Synthesis and Resolution of 2,5-DihydroxyphenylalanineA. NeubergerJ. Biol. Chem. 43, 599-605 (1948)
(
https://www.thevespiary.org/rhodium/Rhodium/pdf/25-dihydroxyphenylalanine.pdf)
Experimental2,5-Dimethoxybenzaldehyde was prepared by two methods:
(a) Gattermann synthesis The method described here is shorter and more convenient than that of Gulland & Virden
1,2.
Into a three-necked flask fitted with a mercury-sealed stirrer, a reflux condenser and an inlet tube was placed 1,4-dimethoxybenzene (30 g), dry benzene (90 ml) and zinc cyanide (40.4 g), The mixture was cooled in ice and dry HCl was passed in, whilst the mixture was rapidly stirred, until saturated with HCl, Finely powdered AlCl
3 (44 g) was then added and the temperature raised to 45°C. The mixture was kept at that temperature for 3-5 h, whilst a slow stream of HCl was passed in. The mixture was then poured into 3N HCl (500 ml), refluxed for 30 min. and cooled, Ethyl acetate (200 ml) was added, the organic layer separated, and the aqueous solution again extracted with ethyl acetate, The combined extracts were then dried, the solvent removed and the remaining oil distilled. A small amount of unchanged dimethoxybenzene came over below 130°C, whilst the bulk of the material distilled sharply at 154°C/18 mmHg. It crystallized in the receiver and had mp 53°C. Yield was 73% of the theoretical.
(b) Reimer-Tiemann synthesis NaOH (80 g) was dissolved in water (100 ml). To this solution, which was kept at 65-70°C, was added 33 g p-methoxyphenol
3 and chloroform (20 g). The solution was kept at 70°C by alternate cooling and warming. When the reaction had subsided a second lot of chloroform (20 g) was added, and after 10 min. a third lot. The mixture was then refluxed for 1 h; excess chloroform was removed by distillation and the solution acidified with 5N H
2SO
4. The aldehyde was then distilled in steam, 1.5-2 L of distillate being collected, The distillate was extracted with ether and concentrated; the resulting oil was distilled in vacuo under N
2, bp 144.5°C/20 mmHg. The crude aldehyde (21 g) was methylated with methyl sulphate (1-2 eqv) and 2N NaOH (1.2 eqv) at 65°C. The aldehyde, after cooling was filtered off and the mother liquor extracted with ethyl acetate, The crystalline material and the oil from the ethyl acetate extraction were combined and distilled, bp 160°C/20 mmHg. Overall yield was 35-40%.
References[1] J. M. Gulland & C. J. Virden, J. Chem. Soc. 921 (1928)
[2] J. M. Gulland & C. J. Virden,
J. Chem. Soc. 1478 (1928)
(
https://www.thevespiary.org/rhodium/Rhodium/pdf/25-dmba.25-paa.pdf)
4[3] R. Robinson & J. C. Smith, J. Chem. Soc. 397 (1926)
[4] This paper also contains a synthesis of 2,5-Dimethoxy-Phenylacetic Acid