Process for the preparation of 2,3-dimethoxy-5-methylbenzoquinone

2,3-Dimethoxy-5-methylbenzoquinone is prepared by oxidizing 3,4,5-trimethoxytoluene by reaction with hydrogen peroxide in the presence of a catalyst which is a heteropolyacid selected from phosphomolybdic acids, phosphotungstic acids, silicomolybdic acids and silicotungstic acids or a salt thereof.

BACKGROUND OF THE INVENTION 
1. Field of the Invention: 
This invention relates generally to a process for the preparation of 
2,3-dimethoxy-5-methylbenzoquinone and, more specifically, to a one-stage 
process for the production of 2,3-dimethoxy-5-methylbenzoquinone by 
oxidation of 3,4,5trimethoxytoluene with hydrogen peroxide using, as a 
catalyst, a heteropolyacid containing molybdenum or tungsten and 
phosphorus or silicon as two heteronucleus metal elements thereof. 
2. Description of the Prior Art 
2,3-Dimethoxy-5-methylbenzoquinone is an important intermediate compound 
for a quinone-type antitumor agent or a coenzyme Q. One known method of 
preparing 2,3-dimethoxy-5-methylbenzoquinone includes coupling 
3,4,5-trimethoxytoluene with a p-nitrobenzenediazonium salt to form an azo 
compound, reducing the azo compound to form an o-toluidine derivative, and 
oxidizing the o-toluidine derivative (Japanese Examined Patent Publication 
No. 38-11,981). This process is, however, low in efficiency because of its 
multi-step process and requires a large amount of an oxidizing agent, 
leading to the production of a large amount of industrial waste as a 
by-product. 
One well known one stage process for the production of 
2,3-dimethoxy-5-methylbenzoquinone includes oxidizing 
3,4,5-trimethoxytoluene using a hexacyanoferrate as a catalyst (J. Org. 
Chem., 50, 1766 (1985)). This process has a problem that the catalyst 
contains highly toxic cyano ions. Furthermore, the yield of the 
benzoquinone with this process is not satisfactory. 
SUMMARY OF THE INVENTION 
In accordance with the present invention there is provided a process for 
the preparation of 2,3-dimethoxy-5methylbenzoquinone, comprising reacting 
3,4,5-trimethoxytoluene with hydrogen peroxide in the presence of a 
heteropolyacid selected from the group consisting of phosphomolybdic 
acids, phosphotungstic acids, silicomolybdic acids and silicotungstic 
acids or a salt thereof. 
As a result of an extensive study on oxidizing catalysts for the 
preparation of 2,3-dimethoxy-5methylbenzoquinone, it has been found that a 
heteropolyacid or its salt containing Mo or W and P or Si as its 
heteronucleus metal ions can produce with a high yield the desired 
benzoquinone when used as a catalyst for the oxidation of 
3,4,5trimethoxytoluene and that commercially easily available hydrogen 
peroxide is effectively used as the oxidation agent in conjunction with 
such a heteropolyacid catalyst. 
In the process according to the present invention, since hydrogen peroxide 
used as the oxidizing agent is converted into water, no dangerous waste 
materials are produced. Further, the process of the present invention is 
advantageous from the standpoint of economy because the oxidation is 
carried out at a temperature not higher than 100 .degree. C, and because 
the starting materials are commercially available at low prices. 
It is an object of the present invention to provide a process which can 
convert 3,4,5-trimethoxytoluene into 2,3-dimethoxy-5-methylbenzoquinone 
with a high yield in an economical manner. 
Another object of the present invention is to provide a process of the 
above-mentioned type which is free of causing industrial pollution. 
Other objects, features and advantages of the present invention will become 
apparent from the detailed description of the invention to follow.

DETAILED DESCRIPTION OF THE INVENTION 
The present invention provides a process for the preparation of 
2,3-dimethoxy-5-methylbenzoquinone, in which 3,4,5-trimethoxytoluene is 
reacted with hydrogen peroxide in the presence of a heteropolyacid 
selected from the group consisting of phosphomolybdic acids, 
phosphotungstic acids, silicomolybdic acids and silicotungstic acids or a 
salt thereof. 
Hydrogen peroxide to be used as an oxidizing agent may be an aqueous 
hydrogen peroxide having various concentrations. A commercially available 
30 % aqueous hydrogen peroxide may be suitably used. More highly 
concentrated hydrogen peroxide solutions, for example those having a 50-60 
% concentration may also be used, if desired. The amount of hydrogen 
peroxide to be used for the oxidation of the 3,4,5-trimethoxytoluene may 
be suitably determined in accordance with an optimum yield and is 
generally in the range of from 1-30 times the stoichiometric amount, 
preferably 2-10 times the stoichiometric amount. 
The phosphorus ions of the phosphomolybdic acids and phosphotungstic acids 
may be both trivalent and pentavalent ions. Both ortho- and 
iso-silicomolybdic or silicotungstric acids may be used for the purpose of 
the present invention. Illustrative of suitable heteropolyacids are 
H.sub.3 PMo.sub.12 O.sub.40, H.sub.3 PW.sub.12040, H.sub.3 PMo.sub.6 
W.sub.6 O.sub.40, H.sub.4 SiMo.sub.12 O.sub.40 and H.sub.4 SiW.sub.12 
O.sub.40. 
Salts of the above heteropolyacids, such as alkali metal salts and ammonium 
slats, may also be used. Examples of suitable alkali metals include 
lithium, potassium and sodium. The heteropolyacid is used in a 
catalytically effective amount, preferably 0.0001-0.05 mole, more 
preferably 0.001-0.03 mole per mole of the starting material 
3,4,5-trimethoxytoluene. 
The oxidation is preferably carried out using a solvent. Since hydrogen 
peroxide is used as an oxidizing agent, the solvent to be used is 
preferably a water-soluble organic solvent so as to provide a homogeneous 
reaction system. Illustrative of suitable water-soluble organic solvents 
are organic acids such as formic acid, acetic acid, propionic acid, acid 
anhydrides such as acetic anhydride, a lower alcohol such as methanol and 
ethanol, ketones such as acetone, and other solvents such as acetonitrile 
and N,N-dimethylformamide. Above all, the use of an organic acid is 
especially preferred. 
The reaction temperature to be used in the process of the present invention 
does not require a particularly strict control and generally ranges from 0 
.degree. C. to 100 .degree. C., preferably from 10.degree. C. to 
70.degree. C. The reaction time varies with the concentration of hydrogen 
peroxide and the amount of the catalyst used but generally ranges from 1 
to 24 hours. 
The color of the reaction solution turns orange as the reaction proceeds. 
After completion of the reaction, water is added to the reaction mixture 
and the resulting mixture is extracted with a water-insoluble organic 
solvent. The extract is dried over magnesium sulfate and is subjected to 
distillation, thereby to leave 2,3-dimethoxy-5-methylbenzoquinone. 
In accordance with the present invention, 
2,3-dimethoxy-5-methylbenzoquinone can be prepared in one step from 
3,4,5-trimethoxytoluene with a high yield. Furthermore, the method of the 
present invention does not produce undesirable industrial wastes. 
The following examples will further illustrate the present invention. 
EXAMPLES 1-4 
In a glass flask was placed a solution of 2 mmol of 3,4,5-trimethoxytoluene 
and 100 mg of a heteropolyacid as indicated in Table 1 below in 10 ml of 
acetic acid. To this solution was dropwise added 2 ml of a 31 % aqueous 
hydrogen peroxide solution. The mixture was stirred at 30 .degree. C. for 
5 hours in a nitrogen atmosphere. After completion of the reaction, 50 ml 
of water was added and the mixture was extracted three times with a 20 ml 
portion of methylene chloride. The extract was dried over magnesium 
sulfate and subjected to distillation for the removal of the solvent. The 
resultant product was confirmed to be 2,3-dimethoxy-5-methylbenzoquinone 
by NMR spectroscopy. The yield of the product was determined by gas 
chromatography. The results are summarized in Table 1. 
TABLE 1 
______________________________________ 
Heteropoly Conver- Selecti- 
Examples 
Acids sion (%) Yield (%) 
vity (%) 
______________________________________ 
1 Phosphomolyb- 
81 32 40 
dic acid 
2 Silicomolybdic 
68 23 34 
acid 
3 Phosphotung- 57 23 40 
stic acid 
4 Silicotungstic 
69 23 33 
acid 
______________________________________ 
EXAMPLE 5 
The procedures of Example 1 were followed with the exception that the 
reaction time was 7 hours and 1 ml of the 31% aqueous peroxide solution 
was used. The results are shown in Table 2 below. 
TABLE 2 
______________________________________ 
Heteropoly Conver- Selecti- 
Examples 
Acids sion (%) Yield (%) 
vity (%) 
______________________________________ 
5 Phosphomolyb- 
89 49 55 
dic acid 
______________________________________ 
EXAMPLES 6-7 
The procedures of Examples 1 and 2 were followed with the exception that 50 
mg of the heteropoly acid as shown below was used and the reaction time 
was 14.5 hours. The results are shown in Table 3 below. 
TABLE 3 
______________________________________ 
Heteropoly Conver- Selec- 
Examples 
Acids sion (%) Yield (%) 
tivity (%) 
______________________________________ 
6 Phosphomolyb- 
97 50 52 
dic acid 
7 Silicomolybdic 
95 52 55 
acid 
______________________________________ 
EXAMPLES 8-9 
The procedures of Examples 1 and 2 were followed with the exception that 
200 mg of the heteropoly acid as shown below and 4 mmol of 
3,4,5-trimethoxytoluene were used. The results are shown in Table 4 below. 
TABLE 4 
______________________________________ 
Heteropoly Conver- Selec- 
Examples 
Acids sion (%) Yield (%) 
tivity (%) 
______________________________________ 
8 Phosphomolyb- 
75 55 73 
dic acid 
9 Silicomolybdic 
77 51 66 
acid 
______________________________________ 
EXAMPLE 10 
The procedures of Example 1 were followed with the exception that 4 mmol of 
3,4,5-trimethoxytoluene and 50 mg of phosphotungstomolybdic acid (H.sub.3 
PMo.sub.6 W.sub.6 O.sub.40) were used, and the reaction time was 15.5 
hours. The results are shown in Table 5 below. 
TABLE 5 
______________________________________ 
Conver- Selec- 
Example sion (%) Yield (%) tivity (%) 
______________________________________ 
10 94 51 54 
______________________________________ 
EXAMPLES 11-12 
The procedures of Examples 1 and 2 were followed with the exception that 
200 mg of the heteropoly acid as shown below and 4 mmol of 
3,4,5-trimethoxytoluene were used, and the reaction temperature was 
40.degree. C. The results are shown in Table 6 below. 
TABLE 6 
______________________________________ 
Heteropoly Conver- Selec- 
Examples 
Acids sion (%) Yield (%) 
tivity (%) 
______________________________________ 
11 Phosphomolyb- 
99 39 39 
dic acid 
12 Silicomolybdic 
98 34 35 
acid 
______________________________________ 
EXAMPLES 13-14 
The procedures of Examples 1 and 2 were followed with the exception that 20 
mg of the heteropoly acid as shown below, 4 mmol of 
3,4,5-trimethoxytoluene, 1 ml of the 31% aqueous hydrogen peroxide 
solution and 10 ml of formic acid as a solvent were used, and the reaction 
time was 1 hour. The results are shown in Table 7 below. 
TABLE 7 
______________________________________ 
Heteropoly Conver- Selec- 
Examples 
Acids sion (%) Yield (%) 
tivity (%) 
______________________________________ 
13 Phosphomolyb- 
96 57 59 
dic acid 
14 Silicomolybdic 
95 56 59 
acid 
______________________________________ 
COMATIVE EXAMPLE 1 
The procedures of Example 1 were followed without use of phosphomolybdic 
acid as the catalyst. The results are shown in Table 8 below. 
TABLE 8 
______________________________________ 
Compara. Conver- Selec- 
Example sion (%) Yield (%) 
tivity (%) 
______________________________________ 
1 40 4 10 
______________________________________ 
COMATIVE EXAMPLE 2 
The procedures of Example 1 were followed with the exception that 50 mg of 
ferrous sulfate 7H.sub.2 O was used in place of phosphomolybdic acid. The 
results are shown in Table 9 below. 
TABLE 9 
______________________________________ 
Compara. Conver- Selec- 
Example sion (%) Yield (%) 
tivity (%) 
______________________________________ 
2 70 9 13 
______________________________________