A Concise Synthesis of Coenzyme Q0

Full text of DOI:10.1080/00304948.2019.1673616

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: https://www.tandfonline.com/loi/uopp20
A Concise Synthesis of Coenzyme Q0
Yong-Fu Qiu, Yi-Yu Yan, Bin Lu, Lei Tang, Yu-Lin Zhai, Ke-Xin Chen & Jin Wang
To cite this article: Yong-Fu Qiu, Yi-Yu Yan, Bin Lu, Lei Tang, Yu-Lin Zhai, Ke-Xin Chen & Jin
Wang (2019): A Concise Synthesis of Coenzyme Q , Organic Preparations and Procedures
0
International, DOI: 10.1080/00304948.2019.1673616
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Organic Preparations and Procedures International, 0:1–4, 2019
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ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2019.1673616
OPPI BRIEF
A Concise Synthesis of Coenzyme Q0
1
1
1,3
1
Yong-Fu Qiu, Yi-Yu Yan, Bin Lu, Lei Tang, , Yu-Lin
1
1
1,2
Zhai, Ke-Xin Chen, and Jin Wang
1
School of Pharmacy, Yancheng Teachers University, Hope Avenue South
Road No. 2, Yancheng, 224007, Jiangsu Province, P. R. China
2
Jiangsu Key Laboratory for Bioresources of Saline Soils, Yancheng Teachers
University, Kaifang Avenue No. 50, Yancheng, 224002, Jiangsu Province,
P. R. China
3
College of Biotechnology and Pharmaceutical Engineering, Nanjing
University of Technology, Nanjing, 211816, Jiangsu Province, P. R. China
Coenzyme Qs (CoQ ), also known as the ubiquinones, act as mobile mediators for elec-
n
tron transfer and protein translocation between redox enzymes in the electron transport
1
chain of mitochondria. CoQ and idebenone are the best known Coenzyme Q com-
1
0
pounds. They act as free radical scavenging antioxidants and they may have value for
2
the treatment of Alzheimer’s disease and other cognitive defects. 2,3-Dimethoxy-5-
methyl-1,4-benzoquinone, known as Coenzyme Q (CoQ ), can serve as a key inter-
0
0
mediate in the synthesis of coenzyme Q , idebenone and other ubiquinones
1
0
3
(
Scheme 1).
Several synthetic methods have been reported for the preparation of CoQ via the
0
catalytic oxidation of commercially available 3,4,5-trimethoxytoluene (1) with hydrogen
peroxide (H O ). Among the catalysts applied have been potassium hexacyanoferrate(III)
2
2
4
5
6
K Fe(CN) , methyltrioxorhenium (CH ReO ), ruthenium complex-bound norvaline,
and c-Keggin divanadium-substituted phosphotungstate. Despite their own merits, none
3
6
3
3
7
of these catalysts is attractive for the large-scale synthesis of CoQ . Their drawbacks
0
include the use of expensive metal catalysts, inconvenient reaction protocols and low
yields. We now report on a simple and efficient route for the synthesis of CoQ . The
0
route is described in Scheme 2.
Thus treatment of 3,4,5-trimethoxytoluene (1) with NaBr–H O system as a bromi-
2
2
ꢀ
nating agent in ethanol at 25 C produced 2 in quantitative yield. Compound 2 was
treated with CH ONa-CH OH in the presence of cuprous bromide and dimethylforma-
3
3
ꢀ
mide (DMF) at 100 C for 4 h to afford 3 in 98% yield. Finally, compound 3 was oxi-
dized with potassium peroxydisulfate (K S O ) at room temperature to give CoQ in
2
2
8
0
9
6% yield.
Received September 11, 2018; in final form January 11, 2019.
Address correspondence to Jin Wang, School of Pharmacy, Yancheng Teachers University,
Hope Avenue South Road No. 2, Yancheng, 224007, Jiangsu Province, P. R. China.
1

2
Wang et al.
Scheme 1. Structures of CoQ , CoQ , and Idebenone.
10
0
In summary, an efficient route for the synthesis of CoQ has been achieved in an
0
overall yield of 94%. The present route eliminates the use of large amounts of bromine.
Moreover, this method has the advantages of mild conditions, easily accessible starting
materials and facile compound isolation. It is also more environmentally friendly. It
could be a promising route for the industrial synthesis of the Coenzyme Q series.
Experimental Section
All reactions were monitored by TLC (SiO , petroleum ether/EtOAc 5:1). Melting
2
points were measured on Melting Point M-565 (BUCHI) and are uncorrected. NMR
and mass spectra were recorded on a Bruker Avance III-HD 400 NMR and TripleTOF
Mass spectrometers, respectively. GC-Mass spectra were recorded on a Triple
Quadrupole GC/MS Agilent 7890B-7000C. All reagents (e. g., NaBr, CuBr, 30%H O ,
2
2
K S O ) were purchased from Adamas, P. R. China, and used without further
2
2 8
purification.
2
-Bromo-3,4,5-trimethoxytoluene (2)
Compound 1 (1.82 g, 0.01 mol), NaBr (1.13 g, 0.011 mol) and sulfuric acid (2 mL) were
dissolved in ethanol (8 mL). The mixture was treated dropwise with 30% H O (5 mL,
2
2
0
.045 mol) at room temperature over a period of 1 h. Then the mixture was quenched
with water (10 mL) and extracted with petroleum ether (15 mL ꢁ 3). The organic layers
were combined and evaporated in vacuo to afford 2, 2.60 g, 100%, yellowish oil.
ꢂ1
1
IR: (cm ) 3490, 2934, 1570, 1466, 1402, 1109, 824. H NMR (400MHz, CDCl ):
3
d 6.61 (s, 1H, ArH), 3.89 (s, 3H, OCH ), 3.86 (s, 3H, OCH ), 3.84 (s, 3H, OCH ),
3
3
3
1
3
2
1
.37 (s, 3H, CH3). C NMR (101 MHz, CDCl ): d 152.2, 150.8, 141.1, 133.4, 110.8,
3
09.5, 61.1 (OCH ), 60.9 (OCH ), 56.1 (OCH ), 23.2(CH ). The spectroscopic data are
3
3
3
3
8
in accord with the literature.
2
,3,4,5-Tetramethoxytoluene (3)
A mixture of 2 (0.26 g, 1 mmol), CH ONa (11.2 g, 0.20 mol), CuBr (0.14 g, 1 mmol)
3
ꢀ
and DMF (1 mL) was stirred at 100 C for 4 h under a N atmosphere. Then, 10 mL 2M
2
HCl was added, and the mixture was refluxed for another 10 minutes. The mixture was
quenched with water (8 mL) and extracted with petroleum ether (10 mL ꢁ 3). The
organic layers were combined and evaporated in vacuo to afford 3, 0.21 g, 98%, yel-
low oil.

Coenzyme Q0
3
ꢀ
Scheme 2. Reagents and conditions: (a) NaBr, 30%H
2
ꢀ
O
2
, EtOH, H
2
SO
4
, 25 C, 100%; (b)
ꢀ
CH
3
ONa, CuBr, DMF, 100 C, 98%; (c) K
2
S
2
O
8
, THF, 25 C, 96%.
ꢂ1
1
IR: (cm ) 2947, 1590,1467, 1232, 1103, 889. H NMR (400 MHz, CDCl ) d 6.45
3
(
s, 1H), 3.93 (s, 3H, OCH ), 3.86 (s, 3H, OCH ), 3.81 (s, 3H, OCH ), 3.78 (s, 3H,
3 3 3
1
3
OCH ), 2.22 (s, 3H, CH ). C NMR (101 MHz, CDCl ) d 149.1, 147.0, 145.4, 140.8,
3
3
3
1
25.8, 108.3, 61.1 (OCH ), 61.0 (OCH ), 60.6 (OCH ), 56.1 (OCH ), 15.8 (CH ). The
3 3 3 3 3
8
spectroscopic data are in accord with the literature.
Coenzyme Q0
Compound 3 (0.32 g, 1.5 mmol) was dissolved in acetonitrile (2 mL), and an excess of a
ꢀ
solution of K S O (1.6 g, 6 mmol) in 3 mL water was added at 25 C. The reaction
2
2 8
mixture was stirred at room temperature for 1 h. The progress of the reaction was moni-
tored by TLC. After completion of the reaction, the mixture was extracted with
dichloromethane (10 mL ꢁ 3). The organic layers were washed with brine until neutral-
ity, then dried over anhydrous Na SO and concentrated in vacuo. The crude product
2
4
was purified by a silica-gel column chromatography with petroleum ether and EtOAc
ꢀ ꢀ
3:1) to give CoQ , 0.26 g, 96%, red needles, m.p 56-57 C (lit 57-59 C). IR: (cm )
0
3
5
ꢂ1
(
1
590, 3415, 1661, 1603, 1291, 1226, 999. H NMR (400 MHz, CDCl ) d 6.44 (q,
3
J ¼ 1.7 Hz, 1H), 4.02 (s, 3H, OCH ), 4.00 (s, 3H, OCH ), 2.04 (d, J ¼ 1.6 Hz, 3H,
3
3
13
CH ). C NMR (101 MHz, CDCl ) d 184.4 (C5O), 184.2(C5O), 145.0, 144.8, 144.0,
3
3
1
31.2, 61.2 (OCH ), 61.1 (OCH ), 15.4 (CH ). GC-MS (EI): m/z ¼ 182. The spectro-
3
3
3
5
scopic data are in accord with the literature.
Acknowledgments
Yong-Fu Qiu, Yi-Yu Yan, and Bin Lu contributed equally to this work. This study
was supported by the National Natural Science Foundation of China (Nos. 31600740
and 81903427), 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).
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