Efficient synthesis of 5-bromo-2,3-dimethoxy-6-methyl-1,4-benzoquinone: key intermediate for preparing Coenzyme Q

Article abstract of DOI:10.1007/s11696-019-00826-6

The title compound, a key intermediate for preparing Coenzyme Qn family, was prepared in an excellent yield by a reaction sequence starting from the commercially available 3,4,5-trimethoxytoluene 1 via bromination, methoxylation and oxidation reactions. A

Full text of DOI:10.1007/s11696-019-00826-6

Chemical Papers
https://doi.org/10.1007/s11696-019-00826-6
ORIGINAL PAPER
Efcient synthesis
of 5‑bromo‑2,3‑dimethoxy‑6‑methyl‑1,4‑benzoquinone: key
intermediate for preparing Coenzyme Q
Yong‑Fu Qiu1 · Bin Lu1 · Yi‑Yu Yan1 · Wan‑Yue Luo1 · Jin Wang1 · Xiao Hu2
Received: 16 March 2019 / Accepted: 20 May 2019
© Institute of Chemistry, Slovak Academy of Sciences 2019
Abstract
The title compound, a key intermediate for preparing Coenzyme Qn family, was prepared in an excellent yield by a reaction
sequence starting from the commercially available 3,4,5-trimethoxytoluene 1 via bromination, methoxylation and oxidation
reactions. An 80% overall yield was demonstrated on a multi-gram scale.
Keywords Coenzyme Q · 1,4-Benzoquinone · Bromination
Introduction
2010a), act as an antioxidant by reducing free radicals that
is widely used in the treatment of cardiovascular disease and
mitochondrial disorders (Gueven et al. 2015).
The Coenzyme Qn (CoQn) family (Wang et al. 2010b),
also known as ubiquinones (Scheme 1) (Wang et al. 2016),
which are composed of the redox active 1,4-benzoquinone
ring with a diferent number of isoprenoid units (n=1–12)
in diferent homologue forms occurring in nature (Ma et al.
2011). Coenzyme Q is known to act as mobile mediators
for electron transfer (Wang et al. 2014b) between redox
enzymes in the electron transport chain of mitochondria and
bacterial respiratory systems (Onoue et al. 2012). CoQ10, the
main homologue of CoQ existing in humans (Wang et al.
5-Bromo-2,3-dimethoxy-6-methyl-1,4-benzoquinone (5),
Coenzyme Q analogue (Wang et al. 2014a), which showed
good electron-transfer activity and radical properties in
aprotic media (Ma et al. 2011). Besides, Jung group (2000)
reported that Pd(0)-catalyzed Stille coupling of compound 5
with isoprenylstannanes can efciently produce Coenzyme
Qn, as shown in Scheme 1. In addition, compound 5 also
has been employed as key intermediate (Lu et al. 2010) for
the preparation of other biological CoQ analogues (Liu et al.
2015). However, little methods were published on the syn-
thesis of compound 5 (Hu et al. 2017). Hence, herein, we
reported an efcient synthetic route for the preparation of
compound 5 (Scheme 2).
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-019-00826-6) contains
supplementary material, which is available to authorized users.
Yong-Fu Qiu, Bin Lu, and Yi-Yu Yan contributed equally to this
work.
Results and discussion
* Jin Wang
As shown in Scheme 2, frst, treatment of 3,4,5-trimethoxytol-
uene (1) with NaBr–H2O2 system instead of bromine or NBS
as the brominating agent in acetic acid produced compound
2 in quantitative yield in an environmentally friendly method.
Second, the compound 2 was treated with CH3ONa–CH3OH
system in the presence of cuprous Bromide (CuBr) at 80 °C for
2 h to aford compound 3 in 89% yield. Third, bromination of
compound 3 with NaBr–H2O2 system to produce compound
4 in quantitative yield. Finally, compound 4 was oxidized with
(NH4)2Ce(NO3)6 in THF at 0 °C to give compound 5 in 90%
jaxdon@126.com
* Xiao Hu
120213512@qq.com
1
School of Pharmacy, Jiangsu Key Laboratory
for Bioresources of Saline Soils, Yancheng Teachers
University, Hope Avenue South Road No. 2,
Yancheng 224007, Jiangsu, People’s Republic of China
2
Library of Yancheng Teachers University, Hope
Avenue South Road No. 2, Yancheng 224007, Jiangsu,
People’s Republic of China
Vol.:(0123456789)
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Chemical Papers
Scheme 1 Coenzyme Qn and
Stille coupling
Scheme 2 Reagents and conditions: a NaBr, 30%H2O2, HOAc, 25 °C, quant.; b CH3ONa, CuBr, 80 °C, 89%; c NaBr, 30%H2O2, HOAc, 40 °C,
quant.; d (NH4)2Ce(NO3)6, THF/H2O, 0 °C, 90%
yield. The overall yield of compound 5 based on compound
1 is 80%.
recorded on a Bruker Avanc III-HD 400 NMR and a Tri-
pleTOF Mass spectrometers, respectively. GC–mass spec-
tra were recorded on Triple Quadrupole GC/MS of Agilent
7890B-7000C. All reagents, e.g., compound 1, NaBr, CuCl,
and (NH4)2Ce(NO3)6, were purchased from Adamas, P. R.
China, and used without further purifcation. Compound
2 and compound 3 were prepared by the literature method
(Wang et al. 2016, 2010a). Compound 5 is a reactive benzo-
quinone which should be stored below 0 °C.
Conclusions
In summary, a convenient method for the synthesis of com-
pound 5 was developed, and the overall yield of 80% (based on
compound 1) is satisfactory. Compared with previous method
utilized large amount of bromine as bromination agent by bro-
mination of the benzoquinone to prepare compound 5, this
method employed NaBr–H2O2 system as a green brominating
agent which eliminates the use of large amounts of bromine.
Moreover, this method not only has the advantages of mild
conditions, easily accessible starting materials and facile of
separation, and it is also less expensive and more practical.
These experimentally simple approaches could be useful for
the synthesis of other biological CoQ analogues.
2‑Bromo‑3,4,5‑trimethoxytoluene (2)
Compound 1 (3.6 g, 20 mmol) and NaBr (2.2 g, 20 mmol)
were dissolved in HOAc (10 mL). The mixture was treated
dropwise with 30% H2O2 (2.4 mL, 20 mmol) at room tem-
perature for 1 h. Then, the mixture was quenched with
water (8 mL) and extracted with diethyl ether (3 × 10 mL).
The combined organic phases were washed with saturated
NaHCO3 (3 × 5 mL) until pH 7, the combined the organic
layers were dried over anhydrous Na2SO4, and evaporated
in vacuo to aford yellow oil 2 (5.2 g) in quantitative yield.
1H NMR (400 MHz, CDCl3): δ 6.61 (s, 1H, ArH), 3.89
(s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.84 (s, 3H, OCH3),
2.37 (s, 3H, CH3).
Experimental section
All reactions were monitored by TLC (SiO2, petrol ether/
EtOAc 5:1), Melting points were measured on Melt-
ing Point M-565 (BuChi). NMR and mass spectra were
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Chemical Papers
13C NMR (101 MHz, CDCl3): δ 152.2, 150.8, 141.1,
133.4, 110.8, 109.5, 61.1 (OCH3), 60.9 (OCH3), 56.1
(OCH3), 23.2(CH3).
5‑Bromo‑2,3‑dimethoxy‑6‑methyl‑1,4‑benzoqui‑
none (5)
Spectroscopic data are according to the literature (Wang
et al. 2016).
Compound 4 (2.9 g, 10 mmol) was dissolved in THF(10 mL),
to the mixture a solution of ammonium ceric nitrate (2.2 g,
6 mmol) in H2O (5 mL) was added dropwise over a period
of 5 min at 0 °C. The mixture was stirred for another 30 min
at room temperature and extracted with dichloromethane
(3 × 30 mL). The organic layers were washed with brine
(3 × 10 mL) until neutrality, then dried over anhydrous
Na2SO4 and concentrated in vacuo. The crude product was
purifed by a silica-gel column chromatography with petro-
leum ether and EtOAc (5:1) to give red needle 5 (2.34 g) in
90% yield. m.p. 68–69 °C.
2,3,4,5‑Tetramethoxytoluene (3)
The mixture of compound 2 (2.6 g, 10 mmol), CH3ONa
(1.2 g, 20 mmol), CuBr (0.14 g, 1 mmol), and methanol
(5 mL) were stirred at 80 °C for 2 h under an N2 atmos-
phere. Then, a solution of 5 M HCl (20 mL) was added,
and the mixture was refuxed for another 10 min. The
reaction mixture was quenched with water (50 mL) and
extracted with diethyl ether (3 × 30 mL). The combined
organic phases were washed with saturated NaHCO3
(3 × 10 mL) until pH 7, then the combined the organic
layers were dried over anhydrous Na2SO4, and evaporated
in vacuo. The crude product was purifed by a silica-gel
column chromatography with petroleum ether and EtOAc
(10:1) to aford yellow oil 3 (1.89 g) in 89% yield.
1H NMR (400 MHz, CDCl3) δ 6.45 (s, 1H), 3.93 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.78 (s,
3H, OCH3), 2.22 (s, 3H, CH3).
1H NMR (400 MHz, CDCl3) δ 4.04 (s, 3H, OCH3), 4.01
(s, 3H, OCH3), 2.21 (s, 3H, CH3).
13C NMR (101 MHz, CDCl3) δ 181.0 (C=O), 176.7
(C=O), 145.2, 144.1, 143.8, 133.6, 61.58 (OCH3), 61.33
(OCH3), 16.75 (CH3).
GC–MS (EI): m/z=260.
Acknowledgements This study was supported by the National Natu-
ral 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 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).
13C NMR (101 MHz, CDCl3) δ 149.1, 147.0, 145.4,
140.8, 125.8, 108.3, 61.1 (OCH3), 61.0 (OCH3), 60.6
(OCH3), 56.1 (OCH3), 15.8 (CH3).
Spectroscopic data are according to the literature (Wang
et al. 2010a).
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