
O
methanol
solution
Cl
O
In electrochemical reactions, the working electrodes have
received much attention because the desired reaction takes place
on its surface. In contrast, the reaction taking place on the
counter electrode has often been neglected. On the other hand,
electrolytic systems that utilize both the reactions at the anode
and cathode are known as “paired electrolysis.”6 If the reduction
of dienone aryl ether with zinc in the diaryl ether synthesis
could be altered by cathodic reduction, and the entire reaction
Cl
O
O
Cl
O
2
Cl
Cl
O
-2e, -2H+
-Cl-,
+CH3O-
Cl
O
OH
Cl
OH
O
Cl
anode
Figure 1. Schematic representation of electrochemical con-
version of dichlorophenol to diaryl ether in methanol solution
using an electrochemical microreactor.
Chem. Lett. 2014, 43, 799–801 | doi:10.1246/cl.140046
© 2014 The Chemical Society of Japan | 799

(A) Graphite
Table 2. Effect of flow rate and current density on the reactiona
O
(B) Glassy carbon
(C) Platinum
O
O
O
O
4.0
2.0
0.0
O
O
Cl
O
Cl
O
Electrochemical conversion
O
2
+
O
Cl
O
Cl
Cl
Cl
O
Anode: Graphite
Cathode: Zn
OH
Cl
O
Cl
OH
1
2
3
Current
Entry density
Charge
passed
Product
ratiob
2:3
Flow rate
/mL min
Conversion Total yield
of 1/%b (2 + 3)/%b
¹1
¹1
¹2
/mA cm
/F mol
1
2
3
4
5
6
0.1
0.2
0.2
0.2
0.5
1
0.005
0.01
0.012
0.017
0.025
0.05
3.7
3.7
3.1
2.2
3.7
3.7
65
80
75
70
87
89
30
36
41
41
31
30
0:100
0:100
0:100
5:95
10:90
33:67
0
0.2
0.4
0.6
0.8
1
1.2
Potential / V vs. SCE
Figure 2. Linear sweep voltammograms of 10 mM of 1
recorded at (A) graphite disc, (B) glassy carbon disc, and
(C) platinum disc electrodes. Scan rate is 20 mV s
aSubstrate, 10 mM of 1; supporting electrolyte, 100 mM of
LiClO4; electrode distance, 80 ¯m; solvent, methanol. Yields
¹1
.
b
Table 1. Effect of anode materials on the reactiona
and product ratios were determined by HPLC analysis. Yields
are based on the theoretical amount of dimeric product.
O
O
O
O
O
O
O
Cl
O
Cl
O
Electrochemical conversion
O
(A) substrate
2
+
O
Cl
O
0.2 mA cm-2
0.012 mL min-1
3.1 F mol-1
Cl
Cl
Cl
O
OH
Cl
OH
O
Cl
4.0
(B) product
1
2
3
Cathode: Zn
Anode
material
Conversion Total yield Product ratiob
Entry
of 1/%b (2 + 3)/%b
2:3
2.0
0.0
1
2
3
Graphite
Glassy carbon
Platinum
75
73
49
41
28
13
0:100
0:100
0:100
aSubstrate, 10 mM of 1; supporting electrolyte, 100 mM of
LiClO4; electrode distance, 80 ¯m; solvent, methanol. Yields
b
0
0.2
0.4
0.6
0.8
1
1.2
Potential / V vs. SCE
and product ratios were determined by HPLC analysis. Yields
are based on the theoretical amount of dimeric product.
Figure 3. Linear sweep voltammograms of (A) 10 mM sub-
strate 1 and (B) 10 mM product 3 recorded at a graphite disc
¹1
trolysis for the conversion of 1 to 3 was carried out using an
electrochemical microreactor with various anode materials
(Table 1).
electrode. Scan rate is 20 mV s .
the best total yield (Table 2, Entry 1). In this case, the over
oxidation of 3 occurs because more charge was applied.
Linear sweep voltammograms of starting material 1 and 3
indicate that 3 is more easily oxidized than 1 (Figure 3), that is,
complete consumption of 1 is difficult without the overoxidation
of 3.
Finally, comparison with a conventional batch-type reactor
was carried out. The electrode distance of the microreactor was
fixed at 80 ¯m, while that of the conventional reactor was
approximately 1.5 cm. As shown in Figure 4, the desired diaryl
ether 3 was hardly obtained with the conventional reactor, and
the reaction proceeded to give intermediate 2 selectively in low
yield. This clearly shows that the significantly short electrode
distance of the microreactor enables a highly efficient sequential
redox reaction, remarkably increasing the ratio of desired
product 3.
In conclusion, a paired electrosynthetic conversion of a
phenol to diaryl ether derivative by using an electrochemical
microreactor was demonstrated. Sequential anodic C-O cou-
pling reaction of phenol 1 to dienone aryl ether 2 and the
following reduction of 2 took place to give a diaryl ether
derivative 3 selectively. In sharp contrast, only intermediate 2
was obtained when a conventional batch reactor was used.9
The microreactor with carbon anodes such as graphite and
glassy carbon electrodes exhibited better performance and
especially, graphite anode gave best yield of 3. In contrast, Pt
anode gave desired product 3 in low yield in spite of better
anodic behavior expected by linear sweep voltammetry. The
product selectivities for 3 was excellent regardless of anode
materials, which indicates that the intermediate 2 was suffi-
ciently consumed under the applied experimental conditions
(current density, flow rate, and charge passed).
Next, reactions with various flow rate and current density
were carried out in order to determine the behavior of the
reaction (Table 2). At low flow rate, 3 was obtained in excellent
selectivity as a result of the sufficient consumption of 2 (Table 2,
Entries 1-3). On the other hand, selectivity for 3 gradually
decreased with increase of flow rate indicating that high flow
rate (short residence time in the reactor) is unfavorable for the
effective consumption of 2 (Table 2, Entries 4-6). This is
because anodically generated 2 passes through the reactor before
sufficient reduction to 3. Additionally, it was expected that
applying a lower current density was favorable for improving
total yield because a lower current density is favorable for one
electron oxidation. However, low current density did not give
800 | Chem. Lett. 2014, 43, 799–801 | doi:10.1246/cl.140046
© 2014 The Chemical Society of Japan

O
O
O
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O
O
O
O
Cl
O
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O
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O
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O
Cl
O
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3.1 F mol-1
Cl
Cl
Cl
O
OH
Cl
OH
O
Cl
1
2
3
3
4
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graphite
Zn
-
+
graphite
Zn
Microreactor
Conventional batch type reactor
Electrode distance: 80 µm
Total yield: 41%
Product ratio (2: 3) : 0 : 100
ca. 1.5 cm
20%
100 : 0
Figure 4. Comparison of the preparative electrolysis between
a microreactor and a conventional batch reactor. Reactions were
carried out in methanol solution containing 100 mM of LiClO4
at 25 °C.
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This work was financially supported by The Grant-in-Aid
for Scientific Research on Innovative Areas “Organic Synthesis
based on Reaction Integration. Development of New Methods
and Creation of New Substances” (No. 2105).
References and Notes
9
Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
1
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Chem. Lett. 2014, 43, 799–801 | doi:10.1246/cl.140046
© 2014 The Chemical Society of Japan | 801