Alternative synthesis of 1,2,3,4-tetramethoxy-5-methylbenzene: A key intermediate for preparing coenzyme Q homologs and analogs

Article abstract of DOI:10.1080/00397910600640396

Preparation of 1,2,3,4-tetramethoxy-5-methylbenzene (1) through a new process from pyrogallol is described. In the preparation, a modified mild brominating agent was employed, and a simple introduction of methyl group into aromatic ring through chloromethylation of the corresponding substrate (4), followed by reductive dehalogenation, was achieved successfully with good yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600640396

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Alternative Synthesis of
1,2,3,4‐Tetramethoxy‐5‐methylbenzene: A
Key Intermediate for Preparing Coenzyme Q
Homologs and Analogs
Jian Yang a , LingLing Weng a & Hu Zheng a
a Department of Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, ChengDu, Sichuan, China
Version of record first published: 22 Sep 2006.
To cite this article: Jian Yang, LingLing Weng & Hu Zheng (2006): Alternative Synthesis of
1,2,3,4‐Tetramethoxy‐5‐methylbenzene: A Key Intermediate for Preparing Coenzyme Q Homologs and
Analogs, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 36:16, 2401-2405
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Synthetic Communicationsw, 36: 2401–2405, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600640396
Alternative Synthesis of
1,2,3,4-Tetramethoxy-5-methylbenzene:
A Key Intermediate for Preparing
Coenzyme Q Homologs and Analogs
Jian Yang, LingLing Weng, and Hu Zheng
Department of Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, ChengDu, Sichuan, China
Abstract: Preparation of 1,2,3,4-tetramethoxy-5-methylbenzene (1) through a new
process from pyrogallol is described. In the preparation, a modified mild brominating
agent was employed, and a simple introduction of methyl group into aromatic ring
through chloromethylation of the corresponding substrate (4), followed by reductive
dehalogenation, was achieved successfully with good yields.
Keywords: CoEnzyme Q, chloromethylation, pyrallol chemistry
1,2,3,4-Tetramethoxy-5-methylbenzene (1) is a key intermediate for the
synthesis of coenzyme Q (Ubiquinone) homologs and analogs, which show
a diversity of biological activities and can be developed for use as pharmaceu-
ticals, cosmetics, nutritional supplements, and so forth.[1,2] There are several
methods[2] to prepare the title compound. With reference to a classic
synthesis starting from the abundant and inexpensive pyrogallol, which had
been reported by Syper and his coworkers,[2b] we proposed an alternative
method to synthesize the compound. Herein, we present the new process.
Our first attempts to obtain the compound 2 in a one-pot reaction[2b] from
pyrogallol with dimethyl sulfate and K2CO3 in acetone resulted in very poor
Received in Japan November 24, 2005
Address correspondence to LingLing Weng, Department of Medicinal Chemistry,
West China School of Pharmacy, Sichuan University, ChengDu, Sichuan 610041,
China. E-mail: huaxi2003@yxybs@126.com
2401

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J. Yang, L. Weng, and H. Zheng
yield (,10%). However, the yield reached about 90% when the etherification
was carried out in and aqueous solution. Bromination[2b] of the ether 2 with Br2
in methylene chloride (DCM) at 210 8C produced the compound 3 with high
yield (.90%), but use of Br2 and the workup were inconvenient because of the
irritation and corrosion of Br2 and the released hydrogen bromide gas. So, we
attempted to develop the NaBr–H2O2 system as the brominating agent in acetic
acid–water for this transformation with high yield. The type of this reaction
became very environmentally friendly. The bromide 3 was treated[3] in the
CH3ONa–CH3OH system in the presence of cuprous salts and dimethyl
formamide (DMF), and readily provided the compound 4 with high yield.
REAGENTS AND CONDITIONS
(a) (CH3)2SO4, 30% aq. NaOH, H2O; (b) NaBr, 30%H2O2, HOAc, rt;
(c) CH3ONa, CH3OH, CuCl, DMF; (d) (HCHO)n, conc. HCl, hexane, rt;
(e) Mg, C2H5OH, 40–45 8C (Scheme 1).
The chloromethylation[4] of the ether 4 using paraformaldehyde and conc.
HCl with benzene, chloroform, or DCM as cosolvents gave the compound 5 in
moderate yields (about 70%). In addition, bis-chloromethylation occurred
heavily. When we used hexane instead of these cosolvents to extract the
product 5 from the reaction system once it formed, the yield reached about
90%. In the final step, the reductive dehalogenation[5] of the benzyl chloride
5 was accomplished in ethanol with magnesium particles, and the title
compound (1) was obtained with high yield while no by-product was observed.
In conclusion, the modification of the brominating reaction and the
method of introducing a methyl group into the aromatic ring were
Scheme 1.

1,2,3,4-Tetramethoxy-5-methylbenzene
2403
developed, and this method not only has a shorter route but also is less
expensive, more practical, and environmentally friendly.
EXPERIMENTAL
All reactions were monitored by TLC, and TLC was performed on silica gel
GF254 with mixed solvents (hexane/ethyl acetate, 9 : 1) as developer. Organic
extracts were dried over anhydrous MgSO4. 1H NMR spectra were measured
at 400 MHz (CDCl3/TMS) on a Varian-Inova 400 spectrometer, and chemical
shifts are reported in parts per million (ppm) (d) relative to TMS as internal
standard. Mass spectra (ESI) were determined on API3000 spectrometer
and reported as m/z. Melting points were uncorrected.
Compound 1
The mixture of the benzyl chloride 5 (4.93 g, 0.02 mol) and magnesium
particles (0.72 g, 0.03 mol) in ethanol (20 ml) was stirred at 40–458C for
2 h. Water (20 ml) and hexane (100 ml) were added and then filtered. The
two layers of the filtrate were separated. The aqueous layer was extracted
with hexane (2 ꢀ 50 ml) again. The organic layer and the extracts were
combined, washed with brine, dried, and evaporated in vacuo to give the
1
title compound (1) as colorless oil[2a] in 94% yield (4.0 g). Rf ¼ 0.51, H
NMR: d 3.92 (s, 3H), d 3.86 (s, 3H), d 3.80 (s, 3H), d 3.78 (s, 3H), d 2.22
(s, 3H), d 6.44 (s, 3H). MS (m/e): 212 (Mþ).
Compound 2
To a stirred mixture of pyrogallol (12.6 g, 0.1 mol) and Me2SO4 (50.4 g,
0.4 mol) in water (150 ml) was added dropwise 30% aq. NaOH solution
(106.0 g, corresponding to NaOH 32.0 g, 0.4 mol) at 30–35 8C for 1 h under
an N2 atmosphere. After the addition, the reaction mixture was refluxed for
another 2 h. Then the mixture was cooled to below 20 8C and filtered, and
the cookie was washed with water and dried to give the crude compound 2
in 90% yield (15.1 g). Recrystallization from CH3OH–H2O (2 : 1) gave
1
needle crystals. Rf ¼ 0.4, mp 42–43 8C. H NMR: d 3.86 (s, 9H), d 6.58
(d, 2H, J ¼ 8.4 Hz), d 6.99 (t, H, J ¼ 8.4 Hz). MS (m/e): 168 (Mþ).
Compound 3
To a stirred mixture of the ether 2 (16.8 g, 0.1 mol) and NaBr (10.3 g, 0.1 mol)
in acetic acid (20 ml) was added dropwise 30% H2O2 (12 ml, corresponding

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J. Yang, L. Weng, and H. Zheng
to H2O2 0.108 mol, roughly) for 2 h at room temperature. Then, water (20 ml)
and hexane (80 ml) were added, and the stirring was continued for 1 min. The
two layers were separated, and the aqueous layer was extracted with hexane
(2 ꢀ 50 ml) again. The organic layer and the extracts were combined,
washed with water, dried, and evaporated in vacuo to afford the slightly
1
yellow oil[6] in 97% yield (23.2 g). Rf ¼0.46, H NMR: d 3.85 (s, 3H),
d 3.88 (s, 3H), d 3.90 (s, 3H), d 6.58 (d, H, J ¼ 9.2 Hz), d 7.20 (d, H,
J ¼ 9.2 Hz). MS (m/e): 247 (Mþ).
Compound 4
Freshly cut sodium (5.75 g, 0.25mol) was dissolved in dry methanol (80ml).
Afterward, most of the methanol was distillated off. Under an N2 atmosphere,
CuCl (0.2 g, 0.002 mol) and the mixture of the bromide 3 (23.9 g, 0.1mol) and
DMF (8 ml) were added in sequence. The mixture was stirred at 1108C for 9 h.
Then, 150ml of water was added, and the mixture was refluxed for another
30 min. The mixture was cooled and filtered. The filtrate and the cookie were
separated. The filtrate was extracted with hexane (2 ꢀ 100 ml) again. The
extracts were dried and evaporated in vacuo. The residue and the cookie were
combined and recrystallized from CH3OH to give the compound 4 as a white
crystal in 90% yield (18.0g). Rf ¼ 0.3, mp 87–87.58C (lit.:[7] 87–87.58C). 1H
NMR: d 3.82 (s, 6H), d 3.90 (s, 6H), d 6.58 (s, 2H). MS (m/e): 198 (Mþ).
Compound 5
To a stirred mixture of the ether 4 (10.0 g, 0.05 mol) and paraformaldehyde
(1.5 g, 0.05 mol) in hexane (100 ml) was added dropwise conc. HCl (50 ml)
at room temperature. After the solid was dissolved completely, the mixture
was stirred for another 30 min and then stood still. The two layers were
separated. The aqueous layer was extracted with hexane (2 ꢀ 50 ml) again.
The organic layer and the extracts were combined, washed with brine,
dried, and evaporated in vacuo. Silica gel chromatography of the residue
provided the benzyl chloride 5 as colorless oil in 90% yield (11.1 g).
1
Rf ¼ 0.42, H NMR: d 3.85 (s, 3H), d 3.90 (s, 6H), d 3.93 (s, 3H), d 4.61
(s, 2H), d 6.65 (s, H). MS (m/e): 246 (Mþ).
REFERENCES
1. (a) Taylor, K. M.; Smith, R. PCT Int. Appl. WO2005019232, 2005; (b) West, D. D.
U.S. Patent 6, 506, 915, 2003; (c) Min, J. H.; Lee, J. S.; Koo, S. J. Org. Chem.
2003, 68, 7925; (d) Arndt, S.; Ernde, U.; Baurle, S.; Frieldrich, T.; Grubert, L.;
Koert, U. Chem.—Eur. J. 2001, 7, 993; (e) Jung, Y. S.; Joe, B. Y.;

1,2,3,4-Tetramethoxy-5-methylbenzene
2405
Seong, C. M.; Park, N. S. Synth. Commun. 2001, 31, 2735; (f) Lipshutz, B. H.;
Kim, S. K.; Mollard, P.; Stevens, K. L. Tetrahedron 1998, 54, 1241;
(g) Shinkawa, N.; Ichino, T.; Tsuruki, T.; Kuroda, H. Jpn. Kokai Tokkyo Koho
JP05148183, 1993.
2. (a) Keinan, E.; Eren, D. J. Org. Chem. 1987, 52, 3875; (b) Syper, L.; Kloc, K.;
Mlochowski, J. Tetrahedron 1980, 36, 123.
3. Aalten, H. L.; Koten, G. V.; Grove, D. M.; Kuilman, T.; Piekstra, O. G.;
Hulshof, L. A.; Sheldon, R. A. Tetrahedron 1989, 45, 5565.
4. Carey, F. L.; Sundberg, R. J. Advanced Organic Chemistry, Part B: Reactions
and Synthesis, 4th ed.; Kluwer Academic/Plenum Publishers: New York, 2001;
Vol. 11, p. 710.
5. Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mech-
anisms, and Structure, 5th ed.; Wiley: New York, 2001; Vol. 10, p. 526.
6. Horning, E. C.; Parker, J. A. J. Am. Chem. Soc. 1952, 74, 2187.
7. Vischero, E. B. J. Chem. Soc. 1953, 815.