Author Topic: 4-Methoxyphenol -> 2-EtO-5-MeO-allylbenzene  (Read 1843 times)

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4-Methoxyphenol -> 2-EtO-5-MeO-allylbenzene
« on: August 21, 2003, 04:48:00 AM »
This reference was requested by Potter, retrieved by Lugh, and is a variation of the first steps in Psycho Chemist's

Synthesis of 2,5-Dimethoxyallylbenzene


Chemistry Of The Podocarpaceae. II.
The Isolation of Genistein from Podocarpus Spicatus and the Constitution of Podospicatin

L. H. Briggs And T. P. Cibalo

Tetrahedron 6, 145-147 (1959)



4-Methoxyphenol (19 g) was allylated by refluxing with allyl bromide (24 ml) in acetone (500 ml) in the presence of anhydrous potassium carbonate (60 g) for 9 hr. The product from the acetone solution was taken up in ether and washed with sodium hydroxide solution and the solvent removed, The resultant liquid (22.5 g) failed to solidify and was submitted to Claisen rearrangement directly.


The allyl ether (22.5 g) and dimethylaniline (12 g) were refluxed for 45 min, dissolved in light petroleum and extracted successively with dilute sulphuric acid and 10 % sodium hydroxide solution. The alkali soluble material, after acidification and extraction with ether, yielded 2-allyl-4-methoxyphenol as an oil, bp 190°C (bath temp)/8 mmHg (17.6 g),


The above phenol (17.5 g) was ethylated by refluxing with diethyl sulphate (18 ml) in acetone (200 ml) in the presence of anhydrous potassium carbonate (60 g) for 16 hr. The material from the acetone solution was taken up in ether and washed with sodium hydroxide solution and the solvent removed. 2-Ethoxy-5-methoxyallylbenzene was obtained as an oil, bp 174-178°C (bath temp)/5 mmHg.

2-ethoxy-5-methoxyphenylacetic acid

The oil (700 mg) was finally ozonized in carbon tetrachloride (25 ml) and the ozonide decomposed and oxidized by solution in glacial acetic acid and treatment with a mixture of hydrogen peroxide (30%, 2.5 ml), sulphuric acid (0.1 ml) and water (5 ml) under reflux for 2 hr. The product was taken up in ether and the acidic material removed with sodium hydrogen carbonate solution. After acidification the material was repeatedly crystallized from water to give colourless plates of 2-ethoxy-5-methoxyphenylacetic acid, mp and mixed mp with the degradation acid, 101-102°C, The infrared spectra of the two acids were also identical.


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prepn. & hydrogenation of 2,5-diMeO-allylbenzene
« Reply #1 on: October 19, 2004, 07:42:00 PM »
From SWIM's old lab journal, slightly edited.


Post 406068

(Rhodium: "For 2,5-Dimethoxyallylbenzene prep", Novel Discourse)


allyl bromide FW 120.98 d 1.398
2-allyl-1,4-dimethoxybenzene FW 178.23
1,4-dimethoxy-2-propylbenzene FW 180.25
dimethyl sulfate FW 126.13 d 1.333
4-methoxyphenol FW 124.14
potassium carbonate FW 138.21


   To a solution of 4-methoxyphenol (15.5 g, 0.125 mol) and allyl bromide (14.5 ml, 0.168 mol) in acetonitrile (80 ml) was added powdered K2CO3 (19.0 g, 0.137 mol), and the mixture was refluxed with stirring overnight (18 h, TLÑ showed no presence of the starting material). The outlet of the condenser was connected to a gas bubbler to prevent excessive contact with the atmosphere during the reflux. The mixture was diluted with water (~100 ml) and extracted with PhMe (3 times). The extracts were washed with water, 10% aq. NaOH (3 times), dried (Na2SO4 - Celite) and evaporated under reduced pressure to give 1-allyloxy-4-methoxybenzene as an oil. The last traces of PhMe which could diminish the boiling point of the product were removed by heating it to a mild reflux (bath temperature 80 °C) in a vacuum of an oil pump.

   The allyl ether was slowly heated to 210 °C (internal temperature!) in an oil bath with stirring under argon. The exotherm was hardly noticeable at this scale. After 1 h at 210 °C the rearrangement was complete (TLC: petr. ether - EtOAc 3:2 v/v). The mixture was heated for an additional 1/2 h, cooled under argon, and the product (2-allyl-4-methoxyphenol) was extracted with 5N aq. NaOH (40 ml). The alkaline solution was washed with PhMe (15 ml) which removed the by-product (2,3-dihydro-5-methoxy-2-methylbenzo[b]furan) and some of colored impurities. The toluene layer was re-extracted with 5N aq. NaOH (~10 ml), and the alkaline solutions were combined.

   To the alkaline solution of 2-allyl-4-methoxyphenol was added dimethyl sulfate (12 ml, 0.127 mol) dropwise with stirring and cooling (cold water bath) over the course of ~5 min. The temperature was kept under 30 °C during the addition. After 1/2 h stirring at r. t., the mixture was gradually (1 h) heated to 100 °C. Then the mixture was cooled to r. t., the organic layer was separated and washed with a small amount of 5N aq. NaOH. A small portion of the aqueous layer gave oily droplets of the starting phenol on acidification, showing incomplete methylation. The alkaline solutions were combined and methylated again with dimethyl sulfate (9 ml, 0.095 mol) as described above. The aqueous phase (still alkaline) was extracted with PhMe; the extract was combined with the organic layers containing 2-allyl-1,4-dimethoxybenzene, washed with aq. NH3 and dried by filtering through a pad of a silica gel - Na2SO4 mixture. The silica gel was washed with DCM; the filtrate and the washings were evaporated under reduced pressure, and the residue was distilled in a vacuum of an oil pump to give 2-allyl-1,4-dimethoxybenzene (19.64 g, 88% based on 4-methoxyphenol), b. p. 76-82 °C, as a colorless liquid, individual by TLC.


   2-Allyl-1,4-dimethoxybenzene (19.64 g, 0.110 mol) was dissolved in 95% EtOH (50 ml); 10% Pd(OH)2 on charcoal (0.73 g) was added, and the reaction flask was rapidly evacuated and filled with hydrogen from a gasometer 3 times. The mixture was stirred at r. t. overnight (~0.6 l of H2 was consumed during the first hour; total uptake ~2.5 l). A portion of fresh catalyst was then added on the tip of a spatula, the flask was evacuated, refilled with hydrogen, and the mixture was stirred for an additional hour to make sure that all the substrate had been hydrogenated. Since no hydrogen uptake was noted, the reaction mixture was filtered through a pad of Celite. The Celite was washed with 95% EtOH, the combined ethanolic solutions of the product were evaporated under reduced pressure, and the residue was distilled in a vacuum of an oil pump to give 1,4-dimethoxy-2-propylbenzene (19.34 g, 97%) as a slightly off-white liquid (quinone admixture?), b. p. 63-68 °C, individual by TLC.

The product was successfully applied in the synthesis of 4-Pr-2,5-DMNS and 4C-P (the identity of the latter was proven by NMR).