Practical synthesis of 2,3-dimethoxy-5-hydroxymethyl-6-methyl-1,4-benzoquinone

Article abstract of DOI:10.1515/chempap-2015-0001

2,3-dimethoxy-5-hydroxymethyl-6-methyl-1,4-benzoquinone (V) was prepared with a 75 % yield by means of a reaction sequence starting from 2,3,4,5-tetramethoxytoluene via Blanc chloromethylation reaction, Kornblum oxidation, NaBH₄ reduction and c

Full text of DOI:10.1515/chempap-2015-0001

Chemical Papers 69 (3) 486–489 (2015)
DOI: 10.1515/chempap-2015-0001
SHORT COMMUNICATION
Practical synthesis of
2,3-dimethoxy-5-hydroxymethyl-6-methyl-1,4-benzoquinone
d
a
e
a
a,b,cJin Wang*, Shuo Li, Tao Yang, Jin-Rong Zeng*, Jian Yang*
aKunming University of Science and Technology, Kunming, Yunnan, 650224, China
bUniversité de Toulouse, Université Toulouse III – Paul Sabatier, 118 route de Narbonne 31062 Toulouse Cedex 9, France
cInstitut de Pharmacologie et de Biologie Structurale, UMR 5089, 205 route de Narbonne, 31077 Toulouse Cedex 04, France
(current address)
dFirst Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China
eJiuzhou Pharmaceutical Co., Ltd. 99 Waisha Road, Taizhou, Zhejiang, 31800, China
Received 8 May 2014; Revised 6 July 2014; Accepted 10 July 2014
2,3-dimethoxy-5-hydroxymethyl-6-methyl-1,4-benzoquinone (V ) was prepared with a 75 % yield
by means of a reaction sequence starting from 2,3,4,5-tetramethoxytoluene via Blanc chloromethy-
lation reaction, Kornblum oxidation, NaBH4 reduction and ceric ammonium nitrate oxidation. The
procedure is operationally simple and amenable to gram-scale synthesis.
c
ꢀ 2014 Institute of Chemistry, Slovak Academy of Sciences
Keywords: coenzyme Q, idebenone, Kornblum oxidation, ceric ammonium nitrate oxidation
2,3-Dimethoxy-5-methyl-1,4-benzoquinones
are
coenzyme Q (CoQ) analogues and have attracted con-
siderable attention owing to their biological and phar-
macological activities (Astolfi et al., 2013; Bentinger
et al., 2007; Tsoukala & Bjørsvik, 2011). A number
of synthetic CoQ analogues have shown significant bi-
ological activities related to their therapeutic effects
(Jung et al., 2005; Okamoto et al., 1988). In particular,
idebenone (Fig. 1) was successfully designed and syn-
thesised as an clinical drug for the treatment of various
cognitive defects such as Alzheimer’s and Parkinson’s
diseases (Bentinger et al., 2007; Tsoukala & Bjørsvik,
2011). Idebenone was also shown to be a free radical
scavenger for reactive oxygen species (ROS) (Tsoukala
& Bjørsvik, 2011).
Fig. 1. Structure of idebenone and V.
published in the literature (Jung et al., 2005; Okamoto
et al., 1988; Lipshutz et al., 2005) for preparing CoQ
analogues have some drawbacks, such as low product
yields, harsh reaction conditions, toxic reagents (tita-
nium(IV) chloride, butyllithium, iodomethane), and
difficult procedures. 2,3,4,5-tetramethoxy-6-methyl-
benzaldehyde (III ) is a key intermediate for the syn-
thesis of CoQ analogues, and several methods (Jung
Many studies show that the C-6 position in some
2,3-dimethoxy-5-methyl-1,4-benzoquinones is substi-
tuted with small groups (alkyl) bearing strong anti-
oxidant activity and anti-glycation activity (Jung et
al., 2005; Okamoto et al., 1988). However, the methods
*Corresponding author, e-mail: woongching@gmail.com, pharmacistkg101@126.com
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J. Wang et al./Chemical Papers 69 (3) 486–489 (2015)
487
Fig. 2. Synthetic route to V: i) (HCHO)n, 37 % HCl, 40◦C 96 % ; ii) method 1 – K2Cr2O7, H2O, TBAB, 60◦C, 69 %; method
2 – NaHCO3, DMSO, 80◦C, 87 %; iii) NaBH4, CH3OH, 25◦C, 97 %; iv) CAN, THF/H2O, 0◦C, 92%; v) POCl3, DMF,
80◦C.
et al., 2005; Nyland et al., 2010) have been reported
for the synthesis of III. Usually, (Jung et al., 2005;
Ma et al., 2011) the formyl group was introduced into
the aromatic ring by using 1,1-dichloromethyl methyl
ether (Cl2CHOCH3) and TiCl4 under strict water-
free conditions at 0◦C; however, the reagent TiCl4
is easily hydrolysed by water to form a strong ir-
ritant gas (HCl), and the yield is not reproducible,
which restricts the multi-gram synthesis of III. In
view of the difficulties associated with the prepara-
tion of previous CoQ analogues (Jung et al., 2005;
Okamoto et al., 1988; Lipshutz et al., 2005), the
availability of 1-chloromethyl-2,3,4,5-tetramethoxy-6-
methylbenzene (II ) (Wang et al., 2010a, 2011a,
2011b) prompted the present initiative to devise a
practical route to 2,3-dimethoxy-5-hydroxymethyl-6-
methyl-1,4-benzoquinone (V) which is an analogue of
idebenone. The current study details a convenient and
practical method for the synthesis of V. The synthetic
route is described in Fig. 2.
All reactions were monitored by TLC. NMR spec-
tra data were recorded on a Bruker DRX 500 NMR
spectrometer (Germany, 500 MHz for 1H NMR and
125 MHz for 13C NMR). TMS was used as an inter-
nal standard and chemical shift is given in δ relative
to TMS, and for mass measurement a LC-MS (API)
(Shimadzu 30& Triple QUAD 5500, Japan) mass spec-
trometer was used (mobile phase; A – water (0.1 vol. %
trifluoroacetic acid (TFA)), B – acetonitrile (0.1 vol. %
TFA), gradient – 5 %–95 % B in 1.2 min; flow-rate –
2.2 mL min−1, column Poroshell 120 EC-C18 (Agilent,
Japan) 4.6 mm × 30 mm × 2.7 m). Ceric ammonium
nitrate (CAN), K2Cr2O7 and NaBH4 were purchased
from Adamas-beta (China).
2,3,4,5-Tetramethoxytoluene (I ) and II were pre-
pared by the method described previously (Wang et
al., 2010a, 2011a, 2011b).
III was prepared using two methods; (i) to a mix-
ture of II (5.20 g, 0.02 mol) and tetrabutylammonium
bromide (0.64 g, 0.002 mol) in CH2Cl2 (10 mL) was
added a solution of K2Cr2O7 (7.0 g, 0.024 mol) in
water (70 mL) at ambient temperature, then the re-
action mixture was heated at 60◦C for 2 h, until the
colour of the reaction solution changed from yellow
to orange. The mixture was cooled to ambient tem-
perature, diluted with water (30 mL), filtered to re-
move the solid (Cr2O3), then the filtrate was extracted
with petroleum ether (3 × 50 mL) and the combined
extracts were washed with brine. The solution was
dried over anhydrous sodium sulphate and the sol-
vent was removed under vacuum to afford a pure yel-
low oil III (3.3 g, 69 % yield); (ii) to a solution of II
(2.60 g, 0.01 mol) in dry dimethylsulphoxide (5 mL)
was added NaHCO3 (1.26 g, 0.15 mol) at ambient tem-
perature and maintained at 80◦C for 3 h. The mix-
ture was then cooled to ambient temperature, water
(50 mL) was added, the mixture was extracted with
petroleum ether (3 × 40 mL) and the combined ex-
tracts were washed with brine. The solution was dried
over anhydrous sodium sulphate and the solvent was
removed under vacuum. The crude products were pu-
rified by silica-gel column chromatography (Adamas-
beta; petroleum ether/EtOAc; ϕr = 5 : 1) to give a
yellow oil III (2.10 g, 87 % yield). 1H NMR data match
the data in the literature (Ma et al., 2011); LC-MS:
m/z =241(M+ + H).
2,3,4,5-Tetramethoxy-6-hydroxymethyltoluene(IV )
was prepared by adding NaBH4 (0.38 g,
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488
J. Wang et al./Chemical Papers 69 (3) 486–489 (2015)
10 mmol) to a solution of III (2.4 g, 10 mmol) in
methanol (10 mL) and the mixture was stirred at
ambient temperature. The progress of the reaction
was monitored by thin-layer-chromatography (TLC).
Once the reaction was complete, the reaction mixture
was extracted with three portions of CH2Cl2 (20 mL).
The orange extracts were washed with brine until a
neutral reaction was achieved, then dried over anhy-
drous Na2SO4 and concentrated under vacuum to give
a yellow oil IV (2.3 g, 97 % yield). 1H NMR data match
the data in the literature (Ma et al., 2011); LC-MS:
m/z = 265 (M+ + Na).
only a trace amount of carboxylic acid was detected
in the reaction product. Recently, a modified method
(Xu et al., 2007) of direct transformation of II to III
via Kornblum oxidation was improved utilising DMSO
as a oxidant which avoids the toxic chromate oxida-
tion; the yield for II to III was 87 % compared to
69 % when proceeding through II (Fig. 2). It is noted
that Kornblum oxidation afforded some by-products
of alcohol and acids, which required long-column chro-
matography to obtain the pure aldehyde III. The re-
duction reaction of III using NaBH4 at ambient tem-
perature afforded IV. Finally, the selective oxidation
of IV employing CAN as a mild oxidant gave V with
a good yield (92 %).
In summary, an operationally simple, efficient and
practical procedure for the preparation of V was devel-
oped; this achieved an overall yield of 75 % based on I.
Compounds III and IV may also be useful as starting
materials for the synthesis of other CoQ analogues.
Furthermore, compound III was successfully obtained
by oxidation using DMSO as a mild oxidation reagent
from benzyl halide II under mild conditions, thereby
eliminating the use of large amounts of a dangerous ox-
idation reagent (dichromate). The advantages of these
reactions are that they are operationally simple, read-
ily processed, amenable to gram-scale synthesis and
are carried out under mild reaction conditions. This
procedure is also applicable to the preparation of a
wide variety of biological idebenone analogues.
V was prepared when the excess solution of ceric
ammonium nitrate (11 g, 20 mmol) in water (11 mL)
was added drop-wise to a solution of compound IV
(1.6 g, 6.61 mmol) in tetrahydrofuran (10 mL) at 0◦C,
then the mixture was stirred at ambient temperature
and the progress of the reaction monitored by thin-
layer-chromatography (petroleum ether/EtOAc; ϕr =
4 : 1). Once the reaction was complete, the crude
product was extracted with three portions of CH2Cl2
(20 mL). The orange extracts were washed with brine
until a neutral reaction was achieved, then dried over
anhydrous Na2SO4 and concentrated under vacuum.
The crude products were purified by silica-gel column
chromatography (petroleum ether/EtOAc; ϕr = 4 : 1)
to give a orange solid V (1.29 g, 92 % yield). M.p.
50–51◦C. 53–55◦C (Okamoto et al., 1985).
1HNMR (500 MHz, CDCl3), δ: 4.45 (s, 2H,
CH2OH), 3.92 (s, 6H, OCH3), 2.92 (s, 1H, OH), 2.02
Acknowledgements. This study was financially supported by
the China Scholarship Council (CSC) (no.201208530032) and
the Science Foundation of Department of Education of Yunnan
Province (no. 2011J077).
(s, 3H, CH3).
13
—
—
CNMR (100 MHz, CDCl ), δ: 184.9 (C O),
3
—
184.5 (C O), 144.6, 144.1, 140.6, 138.6, 61.1 (OCH ),
—
3
56.5 (CH2OH), 11.6 (CH3).
References
Previously (Wang et al., 2010a, 2010b, 2011a,
2011b, 2012), a “green” and efficient synthesis of II
was described and this synthetic methodology has now
been extended to synthesise idebenone homologues.
Fig. 2 shows that I using paraformaldehyde and 37 %
HCl under solvent-free conditions provided II at 40◦C
with a 96 % yield (Wang et al., 2010a, 2010b, 2011a,
2011b). Inspired by some reports (Jung et al., 2005;
Nyland et al., 2010), a direct introduction of the
aldehyde group into the aryl ring via Vilsmeier re-
action employing POCl3 and dimethylformamide was
attempted; however, after many trials, only a trace
amount of the desired compound III was obtained. It
is assumed that the presence of four electron-donor
methoxy groups in the aromatic ring made it more
difficult for the Vilsmeier reagent to attack the C-
6 position of compound I. Next, a treatment of II
with K2Cr2O7 and tetrabutylammonium bromide in
water; modified as described by Freeman et al. (2007)
was assayed. This time the desired aldehyde III was
formed with a good yield without further purification
with chromatography. An aldehyde is known to un-
dergo further oxidation to a carboxylic acid under
aqueous conditions; however, in this transformation
Astolfi, P., Charles, L., Gigmes, D., Greci, L., Rizzoli, C., So-
rana, F., & Stipa, P. (2013). Reactions of nitric oxide and
nitrogen dioxide with coenzyme Q: involvement of the iso-
prenic chain. Organic & Biomolecular Chemistry, 11, 1399–
1406. DOI: 10.1039/c2ob27198b.
Bentinger, M., Brismar, K., & Dallner, G. (2007). The antiox-
idant role of coenzyme Q. Mitochondrion, 7, S41–S50. DOI:
10.1016/j.mito.2007.02.006.
Freeman, F., Ribagorda, M., & Adrio, J. (2007). e-EROS En-
cyclopedia of reagents for organic synthesis. Hoboken, NJ,
USA: Wiley. DOI: 10.1002/047084289x.
Jung, Y. S., Joe, B. Y., Cho, S. J., & Konishi, Y. (2005). 2,3-
Dimethoxy-5-methyl-1,4-benzoquinones and 2-methyl-1,4-
naphthoquinones: glycation inhibitors with lipid peroxida-
tion activity. Bioorganic & Medicinal Chemistry Letters, 15,
1125–1129. DOI: 10.1016/j.bmcl.2004.12.029.
Lipshutz, B. H., Lower, A., Berl, V., Schein, K., & Wetterich,
F. (2005). An improved synthesis of the “miracle nutri-
ent” coenzyme Q10. Organic Letters, 7, 4095–4097. DOI:
10.1021/ol051329y.
Ma, W., Li, D. W., Sutherland, T. C., Li, Y., Long, Y. T., &
Chen, H. Y. (2011). Reversible redox of NADH and NAD+ at
a hybrid lipid bilayer membrane using ubiquinone. Journal
of the American Chemistry Society, 133, 12366–12369. DOI:
10.1021/ja204014s.
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Download Date | 7/3/15 7:39 AM

J. Wang et al./Chemical Papers 69 (3) 486–489 (2015)
489
Nyland, R. L., Luo, M. H., Kelley, M. R., & Borch, R. F. (2010).
Design and synthesis of novel quinone inhibitors targeted
to the redox function of apurinic/apyrimidinic endonuclease
1/redox enhancing factor-1 (Ape1/Ref-1). Journal of Medic-
inal Chemistry, 53, 1200–1210. DOI: 10.1021/jm9014857.
Okamoto, K., Matsumoto, M., Watanabe, M., Kawada, M.,
Imamoto, T., & Imada, I. (1985). Effects of 6-(ω-substituted
alkyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinones and rela-
ted compounds on mitochondrial succinate and reduced
nicotinamide adenine dinucleotide oxidase systems. Chem-
ical and Pharmaceutical Bulletin, 33, 3745–3755.
Wang, J., Yang, J., Yang, B., Sun, J. Q., & Yang, T. (2010b).
Alternative synthesis of 5-chloromethyl-2,3-dimethoxy-6-me-
thyl-1,4-benzoquinone:
a key intermediate for preparing
coenzyme Q analogues. Journal of Chemical Research, 34,
724–725. DOI: 10.3184/030823410x12857507693464.
Wang, J., Yang, J., Zhou, R. G., Yang, B., & Wu, Y. S.
(2011a). Alternative synthesis of 2-(4-benzoyl-piperazin-1-
ylmethyl)-5,6-dimethoxy-3-methyl-[1,4] benzoquinone. Jour-
nal of Chemical Research, 35, 431–432. DOI: 10.3184/17475
1911x13099411630089.
Wang, J., Yang, J., Zhou, R. G., Yang, B., & Wu, Y. S.
(2011b). A facile synthesis of 2,3-dimethoxy-5-methyl-1,4-
benzoquinones. Journal of Chemical Research, 35, 428–430.
DOI: 10.3184/174751911x13099377293263.
Wang, J., Zhou, R. G., Wu, T., Yang, T., Qin, Q. X., Li,
L., Yang, B., & Yang, J. (2012). Total synthesis of api-
genin. Journal of Chemical Research, 36, 121–122. DOI:
10.3184/174751912x13285269293913.
Xu, G., Wu, J. P., Ai, X. M., & Yang, L. R. (2007). Microwave-
assisted Kornblum oxidation of organic halides. Chinese
Chemical Letters, 18, 643–646. DOI: 10.1016/j.cclet.2007.04.
003.
Okamoto, K., Watanabe, M., Morimoto, H.,
& Imada, I.
(1988). Synthesis, metabolism, and in vitro biological ac-
tivities of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-
benzoquinone (CV-2619)-related compounds. Chemical and
Pharmaceutical Bulletin, 36, 178–189.
Tsoukala, A., & Bjørsvik, H. R. (2011). Synthetic route dis-
covery and introductory optimization of a novel process to
idebenone. Organic Process Research & Development, 15,
673–680. DOI: 10.1021/op200051v.
Wang, J., Yang, J., Yang, B., Hu, X., Sun, J. Q., & Yang, T.
(2010a). A green and efficient synthesis of 1-chloromethyl-
2,3,4,5-tetramethoxy-6-methylbenzene. Journal of Chemical
Research, 34, 717–718. DOI: 10.3184/030823410x1285750769
3437.
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