A facile synthesis of 2, 3-dimethoxy-5-methyl-1, 4-benzoquinones

Article abstract of DOI:10.3184/174751911X13099377293263

Several 2, 3-dimethoxy-5-methyl-1, 4-benzoquinones substituted at the C-6 position with alkoxy methyl groups were prepared by a reaction sequence starting from 2, 3, 4, 5-tetramethoxytoluene (alkoxy methyl) via a Blanc chloromethylation reaction, Williams

Full text of DOI:10.3184/174751911X13099377293263

428 RESEARCH PAPER
JULY, 428–430
JOURNAL OF CHEMICAL RESEARCH 2011
A facile synthesis of 2, 3-dimethoxy-5-methyl-1, 4-benzoquinones
Jin Wanga, Jian Yangc*, Rong-Guang Zhoub*, Bo Yanga and Yuan-Shuang Wua
aFaculty of Life Science andTechnology, Kunming University of Science andTechnology, NO.296 BailongTemple, Panlong Zone,
Kunming 650224, Yunnan Province, P. R. China
bInstitute for Drug Research and Development of Kunming Pharmaceutical Corporation, NO.141 Chunyu Road, Wuhua Zone,
Kunming 650100, Yunnan Province, P. R. China
cFaculty of Life Science andTechnology, Kunming University of Science andTechnology (ChengGong Campus), Kunming, 650500,
Yunnan Province, P. R. China
Several 2, 3-dimethoxy-5-methyl-1, 4-benzoquinones substituted at the C-6 position with alkoxy methyl groups were
prepared by a reaction sequence starting from 2, 3, 4, 5-tetramethoxytoluene (alkoxy methyl) via a Blanc chlorometh-
ylation reaction, Williamson reaction and oxidation. The method provided a good yield of 2, 3-dimethoxy-5-methyl-1,
4-benzoquinones and is suitable for the synthesis of other benzoquinone analogues.
Keywords: coenzyme Q, idebenone, Blanc chloromethylation reaction, Williamson reaction
2, 3-Dimethoxy-5-methyl-1, 4-benzoquinones are Coenzyme
Q analogues and have attracted considerable attention owing
to their biological and pharmacological activities.1,2 Synthetic
benzoquinones have protocollagen-proline hydroxylase
inhibiting activity, collagen biosynthesis inhibitory activity
and 5-lipoxygenase suppressant activity, and are useful for the
prevention and treatment of such disease as hepatocirrhosis,
arteriosclerosis, Alzheimer’s disease, Parkinson’s disease,
urticaria, etc.1–5 Hence, several researchers have focused on the
development of new methods for the synthesis of these useful
compounds.
Among the quinone derivatives synthesised previously,
6-(10-hydroxydecyl)-2, 3-dimethoxy-5-methyl-1, 4-benzoqui-
none (idebenone), Fig. 1, was found to improve neurological
symptoms in stroke-prone spontaneously hypertensive rats
with experimental cerebral ischaemia and to show beneficial
effects on the physiological and neurological symptoms
in patients with cerebral vascular diseases.3,8 Furthermore,
6-alkyl-2, 3-dimethoxy-5-methyl-1, 4-benzoquinones showed
effects on mitochondrial succinate and on reduced nicotin-
amide adenine dinucleotide oxidase systems.2,3,6–8 Among
the compounds which have been reported those which had
a different length of the side chain at the C-6 position showed
strong anti-oxidant activity7 and anti-glycation activity2.
We synthesised several idebenone homologues (4a, 4b, 4c)
in preparation for studies on structural effects on redox
functions.
In general, coenzyme Q01,2,9 has been frequently employed
as starting material for benzoquinone synthesis. However,
quinones have been used sparingly because they are much
less nucleophilic than phenols and their ether derivatives.2
The published syntheses of benzoquinones have significant
drawbacks such as long reaction times, low yields of the prod-
ucts, harsh reaction conditions, difficult work-up, and the use
of expensive and environmentally toxic catalysts, reagents,
or media.1,2,6,7,8,9 The development of simple and efficient
methods for the synthesis of 2, 3-dimethoxy-5-methyl-1, 4-
benzoquinones is therefore desirable.
Recently,4,5 we described a green and efficient synthesis of
1-chloromethyl-2, 3, 4, 5-tetramethoxy-6-methylbenzene (2)
and we have now extended this synthetic methodology to
synthesise idebenone homologues. Herein we report a facile
synthesis of 2, 3-dimethoxy-5-methyl-1, 4-benzoquinones
substituted at the C-6 position with alkoxy methyl groups
starting from 2, 3, 4, 5-tetramethoxytoluene (1) via a Blanc
chloromethylation reaction, Williamson reaction and oxidation.
Results and discussion
As shown in Scheme 1, chloromethylation of 2, 3, 4, 5-
tetramethoxytoluene 1 using paraformaldehyde and 37%
Fig. 1
Scheme l
* Correspondent. E-mail: pharmacistkg101@gmail.com

JOURNAL OF CHEMICAL RESEARCH 2011 429
Table 1 Williamson reaction catalysed by KI under solvent-free conditions
Entry
R
Catalyst
Catalyst load/g
Reaction temp./°C
Time/h
Product
Yield/%
1
2
3
CH3
CH3CH2
CH2CH2OH
KI
KI
KI
0.1
0.1
0.1
Reflux
Reflux
70
0.5
0.5
1
3a
3b
3c
99
98
94
Scheme 2
Synthesis of 2, 3-dimethoxy-5-methyl-1, 4-benzoquinones (4); general
procedure
HCl under solvent-free conditions provided 2 at 40 °C in an
excellent yield (95%).4 A direct method for converting 2 to the
ether 3 is by the Williamson reaction. We considered that the
electron-donating effect of four methoxy groups in 2 favoured
a Williamson reaction. Treatment of 2 and the alcohol with Na
catalysed by KI under solvent-free conditions provided 3 in
nearly quantitative yields11–12 ( as shown in Table 1).
Finally, As shown in Scheme 2, the ethers 3 were oxidised
with cerricammoniumnitrate (CAN) to afford the benzoqui-
nones 4 in good yield.10 A summary of the results is given in
Table 2.
In conclusion, the electron-donating effect of methoxy and
methyl groups enhanced the Blanc chloromethylation reaction
and Williamson reaction. 37% HCl and ROH were employed
as both reagent and solvent. An approach based on the reaction
with 2, 3, 4, 5-tetramethoxytoluene (1) as a starting material is
promising for the synthesis of 1, 4-benzoquinones affording an
efficient reaction for the preparation of 2, 3-dimethoxy-5-
methyl-1, 4-benzoquinones of potential synthetic and pharma-
cological interest. We believe that this experimentally simple
approach could be a useful addition to reported methods.1,2,6–9
A solution of compounds 3 (2.5 mmol) in THF (10 mL) was diluted
with water (5 mL), and an excess solution of cerric ammonium nitrate
(CAN) (3.9g, 7 mmol) in 10 mL water was added at 0 °C. The mixture
was stirred at room temperature for 2 h. The progress of the reaction
was monitored by TLC. After completion of the reaction, the THF was
removed under a vacuum at 40 °C, and the crude mixture was extracted
with three portions of CH2Cl2 (20 mL). The orange extracts were
washed with brine until neutrality, then dried over anhydrous Na2SO4
and concentrated in vacuo. The crude products were purified by a
silica-gel column chromatography with petroleum ether and EtOAc as
eluent to give the desired benzoquinones (4).
Previously reported materials were characterised by comparison of
their m.p., IR, 1H NMR, and MS data with those of authentic samples.
All new compounds gave satisfactory spectral data in accordance with
their proposed structures.
1, 2, 3, 4-Ttetramethoxy-5-(methoxymethyl)-6-methylbenzene (3a):
Colourless oil; IR (KBr/cm−1):2930, 2865, 1470, 1412, 1354, 1282,
1204, 1113, 1055; 1H NMR (500 MHz, DMSO-d6):4.34 (s, 2H),
3.80 (s, 3H), 3.78 (s, 3H), 3.73 (s, 3H), 3.67 (s, 3H), 3.30 (s, 3H),
2.15 (s, 3H); 13C NMR (125 MHz, C5D5N-d5 ):148.4, 147.5, 146.6,
144.1, 126.7, 124.5, 65.5, 61.1, 60.4, 60.3, 59.8, 57.5, 10.7; MS (EI):
m/z = 256 (M+). HRMS-EI: m/z (M+) Calcd for C13H20O5: 256.1311.
Found:256.1315.
Experimetal
All reactions were monitored by TLC, Melting points were measured
1-(Ethoxymethyl)-2, 3, 4, 5-tetramethoxy-6-methylbenzene (3b):
Colourless oil; IR (KBr/cm−1):2962, 2858, 1477, 1412, 1353, 1269,
on a YRT-3 temp apparatus and are uncorrected. IR spectra were
NMR
1
recorded on an Impact 400 FT-IR instrument.
spectra data were
1198, 1120, 1055; H NMR (500MHz, CDCl3):4.48 (s, 2H), 3.90 (s,
recorded on a Bruker DRX 500 NMR spectrometer and a ZAB-2F
mass spectrometer, respectively.
2, 3, 4, 5-Tetramethoxytoluene (1) and 1-chloromethyl-2, 3, 4, 5-
tetramethoxy-6-methylbenzene (2) were prepared by the literature
method.4
3H), 3.89 (s, 3H), 3.84 (s, 3H), 3.78 (s, 3H), 3.62–3.56 (q, J = 8.8 Hz,
2H), 2.26 (s, 3H), 1.26–1.23 (t, J = 8.8 Hz, 3H); 13C NMR (125 MHz,
MeOD):148.7, 147.9, 146.9, 127.1, 125.1, 65.8, 64.0, 61.8, 60.9, 60.8,
60.4, 15.2, 11.2.
2-(2, 3, 4, 5-Tetramethoxy-6-methylbenzyloxy)ethanol (3c): Colour-
less oil; IR (KBr/cm−1): 3506, 3434, 2960, 2876, 1467, 1415, 1369,
Synthesis of compounds (3); general procedure
1
1109, 1045; H NMR (500 MHz, C5D5N-d5): 4.40 (s, 2H), 3.77 (s,
Freshly cut sodium (0.5 g, 0.022mol) was dissolved in the dry ROH
(10 mL). The catalyst KI (0.1 g) and 1-chloromethyl -2, 3, 4, 5-tetra-
methoxy-6-methylbenzene 2 (0.7g, 2.69mmol) were added under a N2
atmosphere .The mixture was refluxed for 1 h. The progress of the
reaction was monitored by TLC. After completion of the reaction, the
reaction mixture was cooled to room temperature and water (50 mL)
were added and then neutralized to pH 7 with 1% aqueous HCl. The
mixture was extracted with CH2Cl2 (4 × 30 mL) and the combined
organic layers were dried over anhydrous Na2SO4 and concentrated in
vacuo to give the desired compounds 3.
3H), 3.72 (s, 3H), 3.70 (s, 3H), 3.63 (s, 3H), 3.56 (s, 2H), 3.46–3.45
(m, 2H), 3.14 (brs, 1H), 2.11 (s, 3H); 13 C NMR (125 MHz, MeOD):
148.7, 147.8, 146.9, 144.4, 127.1, 124.6, 71.5, 64.4, 61.6, 61.4, 60.9,
60.8, 60.4, 11.3; MS (ESI): m/z = 285 (M−-H). HRMS-ESI: m/z
(M–-H) Calcd for C 14H 21 O6: 285.1338. Found:285.0396.
2, 3-Dimethoxy-5-(methoxymethyl)-6-methylcyclohexa-2, 5-diene-
1, 4-dione (4a): Orange solid; m.p. 33–34 °C (lit.836 °C);IR (KBr/cm−1):
1
3520, 3300, 2923, 2852, 1665, 1613, 1464, 1269, 1114, 1049; H
NMR (500 MHz, CDCl3): 4.30 (s, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 3.35
(s, 3H), 2.09 (s, 3H); 13C NMR (125 MHz, MeOD):184.3, 183.2,
144.4, 144.2, 143.0, 136.5, 64.0, 61.0, 60.9, 58.6, 11.9; MS (ESI):
m/z = 225 (M−-H).HRMS-ESI: m/z (M−-H) Calcd for C11H13O5:
225.0762. Found: 225.0759.
Table 2 Synthesis of 2, 3-dimethoxy-5-methyl-1, 4-benzoqui-
nones (4)
2-(Ethoxymethyl)-5, 6-dimethoxy-3-methylcyclohexa-2, 5-diene-1,
Compound
R
Yield/%
Colour
4-dione (4b): Orange oil; IR (KBr/cm−1): 3300, 2982, 2949, 2878,
4a
4b
4c
CH3
CH3CH2
CH2CH2OH
88
76
68
Orange
Orange
Orange
1
1665, 1606, 1457, 1282, 1113, 1036; H NMR (500 MHz, CDCl3):
4.33 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 3.55-3.50 (m, 2H), 2.09 (s,
3H), 1.19–1.16 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):

430 JOURNAL OF CHEMICAL RESEARCH 2011
184.5, 183.3, 144.5, 144.4, 143.1, 136.9, 66.6, 62.2, 61.1, 61.1, 15.1,
12.0; MS (ESI): m/z = 263 (M+ + Na). HRMS-ESI: m/z (M+ + Na)
Calcd for C12H16O5Na: 263.0895. Found:263.0892.
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13
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O6: 255.0868. Found: 255.0869
This study was supported by Fund of Kunming University of
Science and Technology and Office of Education Research
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Received 29 May 2011; accepted 17 June 2011
Paper 1100717 doi: 10.3184/174751911X13099377293263
Published online: 5 August 2011

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