This is taken from
J. Chem. Soc. p.662-670 (1941):
Pentamethoxybenzene (IV) is best prepared in quantity from the very accessible 1,2,3,5-tetramethoxybenzene (I)
via the compounds 2-hydroxy-3,4,6-trimethoxyacetophenone (II) and 1,2-dihydroxy-3,4,6-trimethoxybenzene (III).
In the present work a very simple synthesis of pentahydroxybenzene derivatives has been developed starting from pyrogallol. This was converted by known methods into 1,2,3,5-tetramethoxybenzene (I), and with improvements described in the experiment section the over-all yield of (I) was rather over 50%. Compound (I), when treated with acetyl chloride and anhydrous AlCl
3 in dry ethereal solution at room temperature, gave a 70% yield of (II), the highest yield previously claimed in this much investigated reaction being 42% (Wesseley and Kallab,
Monatsh., 1932, 60, 26); the increase is due to the use of ether as a solvent, and employment of low temperature. When 2-hydroxy-3,4,6-trimethoxyacetophenone (II) was oxidised by hydrogen peroxide in alkaline solution under the conditions of the Dakin reaction, it yielded 1,2-dihydroxy-3,4,6-trimethoxybenzene (III). Methylation of (III) with Me
2SO
4 and alkali readily gave pentamethoxybenzene (IV), identical with that described by Aulin and Erdtman (
Svensk Kem. Tidskr., 1937, 49, 208). By this route it is possible to prepare just over 50 gr. of pentamethoxybenzene from 126 gr. of pyrogallol.
An alternative route to pentamethoxybenzene started from gallacetophenone, which was converted into its dimethyl ether (V) (improved preparation), and oxidation of this with alkaline potassium persulfate gave 2,5-dihydroxy-3,4-dimethoxyacetophenone (VI) in 36% yield. Partial methylation of (VI) with Me
2SO
4 and K
2CO
3 in benzene gave 2-hydroxy-3,4,5-trimethoxyacetophenone (VII), which was then oxidised with H
2O
2 in alkaline solution to give 1,2-dihydroxy-3,4,5-trimethoxybenzene (VIII). Methylation of (VIII) again gave pentamethoxybenzene (IV).
A considerable less convenient way to prepare (VIII) is from 2,6-dimethoxyquinol diacetate, which is converted first by the action of AlCl
3 into 2,5-dihydroxy-4,6-dimethoxyacetophenone (IX) (Mauthner,
J. pr. Chem., 1933, 147, 287), and then by monomethylation with Me
2SO
4 and anhydrous K
2CO
3 in benzene into the bright yellow 2-hydroxy-4,5,6-trimethoxyacetophenone (X). Oxidation of (X) with H
2O
2 then gave 1,2-dihydroxy-3,4,5-trimethoxybenzene (VIII), identical with that prepared by the oxidation of the isomer (VII).
Two routes leading to the preparation of pentahydroxyacetophenone derivatives have been investigated. In the first, (II) was oxidised by potassium persulfate in alkaline solution to give 2,5-dihydroxy-3,4,6-trimethoxyacetophenone (XVI), and this readily yielded 2,3,4,5,6-pentamethoxyacetophenone (XVII) on treatment with excess Me
2SO
4 and alkali.
in the second route pentamethoxybenzene (IV) was treated with acetyl chloride and AlCl
3 in ethereal solution and yielded the bright yellow 2-hydroxy-3,4,5,6-tetramethoxyacetophenone (XIX), and important intermediate for the synthesis of flavones and related compounds; it yielded pentamethoxyacetophenone (XVII) on methylation with methyl sulfate and alkali.
The partial methylation of 2,5-dihydroxy-3,4,6-trimethoxyacetophenone (XVI) to give 2-hydroxy-3,4,5,6-tetramethoxyacetophenone (XIX), under conditions which converted (IX) into (X), gave only traces of the desired product.
EXPERIMENTAL1,2,3,5-tetramethoxybenzene (I).
Considerable quantities of this substance have been made from pyrogallol via the stages (1) pyrogallol methyl ether, (2) 2,6-dimethoxy-1,4-benzoquinone, and (3) 2,6-dimethoxyquinol, and the yields represent a very considerable improvement over those previously described. The modifications of recorded conditions are described in the following notes, and enable over 100 gr. of the tetramethoxybenzene to be obtained from 126 gr. of pyrogallol.
(1) Pyrogallol trimethyl ether : The methylation of pyrogallol (126 gr) is carried out as described by Chapman, Perkin and Robinson (
J.Chem.soc., 1927, 3028) but it is essential that the reaction mixture should be cooled in a trough of water so that the temp. keeps between 18° and 22°, and the addition of NaHSO
3 (10 gr) as recommended by Kohn and Grün (
Monatsh., 1925, 46, 27) ensures a water-white product. After stirring for a total of 6 hours, crushed ice (1 kg) is added, and the product collected, washed and dried. Yield: 155 gr.
(2) 2,6-dimethoxybenzoquinone (see Graebe and Hess,
Annalen, 1905, 340, 237) : The above pyrogallol trimethyl ether (155 gr), alcohol (775 cc), and nitric acid (775 cc; d 1.2) are warmed to 35°
and allowed to stand until the vigorous reaction sets in, and the temp. then kept just below 50° till the main heat evolution ceases (15 min). After 4 hours with occasional shaking the quinone is collected, drained, washed with alcohol (400 cc), then water (800 cc) and dried on the water bath. Yield : 124 gr.
(3) 2,6-dimethoxyquinol : To the above quinone (124 gr) and NaHSO
3 was quickly added boiling water (1250 cc), and the mixture vigorously shaken till a clear solution was obtained (less than 1 min.) and then cooled rapidly under the tap with shaking. After 30 min. the product was collected, drained, washed with ice-water (600 cc) and dried on the steam-bath (local darkening). Yield : 110 gr. If the filtrate and the washings from the quinol are saturated with NaCl and extracted with EtOAc at 40-50°, a further 8 gr of the quinol are obtained, but the labour involved is hardly justified.
(4) 1,2,3,5-tetramethoxybenzene : To a continually stirred mixture of 2,6-dimethoxyquinol (55 gr), alcohol (130 cc), Me
2SO
4 (250 gr) and NaHSO
3 (4 gr) in an atmosphere of coal gas was added dropwise during 4 hours a solution of NaOH (80 gr) in water (180 cc), the temp. being kept at 15-20°C. The mixture was then heated on the water bath for 30 min. with frequent shaking, diluted with water (500 cc), cooled and seeded, and the solid product collected, thoroughly washed, and dried. Yield : 54 gr, mp. 35-40° (mp. of pure material : 47°)
2-hydroxy-3,4,6-trimethoxyacetophenone (II).
Anhydrous AlCl
3 (50 gr) was dissolved in absolute ether (250 cc) with cooling, and then 1,2,3,5-tetramethoxybenzene (50 gr as obtained from the above reaction) added. To the mixture ,which was vigorously stirred and cooled in a vessel of water, acetyl chloride (25 gr) was added during 1 hour, and stirring continued for a further 6 hours. During this time the yellow, solid Al-complex of (II) began to separate. After standing overnight, water (350 cc) and conc. HCl (50 cc) were cautiously added and the mixture was heated on the water bath for 30 min., the ether being allowed to distill away, and, while hot, extracted with benzene (200 cc). The benzen layer was washed with dil. HCl and shaken with an excess of 10% aq. NaOH, and the aqueous layer acidified. The rather dark, solid product was collected, washed (dry weight 46.5 gr; mp. 101-104°) and crystallised from dilute alcohol (charcoal), giving a light fawn, crystalline powder (42.5 gr; 70% yield) mp. 103-105°
1,2-dihydroxy-3,4,6-trimethoxybenzene (III).
2-hydroxy-3,4,6-trimethoxyacetophenone (22.6 gr) was dissolved in a solution of NaOH (8 gr) in water (160 cc) with heating, and cooled to 20°, and a 3% solution of H
2O
2 (142 cc; 1.25 mol) at 20° added. The temp rose gradually at first, then rapidly to 54°, and then fell. After 2 hours the solution was acidified with H2SO4, and unchanged material collected by filtration, washed and dried (2.2 gr). The filtrate was saturated with NaCl and extracted 3x with ether (100 cc each time) and the extracts shaken with an excess of NaHCO
3 suspension and water to remove AcOH, dried over Na
2SO
4 and distilled, leaving 1,2-dihydroxy-3,4,6-trimethoxybenzene as an oil which completely solidified on scratching (yield : 12.3 gr)
Recrystallize from benzene/light petroleum, mp. 82°
Pentamethoxybenzene (IV).
The preceding compound (III) (10 gr; not crystallised), alcohol (10 cc) and NaHSO
3 (1 gr) were vigorously shaken during the alternate portionwise addition of methyl sulphate (25 gr) and a solution of NaOH (50 cc containing 10gr). The temp was allowed to rise to about 50°, and the reaction was completed by heating on the water-bath for 30 min. The alkaline solution was extracted 3x with benzene, and the extracts dried and distilled, leaving a viscious brown oil (10.2 gr) which solidified on cooling (mp. ca 45-53°). The compound separated from light petroleum (bp. 40-60°) in which it was easily soluble, in colourless, nacreous, rhombic plates, mp. 58-59°. It is most easily purified by vacuum distillation; bp. 150°/14mm.; 167°/21mm.