Practical synthesis of 2,3,4,5-tetramethoxytoluene

Article abstract of DOI:10.1080/00397910600633995

The title compound, a key material for synthesis of coenzyme Q 10 , was effectively prepared in high yield by a reaction sequence starting from 3,4,5-trimethoxybenzadehyde via Wolff-Kishner reduction, Vilsmeier-Haack reaction, Dakin reaction, and methylation. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600633995

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Practical Synthesis of
2
,3,4,5‐Tetramethoxytoluene
a a a
a
Yafei Ji , Wanmei Xu , Wenhu Jin & Yue Weimin
a
Department of Pharmacy Engineering , East China University of Science
and Technology , Shanghai, China
Published online: 20 Aug 2006.
To cite this article: Yafei Ji , Wanmei Xu , Wenhu Jin & Yue Weimin (2006) Practical Synthesis of
2,3,4,5‐Tetramethoxytoluene, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 36:14, 1961-1965, DOI: 10.1080/00397910600633995
To link to this article: http://dx.doi.org/10.1080/00397910600633995
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Synthetic Communications , 36: 1961–1965, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600633995
Practical Synthesis of 2,3,4,5-
Tetramethoxytoluene
Yafei Ji, Wanmei Xu, Wenhu Jin, and Yue Weimin
Department of Pharmacy Engineering, East China University of Science
and Technology, Shanghai, China
Abstract: The title compound, a key material for synthesis of coenzyme Q10, was
effectively prepared in high yield by a reaction sequence starting from 3,4,5-trimethoxy-
benzadehyde via Wolff–Kishner reduction, Vilsmeier–Haack reaction, Dakin reaction,
and methylation.
Keywords: Coenzyme Q10, Dakin reaction, methylation, 2,3,4,5-tetramethoxytoluene,
3,4,5-trimethoxybenzadehyde, Vilsmeier–Haack reaction, Wolff–Kishner reduction
Coenzyme Q10 1 performs an important role in many physiological electron-
transfer processes for respiration as a redox carrier. The compound plays a
good treatment effect on various heart-related diseases as a drug or dietary
supplement sold in many countries, and there is an increasing market
[
1]
demand. In the past thirty years, the synthesis of coenzyme Q10 has
received special attention and remains interesting. Organic chemists have
brought forward many total and semisynthetic methods for stereoselective
and cost-efficient preparation of coenzyme Q . In general there may be con-
1
0
sidered to be two strategies, one from 2,3,4,5-tetramethoxytoluene 2 as
1–9]
[
starting material
quinone (coenzyme Q , 3) as starting material.
and the other from 2,3-dimethoxy-5-methyl-1,4-benzo-
[10–16]
Likewise, 2 is a
Several synthetic methods
0
[17]
valuable material for synthesis of idebenone.
were reported for preparation of 3 via 3,4,5-trimethoxytoluene 5
however, a more practical process for preparation of 2 has rarely been
[18–20]
;
Received in Japan December 12, 2005
Address correspondence to Yafei Ji, Department of Pharmacy Engineering, East
China University of Science and Technology, P.O. Box 363, 130 Meilong Road,
Shanghai 200237, China. E-mail: ji_yafei@yahoo.com
1
961

1
962
Y. Ji et al.
investigated. The reported method uses expensive reagent and severe reaction
conditions and is unfavorable for large-scale production of 2, in particular
during the trimethoxylation of 2,3,6-tribromo-4-methylphenol in the
[
8,9]
presence of CuCN.
In the face of the increasing commercial demand for coenzyme Q , to
1
0
develop an industrial route to 2 becomes an urgent matter. Because an
improved technique has been successfully applied for the large-scale manu-
facture of 3,4,5-trimethoxybenzadehyde 4 in China to make it an inexpensive
[21]
reagent (commercial price of 4 ca. $10/kg in China),
there is an actual
possibility of producing 2 from 4 to avoid the difficult reaction conditions.
Herein we propose a novel and practical synthesis of 2 from 4 via Wolff–
Kishner reduction, Vilsmeier–Haack reaction, Dakin reaction, and methyl-
ation to give an overall yield of 76.5% (Scheme 1).
The most direct method to reduce aldehyde 4 to toluene 5 is by the
Wolff–Kishner reduction. We speculate that the electron-donating effect of
three methoxy groups at 4 is more propitious for the reduction of the
aldehyde. Actually, treatment of 4 under Wolff–Kishner conditions
(
NH NH , glycol, KOH) provided 5 in nearly quantitative yield. The
2 2
reaction could be performed at the temperature of 1208C rather than a usual
Scheme 1. Reagents and conditions: (a) NH
3
2 2
NH , glycol, KOH, 708C/3 h, 1208C/
h, 97%; (b) POCl3 DMF, 658C, 5 h, 95%; (c) 50% H O , H SO , 158C, 0.5 h;
2
2
2
4
(
2 4
d) Me SO , NaOH, 558C, 83% from 6.

Practical Synthesis of 2,3,4,5-Tetramethoxytoluene
1963
2
008C. The reaction of 4 under Clemmensen conditions only afforded 5 in
5% yield along with 3,4,5-trimethoxybenzyl alcohol as a by-product
6
according to the literature.
[
19]
Similarly, the electron-donating effect of methoxy and methyl groups
would induce a beneficial influence on the following Vilsmeier–Haack
reaction and Dakin reaction. The Vilsmeier–Haack reaction was carried out
by treating 5 with POCl and dimethyl formamide (DMF) at 658C for 5 h to
3
give aldehyde 6 in 95% yield. DMF was employed as both reagent and
solvent. Even though a low ratio of 1/1 (5/DMF, w/mL) was introduced, the
reaction results were perfectly reproduced. The oxidation of 6 with 50%
H O was executed via Dakin reaction to provide 7 without separation; the
2
2
organic solvent was removed and followed by methylation with Me SO in
2
4
H O and benzene in the presence of a phase-transfer catalyst to afford 2
2
directly in 83% yield based on 6 (both carried out in one pot). We found that
5
0% H O was more efficient to facilitate the Dakin reaction than 30% H O .
2 2 2 2
EXPERIMENTAL
All reactions were monitored by TLC, and the spots were visualized with
iodine vapor. Melting points were determined by the capillary method
1
without correction. H NMR spectra were recorded on Bruker Avance 500
instrument in CDCl , and the residual solvent peaks were used as internal
3
standard. Mass spectra were recorded on Micromass GCT mass spectrometer
with the electronic impacts (EI) at 70 eV.
3
,4,5-Trimethoxytoluene (5)
3
,4,5-Trimethoxybenzadehyde 4 (19.6 g, 0.10mol), 98% hydrazine hydrate
15.3g, 0.30mol), and KOH (2.0g, 0.036 mol) in glycol (200mL) were
(
heated at 708C for 3 h, and then the mixture was further heated at 1208C for
3
h. The resulting mixture was extracted with petroleum ether (4 ꢀ 100 mL),
and the combined extracts were washed with water (100mL). The solution
was dried over Na SO and solvent was removed in vacuo to afford a yellowy
2
4
1
solid 5 (17.6 g) in 97% yield. Mp 32.7–35.48C. H NMR (500MHz): d 6.30
(
s, 2H, ArH), 3.80 (s, 6H, OCH ), 3.72 (s, 3H, OCH ), 2.25 (s, 3H, CH ). MS
þ
3 3 3
(m/z): 182 (M , 100), 167 (90), 152 (7), 139 (36), 124 (31).
2
,3,4-Trimethoxy-6-methylbenzadehyde (6)
To a solution of 5 (18.2 g, 0.10 mol) in dry DMF (18.5 mL), POCl (19.9 g,
3
0
.13 mol) was added dropwise at 258C over a period of 1 h under an N2
atmosphere. Then the reaction mixture was intensely stirred at 658C for

1
964
Y. Ji et al.
another 5 h. The resulting solution was poured into water (500 mL) and then
neutralized to pH 7 with 30% aqueous NaOH. The mixture was cooled to
0
8C, and the precipitate was filtrated and dried in vacuo to obtain 6 (20.0 g)
1
as a white solid in 95% yield. Mp 59.5–61.08C; H NMR (500 MHz): d
9
.83 (s, 1H, CHO), 7.14 (s, 2H, ArH), 3.88 (s, 9H, OCH ), 2.12 (s, 3H,
þ
3
CH ). MS (m/z): 210 (M , 100), 195 (46), 177 (32), 162 (26), 134 (34).
3
2
,3,4,5-Tetramethoxytoluene (2)
Freshly prepared 6 (21.0 g, 0.10 mol) and 98% H SO (1.0 g, 0.01 mol) was
2
4
dissolved in methanol (200 mL). To the solution, 50% H O (7.6 g,
2
2
0.20 mol) was added dropwise at 108C over a period of 30 min. The mixture
was stirred at room temperature for additional 30 min. Then the excessive
H O was reductively removed by addition of 10% aqueous NaHSO . The
2
2
3
solvent methanol was distilled out in vacuo, and water (200 mL), benzene
200 mL), Me SO (64.0 g, 0.50 mol), and polyglycol-400 (3 g) were added
(
2
4
to the residue. The reaction mixture was treated by slowly dropping 30%
aqueous NaOH into it at 558C over a period of 2.5 h. The pH value was
carefully controlled within a range of 9.0–9.5 in course of the reaction. The
organic layer was washed by 5% aqueous NaOH, dried over Na SO , and
2
4
evaporated. Finally the concentrated residue was distilled in vacuo to afford
the desired product 2 as a colorless liquid (17.6 g) in 83% yield based on 6.
1
Bp 118–1208C/160 Pa. H NMR (500 MHz): d 6.42 (s, 2H, ArH), 3.79
þ
(
s, 12H, OCH ), 2.22 (s, 3H, CH ). MS (m/z): 212 (M , 78), 197 (100),
3
3
169 (17), 154 (38).
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