PAPER
▌2371
paper
Two-Step Synthesis of 2-(9-Hydroxynonyl)-5,6-dimethoxy-3-methyl-1,4-
benzoquinone
2-(9-Hydroxynonyl)-5,6-dimethoxy-3-methyl-1,4-benzoquinone
Jin Wang,*1 Xiao Hu, Jian Yang*
Kunming University of Science and Technology, Kunming, Yunnan 650224, P. R. of China
E-mail: woongching@gmail.com
Received: 21.02.2014; Accepted after Revision: 23.04.2014
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Abstract: 2-(9-Hydroxynonyl)-5,6-dimethoxy-3-methyl-1,4-ben-
zoquinone was readily synthesized from commercially available
3,4,5-trimethoxytoluene in two steps. First, 2,3-dimethoxy-5-meth-
yl-1,4-benzoquinone (coenzyme Q0) was obtained in one step by
treatment of 3,4,5-trimethoxytoluene with hydrogen peroxide under
metal-free conditions, followed by free-radical alkylation with 10-
hydroxydecanoic acid in the presence of potassium peroxodisulfate
and silver nitrate in a mixed solvent (MeCN–H2O, 1:1) to afford the
title compound in good yields (60%, based on coenzyme Q0).
MeO
MeO
MeO
MeO
n H
coenzyme Qn, n = 0–12
coenzyme Q0
O
O
MeO
MeO
Key words: coenzyme Q0, decarboxylative cross-coupling, ideben-
one analogue, free-radical alkylation
CH2
OH
n
idebenone, n = 10
Figure 1
Coenzymes Q (CoQ or CoQn, Figure 1), also known as
the ubiquinones, occur naturally in all cells, acting as mo-
bile mediators for electron transfer and protein transloca-
tion between redox enzymes in the electron-transport
chain of mitochondria respiratory systems.2 Coenzyme Q
(CoQ) is also known to act as an antioxidant by reducing
free radicals that can cause damage to structural lipids or
proteins in membranes. Among the synthetic coenzyme Q
analogues, idebenone (Figure 1) is an experimental drug
intended for the treatment of various cognitive defects
such as Alzheimer’s and Parkinson’s diseases. Idebenone
was also shown to be a free radical scavenger for a variety
of reactive species such as the oxidant peroxynitrite. In
comparison with coenzyme Q10 (C40 side chain), ideben-
one (C10 side chain) has a shorter carbon side chain that
facilitates interception of free radicals both in hydropho-
bic and hydrophilic environments.3 In recent work,4,5
some analogues of idebenone have shown ability to sup-
port oxygen consumption in the mitochondrial respiratory
chain.
tical method for the synthesis of idebenone analogues un-
der mild reaction conditions is still in demand.
In recent years, transition-metal-catalyzed decarboxyl-
ative cross-coupling reactions using carboxylic acids as
coupling partners have been widely studied in organic
synthesis as novel methods for the formation of carbon–
carbon bonds. Since carboxylic acids and their derivatives
as cross-coupling components are nontoxic, stable, and
structurally diverse, extensive studies have been accom-
plished in this area, particularly since Minisci reported the
silver-catalyzed decarboxylative alkylation of pyridines
and quinolines in the 1970s.8,9 In this paper we report an
easy method [Scheme 1 (3)] for a two-step synthesis of 2-
(9-hydroxynonyl)-5,6-dimethoxy-3-methyl-1,4-benzo-
quinone (3) from 3,4,5-trimethoxytoluene (1). Firstly,
2,3-dimethoxy-5-methyl-1,4-benzoquinone (coenzyme
Q0) was obtained in single step by treatment of 3,4,5-tri-
methoxytoluene (1) with hydrogen peroxide in formic
acid–acetic acid (2:1) without a metal catalyst, and this
was followed by decarboxylative cross-coupling reaction
of coenzyme Q0 with 10-hydroxydecanoic acid (2) cata-
lyzed by silver nitrate in acetonitrile–water (1:1) to
achieved the desired compound 3 in good yields.
Inspired by reports8,9 that radicals generated by decarbox-
ylation of carboxylic acids with potassium peroxodisul-
fate and silver nitrate could be used for the alkylation of
quinones, we envision that idebenone analogues might be
synthesized from coenzyme Q0 and a monocarboxylic
acid via free-radical alkylation in the presence of potassi-
um peroxodisulfate and silver nitrate. To test our hypoth-
esis, commercially available 10-hydroxydecanoic acid (2)
was selected as the monocarboxylic acid to react with co-
Currently, there are a number of synthetic methodologies
available for the synthesis of idebenone and its analogues,
these are shown in Scheme 1 and classified into two main
routes starting from: (1) 3,4,5-trimethoxytoluene;6 and (2)
2,3,4,5-tetramethoxytoluene.4,7 However, these processes
have the following drawbacks: (i) multistep synthesis,
which leads to low overall yields; (ii) tedious reactions
conditions (Friedel–Crafts, hydrogenation, Heck reaction,
etc.); (iii) use of metallic catalysts [Fremy’s salt, 10%
Pd/C, Pd(OAc)2, etc.].7 Therefore, a convenient and prac-
SYNTHESIS 2014, 46, 2371–2375
Advanced online publication: 28.05.2014
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DOI: 10.1055/s-0033-1338643; Art ID: ss-2014-z0125-op
© Georg Thieme Verlag Stuttgart · New York