A Simple and Convenient Two-step Synthesis of Idebenone

Full text of DOI:10.1080/00304948.2021.1917945

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Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/uopp20
A Simple and Convenient Two-step Synthesis of
Idebenone
Rong-Ye Zhou, Na Li, Wan-Yue Luo, Li-Li Wang, Ye-Yu Zhang & Jin Wang
To cite this article: Rong-Ye Zhou, Na Li, Wan-Yue Luo, Li-Li Wang, Ye-Yu Zhang & Jin Wang
(2021) A Simple and Convenient Two-step Synthesis of Idebenone, Organic Preparations and
Procedures International, 53:4, 397-401, DOI: 10.1080/00304948.2021.1917945
To link to this article: https://doi.org/10.1080/00304948.2021.1917945
Published online: 28 May 2021.
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
2021, VOL. 53, NO. 4, 397–401
https://doi.org/10.1080/00304948.2021.1917945
EXPERIMENTAL PAPER
A Simple and Convenient Two-step Synthesis of Idebenone
Rong-Ye Zhou, Na Li, Wan-Yue Luo , Li-Li Wang, Ye-Yu Zhang, and Jin Wang
School of Pharmacy, Yancheng Teachers University, Yancheng, Jiangsu Province, P. R. China
ARTICLE HISTORY Received 11 April 2020; Accepted 18 November 2020
Idebenone (Figure 1) is a synthetic analogue of Coenzyme Q10 (CoQ10),1 which func-
tions as an antioxidant and free radical scavenging molecule. Structurally, idebenone
and CoQ10 share the same 1,4-benzoquinone moiety but have a different side chain at
the C-5 position. Idebenone has a hydroxydecyl side chain (10 carbon atoms) while
CoQ10 has a long side chain of 10 isoprene moieties.2 Both idebenone and CoQ10 are
involved in the electron transport chain by neutralizing free radicals. Unlike natural
CoQ10, however, idebenone is more efficacious because it can bypass mitochondrial
complex I and maintain normal ATP production.3 Idebenone is a synthetic drug ini-
tially developed by Takeda Pharmaceutical company in 1980, and it has been widely
used in the treatment of Friedreich’s ataxia,4 Alzheimer’s disease, and other mitochon-
drial disorders.5
To date, methods for the synthesis of idebenone and its analogues are limited. Two
main routes for the preparation of idebenone are shown in Scheme 1. The major differ-
ences between these protocols are the starting materials. Park and colleagues6 started
from 2,3,4,5-tetramethoxytoluene 1 to obtain idebenone in seven steps with a total yield
of 16% (Scheme 1, eq. 1), while Bjørsvik and co-workers7 reported a six-step synthesis
of idebenone by starting from 3,4,5-trimethoxytoluene 2 in a total yield of 20% (Scheme
1, eq. 2). These approaches involved multistep procedures under harsh reaction condi-
tions (including Friedel-Crafts or Heck reactions and hydrogenation) and the use of
toxic reagents. Therefore, a general and practical method for an efficient idebenone syn-
thesis would be in high demand.
In recent years, transition-metal-catalyzed decarboxylative cross-coupling reactions
using carboxylic acids as coupling partners have been widely studied in organic synthe-
sis as novel methods for the formation of C-C bonds.8 Practical C-H functionalization
of 1,4-benzoquinone with boronic acids in the presence of K2S2O8 and AgNO3 was
reported by Baran et al.9 Following our recent work on the synthesis of Coenzyme Q
analogues,10 in this paper we now describe a two-step synthesis of idebenone starting
from 3,4,5-trimethoxytoluene 2 with a total yield of 70% (Scheme 1, eq. 3).
As shown in Scheme 2, we here describe a two-step synthesis of idebenone by oxida-
tion of 3,4,5-trimethoxytoluene 2 to obtain Coenzyme Q0 (CoQ0),11–12 followed by a
decarboxylative cross-coupling reaction of CoQ0 with 11-hydroxyundecanoic acid under
silver catalysis to afford the target compound. We began our study with the preparation
CONTACT Jin Wang
wangj01@yctu.edu.cn
School of Pharmacy, Yancheng Teachers University, Hope Avenue
South Road No. 2, Yancheng, 224007, Jiangsu Province, P. R. China
ß 2021 Taylor & Francis Group, LLC

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398 R.-Y. ZHOU ET AL.
Figure 1. Structures of Idebenone and CoQ10.
Scheme 1. Various approaches for Idebenone.
Scheme 2. Two-step synthesis of Idebenone.
of CoQ0, by the oxidation of commercially available 3,4,5-trimethoxytoluene 2 with dif-
ferent oxidants in acetic acid (Table 1).

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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
399
Table 1. Single-step synthesis of CoQ0.
Entry
oxidant
Temp (oC )
Yield (%)
1
2
3
4
30% H2O2
K2S2O8
(NH4)2S2O8
CAN
25
25
25
25
30
88
62
0
Reaction Conditions: 2 (0.02 mol), oxidant (1.5 equiv), 4 hr.
As shown in Table 1, the oxidation was conducted in formic acid at 25 ꢀC in air without
using any metal catalyst. The traditional method employing 30% H2O2 as oxidant gave a yield
of 30% (entry 1, Table 1). The use of (NH4)2S2O8 as oxidant improved the reaction yield to
62% (entry 3, Table 1). The best yield was obtained when using K2S2O8 as oxidant, which
gave the desired product CoQ0 in 88% yield (entry 2, Table 1). When ceric ammonium nitrate
(CAN) was used as oxidant we did not observe any product CoQ0 (entry 4, Table 1).
Our initial optimization studies of the AgNO3-catalyzed decarboxylative coupling
reaction between CoQ0 and 11-hydroxyundecanoic acid focused on different reaction
atmospheres (Table 2). The reaction was performed in N2 (1 atm), O2 (1 atm) and ambi-
ent air. Interestingly we found that the yield increased to 80% yield when the reaction
was performed under an O2 atmosphere (entry 3, Table 2). Examination of different sol-
vents at 80 ꢀC under O2 (1 atm) for 2 h revealed that the best reaction solvent was aceto-
nitrile (entry 3-8, Table 2). Several other oxidants were screened in the reaction. We
found that Na2S2O8 and (NH4)2S2O8 catalyzed the reaction with moderate efficiency
(entry 9-10, Table 2). Without the silver salt oxidant, the reaction cannot proceed (entry
11, Table 2). The optimal conditions employed AgNO3 (20%), and K2S2O8 (1.5 equiv)
in acetonitrile at 80 ꢀC for 2 h (entry 3, Table 2).
In conclusion, a practical and convenient two-step total synthesis of idebenone by oxida-
tion and silver-catalyzed decarboxylative cross-coupling has been developed. The 70% over-
all yield is suitable for large-scale industrial production. Firstly, CoQ0 can be synthesized in
a single step from the cheap and readily available 3,4,5-trimethoxytoluene 2 by oxidation
without using a metal catalyst. It is of course worthy of note that CoQ0 can serve as a key
intermediate for the synthesis of a vast number of Coenzyme Q compounds, not just idebe-
none. Secondly, the silver-catalyzed decarboxylative cross-coupling reaction between CoQ0
and carboxylic acids is operationally simple, mild, efficient, and amenable to the gram-scale
synthesis of idebenone. It is our expectation that the methods described here will lead to
further explorations of high value Coenzyme Q analogues.
Experimental section
All reactions were monitored by TLC (SiO2, petroleum ether (PE)/EtOAc 5:1). Melting
points were measured on Melting Point M-565 (BUCHI) apparatus and are uncorrected.