A convenient two-step synthesis of Coenzyme Q1

Article abstract of DOI:10.1177/1747519819876524

A convenient method for the preparation of Coenzyme Q₁ from cheap and readily available 3,4,5-trimethoxytoluene is developed. Coenzyme Q₁ is synthesized in a moderate yield by a two-step procedure involving the key reaction of an allyl bromide with Coenzyme Q₀ through a redox chain reaction. The reaction is efficient and can be used for the synthesis of other Coenzyme Q compounds.

Full text of DOI:10.1177/1747519819876524

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research-arti
7cle2019 6524CHL0010.1177/1747519819876524Journal of Chemical ResearchLu et al.
Research Paper
Journal of Chemical Research
–4
1
A convenient two-step synthesis of
Coenzyme Q1
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Bin Lu , Yong-Fu Qiu , Shi Qi and Jin Wang
Abstract
A convenient method for the preparation of Coenzyme Q from cheap and readily available 3,4,5-trimethoxytoluene
1
is developed. Coenzyme Q is synthesized in a moderate yield by a two-step procedure involving the key reaction of
1
an allyl bromide with Coenzyme Q through a redox chain reaction. The reaction is efficient and can be used for the
0
synthesis of other Coenzyme Q compounds.
Keywords
3
,4,5-trimethoxytoluene, chain reaction, Coenzyme Q
Date received: 23 April 2019; accepted: 26 August 2019
and the requisite organotellurium reagent were difficult to
Introduction
9
prepare. Tabushi et al. reported a β-cyclodextrin-catalyzed
Coenzyme Q (CoQ ; Figure 1) is an isoprenoid quinone
1
0
10
allylation–oxidation of hydroquinone to form CoQ in 11%
1
1
compound and plays a pivotal role in the electron transport
5
10
yield (Scheme 1, eq 2). Recently, Chen and Borioni et al.
2
chain in respiratory processes. CoQ is a natural antioxi-
1
0
started from 3,4,5-tetramethoxytoluene (TMT) to obtain
3
dant that scavenges free radicals. It is widely used in the
treatment of cardiovascular disease and mitochondrial dis-
CoQ in multiple steps (Scheme 1, eq 3). Unfortunately, all
1
these methods generally gave low yields and complex by-
products. Therefore, a general and practical method for effi-
4
orders. Coenzyme Q (CoQ ; Figure 1) is an important
1
1
fragment of the Coenzyme Q (CoQ) series which are active
in the electron transport and oxidative phosphorylation pro-
cesses in mitochondria. CoQ also acts as a key intermedi-
cient CoQ synthesis is highly desirable. Here, we report a
1
two-step synthesis of CoQ by starting from 3,4,5-trimethox-
1
1
ytoluene with a total yield of 60% (Scheme 1, eq 4).
5
ate in the synthesis of higher CoQ analogues.
There have been several methods published for the prepa-
ration of CoQ , most of which involve a Lewis acid-catalyzed
1
2
School of Pharmacy, Jiangsu Key Laboratory for Bioresources of Saline
Soils, Yancheng Teachers University, Yancheng, P.R. China
Department of Chemistry, Yale University, New Haven, CT, USA
1
reaction between an allylic alcohol and hydroquinone, fol-
2
lowed by oxidation to the quinones. Hegedus and Waterman
6
and Sato et al. synthesized CoQ by reaction of π-allylic *These authors contributed equally to this work.
1
nickel complexes with quinones in 26% yield (Scheme 1, eq
7
Corresponding author:
1
). Yamago et al. reported a radical-mediated synthesis of
Jin Wang, School of Pharmacy, Jiangsu Key Laboratory for Bioresources
of Saline Soils, Yancheng Teachers University, Hope Avenue South Road
No. 2, Yancheng 224007, Jiangsu, P.R. China.
8
substituted quinones with organotellurium compounds.
However, these reactions were quite sensitive to the reaction
conditions, the key reagents π-allylnickel bromide complex Email: jaxdon@126.com; jin.wang.jw2624@yale.edu

2
Journal of Chemical Research 00(0)
Figure 1. Structures of CoQ10 and CoQ1.
Scheme 1. Various methods for the syntheses of CoQ : (a) previous work and (b) this work.
n
Results and discussion
as an oxidant to afford the desired product CoQ in 85%
0
First, a single-step synthesis of CoQ is shown in Table 1; yield (Table 1, entry 2). However, when cerium ammonium
0
this oxidation reaction of TMT is conducted in acetic acid nitrate (CAN) was used as the oxidant, we did not observe
at 50°C in less than 2h and without using any metal cata- any product CoQ (Table 1, entry 5).
0
11
lyst. This environmentally friendly procedure is based on
Inspired by Xu and Li’s work on the alkylation of
the oxidant as an oxygen atom donor, and the acidic solvent p-quinones by a redox chain reaction, we tried to synthe-
acetic acid plays an important role in the transformation. size CoQ by the allylation of CoQ with 1-bromo-3-me-
1
0
The traditional method employing 30% H O as an oxidant thyl-2-butene 1; the results are shown in Table 2. Diethyl
2
2
gave a yield of 50% (Table 1, entry 1). The use of Na S O
1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate
and (NH ) S O improved the reaction yield (Table 1, (Hantzsch ester) was selected as an initiator which can
2
2
8
4
2
2
8
1
2
entries 3 and 4). The best yield was obtained using K S O
accelerate the alkylation according to the literature, and
2
2
8

Lu et al.
3
the reaction works with many Lewis acids as catalysts in readily available 3,4,5-trimethoxytoluene (TMT) in two
dichloromethane as the solvent at room temperature (r.t.). steps. The overall yield of CoQ is 60%. The intermediate
1
Typical Lewis acid catalysts were screened in the reac- CoQ was also obtained in 85% yield in the first step. The
0
tion; however, AlCl , ZnCl , and FeCl did not catalyze second redox chain reaction between allyl bromide and
3
2
3
the reaction (Table 2, entries 1–3). The solvents used for CoQ provided a one-step procedure for the direct intro-
0
this reaction was crucial, acetone, tetrahydrofuran (THF), duction of allyl groups on quinones in good yield. The
CH CN, or toluene as the solvent led to low yields of reaction is efficient, clean, and the workup is easy. This
3
CoQ (Table 2, entries 5–8). On the basis of these screen- method may find use for the synthesis of other CoQ
1
ing studies, the optimum conditions employed BF ·Et O compounds.
3
2
as the catalyst and dichloromethane as the solvent.
Experimental section
Conclusion
All reactions were monitored by thin-layer chromatogra-
In summary, we have developed a convenient synthetic phy (TLC; SiO , petroleum ether (PE; b.p. 50°C–70°C)/
2
protocol for the preparation of CoQ from cheap and ethyl acetate (EtOAc), 5:1). Melting points were measured
1
on BUCHI Melting Point M-565. Nuclear magnetic reso-
nance (NMR) and mass spectra were recorded on a Bruker
Avance III-HD 400 NMR and a TripleTOF mass spectrom-
Table 1. Single-step synthesis of CoQ0.
eter, respectively. Potassium persulfate, ammonium persul-
fate, Hantzsch ester, and BF ·Et O were purchased from
3
2
Adamas, P. R. of China, and used without further
purification.
General method for the preparation of
2
,3-dimethoxy-5-methyl-1,4-benzoquinone
(
CoQ )
0
Entry
Oxidant
Yield (%)
3
,4,5-Trimethoxytoluene (1.82 g, 10 mmol) was dis-
1
2
3
4
5
30% H O
50
85
70
60
0
solved in a mixture of acetic acid (10 mL) and catalytic
H SO (0.01 mL), then a solution of the oxidant
2
2
K S O
2
2
8
2
4
(NH ) S O
(15 mmol) was added dropwise over 10 min. The mixture
was stirred and heated at 50°C for 1 h. After cooling, the
reaction mixture was extracted with CH Cl (3 × 10 mL).
4
2
2
8
Na S O
8
2
2
CAN
2
2
The combined organic phases were washed with H O
2
CAN: cerium ammonium nitrate.
Reaction conditions:TMT (0.01mol), oxidant (1.5 equiv.), 2h, open air.
Bold values represents the best condition.
and NaHCO , then dried over anhydrous Na SO and
3
2
4
evaporated under reduced pressure. The residue was
Table 2. Redox chain reaction for the synthesis of CoQ1.
Entry
Lewis acid
Solvents
Yield (%)
1
2
3
4
5
6
7
8
AlCl3
ZnCl2
FeCl3
CH Cl2
N.R.
N.R.
N.R.
70
8
32
2
CH Cl2
2
CH Cl2
2
BF ·Et O
CH Cl2
3
2
2
BF ·Et O
Acetone
THF
3
2
BF ·Et O
3
2
BF ·Et O
CH CN
20
10
3
2
3
BF ·Et O
Toluene
3
2
CoQ : coenzyme Q ; N.R.: no reaction;THF: tetrahydrofuran; r.t.: room temperature.
1
1
Reaction conditions: CoQ (0.01mol), compound 1 (0.01mol), Hantzsch ester (1mmol), Lewis acid (0.01mol), r.t., N atmosphere.
0
2
Bold values represents the best condition.

4
Journal of Chemical Research 00(0)
purified by silica gel column chromatography (PE/ Declaration of conflicting interests
EtOAc, 5:1) to give CoQ0.
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
1
3
CoQ , red-colored needles, m.p. 55°C–58°C (Lit.
0
5
7°C–59°C).
1
H NMR (400MHz, CDCl ): δ=6.44 (q, J=1.7Hz, 1H),
3
Funding
4
.02 (s, 3H, OCH ), 4.00 (s, 3H, OCH ), 2.04 (d, J=1.6Hz,
3
3
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
study was supported by the National Natural Science Foundation
of China (Nos 31600740 and 81803353), the Natural Science
Foundation of Jiangsu Province (BK20160443), the Six Talent
Peaks Project in Jiangsu Province (SWYY-094), the Jiangsu
3
H, CH ).
3
1
3
C NMR (101MHz, CDCl ): δ=184.4 (C=O), 184.2
3
(
(
C=O), 145.0, 144.8, 144.0, 131.2, 61.2 (OCH ), 61.1
OCH ), 15.4 (CH ).
3
3
3
MS (ESI): m/z=205 [M+Na]+.
The spectroscopic data are in accord with the literature.13 Provincial Key Laboratory for Bioresources of Saline Soils (Nos
JKLBS2016013 and JKLBS2017010), and the College Students
Practice Innovation Training Program of Yancheng Teachers
University (Provincial key projects).
General method for the preparation of
,3-dimethoxy-5-methyl-6-(3-methyl-2-
butenyl)-1,4-benzoquinone (CoQ )
2
1
ORCID iD
1
-Bromo-3-methyl-2-butene (1; 1.49 g, 0.01 mol), Jin Wang
Hantzsch ester (0.25 g, 1 mmol), and CoQ0 (1.82 g,
.01 mol) were dissolved in dichloromethane (10 mL)
https://orcid.org/0000-0002-2929-6381
0
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1
1H NMR (400MHz, CDCl3): δ=4.32 (t, 1H, J=7.0Hz,
8
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C=CH), 3.96 (s, 3H, CH3O), 3.94 (s, 3H, CH3O), 3.12 (d,
3
2
1
H, J=7.0Hz, CH2), 2.14 (s, 3H, CH3), 1.75 (s, 3H, CH3),
.65 (s, 3H, CH3).
9
1
1
3
C
NMR (101MHz, CDCl3): δ=180.0 (C=O),
1
1
75.6(C=O), 144.1, 143.0, 142.7, 132.6, 126.5, 123.4, 60.5
2
(
OCH ), 60.3 (OCH ), 30.4, 29.1, 25.4, 15.7(CH ).
MS (ESI): m/z=251 [M+H] .
3
3
3
+
1