Efficient synthesis of 2,3-dimethoxy-5-methyl-6-morpholinomethyl-1,4-benzoquinone hydrochloride

Article abstract of DOI:10.1515/znb-2014-0208

The title compound (5) was prepared by a reaction sequence starting from 2,3,4,5-tetramethoxytoluene (1) via the Blanc reaction, oxidation and alkylation. The described method provides a good yield of the C-6 heterocyclic-substituted benzoquinone derivati

Full text of DOI:10.1515/znb-2014-0208

Z. Naturforsch. 2015; 70(4)b: 221–223
Jin Wanga,*, Teng-huo-sheng Liao and Jian Yang*
Efficient synthesis of 2,3-dimethoxy-5-methyl-
6-morpholinomethyl-1,4-benzoquinone
hydrochloride
Abstract: The title compound (5) was prepared by a reac- in the improvement of immunotherapy [3, 4]. CoQ10 is also
tion sequence starting from 2,3,4,5-tetramethoxytoluene used as a food supplement in many countries, and there is
(1) via the Blanc reaction, oxidation and alkylation. The an increasing market demand [5].
described method provides a good yield of the C-6 hetero-
Previous studies [2, 6] have shown that some metabo-
cyclic-substituted benzoquinone derivative and is suitable lites of CoQ10, and a number of short-chain CoQ analogs
for the synthesis of other benzoquinone derivatives.
exhibit significant biological activities, such as inhibition
of mitochondrial complex I (NADH-ubiquinone reduc-
Keywords: benzoquinone derivative; blanc reaction; tase), cardiotonic activity, 5-lipoxygenase suppressant
coenzyme Q analogs.
activity, blood platelet aggregation inhibition, etc. [7, 8].
Among the previously synthesized CoQ analogs, some C-6
heterocyclic-substituted benzoquinone derivatives can be
used as drugs [9, 10]. However, the methods described in
the literature [8–10] for the preparation of these heterocy-
clic-substituted CoQ analogs have significant drawbacks
such as tedious reaction conditions, low yields of the
products and difficult work-up. In view of the difficulties
associated with the preparation of previous CoQ analogs
[5–10], the availability of compound 1 [11–18] prompted
us to devise a practical route to 2,3-dimethoxy-5-methyl-
DOI 10.1515/znb-2014-0208
Received September 4, 2014; accepted October 16, 2014
1 Introduction
The ubiquinone coenzyme Q (CoQ, or CoQn) is biosyn-
thesized in mitochondria and occurs naturally in our
dietary foods (beef, pork, fish, oils, etc.), which is a ben-
zoquinone with a side-chain of different hydrophobic
isoprenoid units (Fig. 1), acting as mobile mediators for
electron transfer and protein translocation between redox
enzymes in the electron transport chain of mitochondria
[1, 2]. CoQ10, the main homolog of CoQ existing in humans,
is our only lipid-soluble antioxidant synthesized endog-
enously and efficiently prevents the oxidation of proteins,
lipids and DNA. CoQ10 is widely used in the treatment of
cardiovascular disease, neurodegenerative disorders and
6-morpholinomethyl-1,4-benzoquinone
hydrochloride
(5), a heterocyclic-substituted CoQ analog which showed
good activity to restore succinate oxidation [9]. In order
to better understand the relationship between the dif-
ferent heterocyclic-substituted side chains and the bio-
logical activities, the development of simple and efficient
methods for the synthesis of C-6 heterocyclic-substituted
CoQ analogs are therefore desirable.
We now report a convenient and efficient synthesis
of 2,3-dimethoxy-5-methyl-6-morpholinomethyl-1,4-ben-
zoquinone hydrochloride (5) from the easily available
2,3,4,5-tetramethoxytoluene (1). The synthetic route is
shown in Scheme 1.
aCurrent address: Université de Toulouse, Université Toulouse III –
Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 9,
France; and Institut de Pharmacologie et de Biologie Structurale,
UMR 5089, 205 route de Narbonne, 31077 Toulouse Cedex04, France.
*Corresponding authors: Jin Wang, Faculty of Life Science and
Technology, Kunming University of Science and Technology,
Kunming, Yunnan, 650224, P. R. China,
2 Results and discussion
e-mail: woongching@gmail.com; and Jian Yang, Faculty of Life
Science and Technology, Kunming University of Science and
Technology, Kunming, Yunnan, 650224, P. R. China,
As shown in Scheme 1, first, bromomethylation of 1 using
paraformaldehyde and 47% HBr (Blanc reaction) under
solvent-free conditions provided 2 at 40 °C in an excellent
yield (97 %) [12]. Then, direct transfer of 2 to benzoqui-
none 3 by employing ceric ammonium nitrate (CAN) as
e-mail: pharmacistkg101@126.com
Teng-huo-sheng Liao: Zhejiang MENOVO pharmaceutical Co., Ltd,
ShangYu, Zhejiang, 312300, P. R. China
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222ꢀ
ꢀJ. Wang et al.: Efficient synthesis of 2,3-dimethoxy-5-methyl-6-morpholinomethyl-1,4-benzoquinone hydrochloride
O
3 Experimental section
H3CO
H3CO
CH3
All reactions were monitored by TLC, the melting points
H
n
O
were measured with an YRT-3 temperature apparatus
(Tianda Tianfa Technology Co., Ltd. Tianjin, China) and
are uncorrected. IR spectra were recorded on an Impact
400 FT-IR instrument (PerkinElmer, USA). 1H NMR spectra
were recorded on a Bruker DRX NMR spectrometer (Bruker,
Germany) and mass spectra were obtained on a LC mass
spectrometer (Shimadzu 30& Triple QUAD 5500, Japan),
Coenzyme Qn
(ubiquinones; n < 12)
Fig. 1:ꢀCoenzyme Q (CoQ, or CoQn).
a selective oxidant, gave a good yield (84 %) of 3 which respectively. All reagents were purchased from Adamas-
is the key intermediate for the preparation of CoQ10 and beta, P. R. China, and used without further purification.
its analogs. In this transformation, benzoquinone 3 is the 2,3,4,5-tetramethoxytoluene (1) was prepared by methods
major product, but we also detected a small amount of mentioned in the literature [11–15, 19, 20].
other benzoqunione by-product on the TLC. Finally, direct
alkylation of 2 with morpholine in the presence of K2CO3
under mild conditions provided 4 (81 % yield, based on 3.1 1-(Bromomethyl)-2,3,4,5-tetramethoxy-
3), which was subsequently converted into its hydrochlo-
6-methylbenzene (2)
ride salt 5 in a good yield by addition of concentrated
hydrochloric acid in ethanol.
To a stirred mixture of compound 1 (0.212 g, 0.001 mol)
In conclusion, a short route for the synthesis of com- and paraformaldehyde (0.060 g, 0.002 mol) was added
pound 5 has been found in an overall yield (63 %, based 47 % HBr (8 mL) dropwise at room temperature. Then the
on 1). From the synthetic point of view, an approach based mixture was stirred at 40 °C for 1 h, quenched with water,
on the reactions with 3 looked promising for the synthesis and the mixture was extracted with petroleum ether, the
of C-6 substituted CoQ analogs bearing a heterocyclic ring, combined organic layers were washed with brine. The
which also avoids the heterocyclic ring being oxidized solution was dried over anhydrous sodium sulfate, and
by the oxidant CAN during the reaction. Moreover, this the solvent was removed in vacuo to afford 2 (0.295 g,
method not only has the advantages of mild conditions, 97 % yield) as a yellow oil. – IR (KBr): v ꢀ=ꢀ 2979, 2940, 1473,
easily accessible starting materials and facile separation, 1415, 1278, 1213, 1116 cm-1. – 1H NMR (400 MHz, CDCl3): δ ꢀ=ꢀ
but it is also less expensive, more practical, and environ- 4.59 (s, 2H, CH2Br), 3.94 (s, 3H, OCH3), 3.92 (s, 3H, OCH3),
mentally friendly. Hence, we believe that this experimen- 3.89 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 2.26 (s, 3H, CH3).
tally simple approach could be a useful addition to the 1H NMR data were in agreement with values found in the
reported methods for the preparation of CoQ analogs.
literature [21].
OCH3
O
OCH3
CH2Br
H3CO
H3CO
H3CO
H3CO
CH2Br
H3CO
H3CO
a
b
CH3
CH3
CH3
OCH3
OCH3
O
2
1
3
c
O
O
O
O
H3CO
H3CO
CH2R
CH3
H3CO
H3CO
N
O
d
H3CO
H3CO
N
O
CH3
HCl
CH3
O
O
Coenzyme Q
R = Alkyl
4
5
Scheme 1:ꢀReagents and conditions: (a) (HCHO)n, 47 % HBr, 40 °C, 97 %; (b) CAN, THF/H2O, 0 °C, 84 %; (c) K2CO3, ethanol, 60 °C, 81 %; (d)
37 % HCl, ethanol, 0 °C, 95 %.
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ꢂ223
formed immediately, the solids were filtered and recrys-
tallized from ethanol to afford the required hydrochloride
salts 5 (0.32 g, 95 % yield). M. p. 164–166 °C (lit. 163–165 °C)
3.2 2-Bromomethyl-5, 6-dimethoxy-3-methyl-
[1, 4]benzoquinone (3)
Excess CAN (62.5 g, 0.114 mol) in water (120 mL) was added [9]. – IR (KBr): v ꢀ=ꢀ 3443, 2538, 2435, 1671, 1649, 1605, 1463,
1
dropwise at 0 °C to a solution of compound 2 (11.6 g, 0.038 1266, 1206, 1020 cm–1. – H NMR (500 MHz, D2O): δ ꢀ=ꢀ 4.15
mol) in THF (20 mL). The mixture was stirred at room tem- (s, 2H, CH2), 3.85 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.4 (brs,
perature for 2 h. The progress of the reaction was moni- 8H, H-morpholino), 2.04 (s, 3H, CH3). – MS (API): m/z ꢀ=ꢀ
+
tored by TLC. After completion of the reaction, the crude 282 [M+H] . 1H NMR and 13C NMR data were in agreement
was extracted with three portions of CH2Cl2 (15 mL). The with the values in the literature [9].
orange extracts were washed with brine until the water
phase was neutral (PH~7), then dried over anhydrous Acknowledgments: This investigation was supported by
Na2SO4 and concentrated in vacuo. The crude product was the China Scholarship Council (CSC) (no. 201208530032)
purified using silica-gel column chromatography with and the Science Foundation of the Department of Educa-
petroleum ether and EtOAc (3:1) as an eluent to give the tion of Yunnan Province (no. 2011J077).
desired benzoquinone 5 (8.7 g, 84 % yield) as an orange
oil. – IR (KBr): v ꢀ=ꢀ 2949, 1665, 1619, 1457, 1282, 1211, 1159,
1113, 1023 cm–1. – H NMR (500 MHz, C5D5N): δ ꢀ=ꢀ 4.29 (s,
1
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