Regioselective Radical Cyclization by Electrochemical Reduction Using an Arene Mediator. Environmentally Benign Method

Article abstract of DOI:10.1246/cl.2003.720

Electrochemical reduction of 2-(but-3-enyl)-1-haloarenes in the presence of phenanthrene as a mediator generated the corresponding aryl radicals and gave cyclized products in good yields. Higher regio- and stereoselectivities than those of usual radical cyclization using AIBN-TBTH were achieved.

Full text of DOI:10.1246/cl.2003.720

720
Chemistry Letters Vol.32, No.8 (2003)
Regioselective Radical Cyclization by Electrochemical Reduction
Using an Arene Mediator. Environmentally Benign Method
Nobuhito Kurono, Eiichi Honda, Fumikazu Komatsu, Kazuhiko Orito, and Masao TokudaÃ
Division of Molecular Chemistry, Graduate School of Engineering,
Hokkaido University, Sapporo 060-8628
(Received May 29, 2003; CL-030479)
Electrochemical reduction of 2-(but-3-enyl)-1-haloarenes in
OH
the presence of phenanthrene as a mediator generated the corre-
sponding aryl radicals and gave cyclized products in good
yields. Higher regio- and stereoselectivities than those of usual
radical cyclization using AIBN-TBTH were achieved.
OH
OH
Pt
Metal
Undivided Cell
+
0.1M Et4NClO4-DMF
Mediator
X
1
2a
3a
Scheme 1.
Radical cyclization is a useful method for synthesizing cy-
clic compounds. Carbon radicals are usually generated from the
corresponding organic halides by their reaction with AIBN-or-
ganotin reagents such as tributyltin hydride (TBTH). However,
there are drawbacks in this method, such as toxicity of tin com-
pounds and difficulty in isolating products due to contamination
of R3SnX.
Electrochemical reaction is an environmentally benign
method for organic synthesis since it can be carried out under
mild conditions by using electrons as clean reagents. Therefore,
development of a method for electrochemical generation of car-
bon radicals from the corresponding organic halides is desira-
ble, but a preferential two-electron reduction usually occurs to
give the corresponding carbanions, which finally gives simple
reduction products. Only a few methods for electrochemical
generation of radicals to give cyclization products have been re-
ported; i.e., direct electrochemical reduction of 2-halo-N-aryl-
benzamide derivatives1 and arenediazonium salts carrying alk-
2-enylamino groups2 and electrochemical reduction of alkenyl
halides using Ni(II) or Co(II) catalyst3,4 and of N-(2-iodophen-
yl)-N-alkylcinnamides using an oxygen mediator.5
We intended to develop a method for electrochemical gen-
eration of aryl radicals from the corresponding aryl halides by
the use of arene as a single electron transfer mediator,6 since
we have found that naphthalene radical anion generated electro-
chemically worked successfully as a single electron transfer re-
agent in the preparation of highly reactive zinc.7 We also in-
tended to develop regio- and stereoselective cyclization
reactions by the use of an electrochemical method. Although
similar electrochemical cyclization of N-allyl-2-chloroacetani-
lide using (E)-stilbene as an electron transfer agent was reported
by Grimshaw et al.,8 only substrates carrying cyano groups at
their phenyl rings could be used for the cyclization, and yields
of the cyclization products were not satisfactory. Here we wish
to report the electrochemical radical cyclization of aryl halides
using an arene mediator in which higher regio- and stereoselec-
tivities than those of usual radical cyclizations using AIBN-
TBTH were achieved.
divided cell equipped with a platinum cathode and a sacrificial
anode. An anode material used as a sacrificial anode was the
most effective for the reactions. It was found that the use of
Mg, Zn, Al, Fe or Ti metal as an anode gave a cyclized product
2a, whereas the use of Cu, Ni, In, Pb, Sn, or Ag metal as an
anode resulted in a preferential formation of 3a. No reduction
of 1a occurred when a Pt anode was employed. Therefore, a
platinum cathode and a magnesium anode were used in the fol-
lowing electrolyses. The effect of current density was also ex-
amined, and the electrolysis of 1a at current densities of 45,
60, 75, and 90 mA/cm2 gave 2a in yields of 67, 69, 76, and
58%, respectively. Electricity of 5 F/mol was needed for com-
plete consumption of 1a.
Effects of various mediators and their amounts on the cyc-
lization of 1a were also examined, and the results are summa-
rized in Table 1. Use of 6 equiv. of naphthalene gave 2a in
76% yield (Entry 1). When phenanthrene was used as a media-
tor, 2a was obtained in 73% yield even when 2 equivalents of
phenanthrene was used (Entry 4). When 9,10-diphenylanthra-
cene, 9-phenylanthracene or 9-cyanophenanthrene was used,
the cyclized product was obtained in low to moderate yields
(Entries 7-9).
The present electrochemical method for radical cyclization
has several advantages, such as cleanness, feasibility, regiose-
lectivity and stereoselectivity, compared with the usual radical
cyclization using AIBN-TBTH. Aryl iodide (1a), bromide
(1b), or chloride (1c) can be used as a radical precursor in this
electrochemical cyclization method. Electrolysis of 1a, 1b or 1c
in the presence of 2.0or 4.0equiv. of phenanthrene gave the
cyclization product 2a in yields of 62-80% (Table 2, Entries
1-6), although conventional radical cyclization of 1c using
AIBN-TBTH gave no 2a and the starting 1c was recovered un-
reacted (Table 2, Entry 8). A higher diastereomeric ratio of syn-
and anti-2a9 was obtained in the electrochemical cyclization of
1a (Table 2, Entries 1 and 2), although a similar cyclization us-
ing AIBN-TBTH gave a 1.4:1 ratio of syn- and anti-2a (Entry
7).
Electrochemical radical cyclization of 1-(2-iodophenyl)-1-
hydroxy-3-butene (1a; X = I) was examined under various con-
ditions to optimize the cyclization reactions (Scheme 1).
Electrolysis was carried out at a constant current in an un-
Regioselectivity of the present electrochemical cyclization
is interesting from a synthetic viewpoint. In usual cyclization
of carbon radicals, 6-endo cyclization preferentially occurs to
give a six-membered ring in the case of a 5-hexenyl radical car-
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.8 (2003)
721
Table 1. Effects of various polyaromatic compounds on elec-
trochemical radical cyclization
Y
Y
Y
+
X
1
Pt
Mg
4
2
Undivided Cell
+
1a
2a
3a
2
4
0.1M Et4NClO4-DMF, 0 °C,
5 F/mol, 75 mA/cm2
X= Br, Y= CH(OH)
X= Br, Y= CH(OH)
Electrolysis at 0 °C 53%
AIBN/TBTH
toluene, reflux
15%
(1e)
(1e)
32%
39%
Equiv.a)
Mediator
Entry
Yieldb) / %
X= I, Y= O
(1f) Electrolysis at 0 °C 79%
(1g) Electrolysis at 0 °C 51%
nd
nd
Red. Potential
(V vs Ag/Ag+)
2a
3a
recov.1a
X= I, Y= NMe
1
Naphthalene
(-2.94)
6.0
76
14
0
Scheme 2.
2.0
4.0
59
80
8
18
0
Naphthalene
2
3
lization of 1e using the electrochemical method preferentially
gave 5-exo cyclization product 2. Electrochemical cyclization
of 2-methallyloxyphenyl iodide (1f) and 2-iodo-N-methallyl-
N-methylaniline (1g) gave exclusively 5-exo cyclization prod-
uct 2 (Scheme 2). These higher regio- and stereoselectivities
are probably due to a lower reaction temperature of the present
electrochemical radical cyclizations, although a higher temper-
ature is required to initiate a radical reaction when the AIBN-
TBTH method is used.
In conclusion, electrochemical reduction of haloarenes in
the presence of phenanthrene mediator generated the corre-
sponding aryl radicals efficiently and gave cyclized products
in higher regio- and stereoselectivies than those of usual radical
cyclizations using AIBN-TBTH.
Phenanthrene
(-2.87)
Phenanthrene
14
4
5
6
2.0
1.0
0.5
73
58
36
12
4
0
22
44
Phenanthrene
Phenanthrene
3
9,10-Diphenylanthracene
(-2.27)
7
2.0
48
8
23
9-Phenylanthracene
8
9
2.0
2.0
30
47
15
4
21
22
(-2.31)
9-Cyanophenanthrene
(-2.22)
aEquivalents of mediator to 1a.
bIsolated yields.
Table 2. Electrochemical radical cyclization of various aryl
halides and conventional reaction using AIBN-TBTH
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5
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(1a)
Cl
Cl
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7
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AIBN-TBTH 86 (1.4:1)
Cl (1c) AIBN-TBTHc)
No Reaction
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tributyltin hydride.
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Published on the web (Advance View) July 14, 2003; DOI 10.1246/cl.2003.720