US Patent 2516412
Method of Synthesizing Syringaldehyde
The synthesis of syringaldehyde in good yield and on a large scale from 1,3-dimethoxy-2-hydroxybenzene, obtained from distillate of beechwood tar or is obtained from the controlled methylation of pyrogallol. (The following reactions begin with pyrogallol.)
Example 1:
Preparation of 1,2-dimethoxy-2-hydroxybenzene
From: Krauss and Crede, J. Am. Chem. Soc. 39, 1433 (1917)
A flask containing 126 parts of pyrogallol is connected to a reflux condensor. Methyl bromide is passed into the flask by a glass tube ending in a capillary and passing through the condensor to near the bottom of the flask until the air is displaced. A solution of sodium methylate (prepared by dissolving 57.5 parts of sodium in 640 parts of absolute methanol) is run into the flask together with a continuous stream of methyl bromide. The flask in heated on the water bath and the current of methyl bromide continued until the reaction is nearly neutral. The gas is rapidly absorbed and sodium bromide appears. The 1,3-dimethoxy-2-hydroxybenzene is isolated as follows: Water is added until the sodium bromide dissolves. The methanol is evaporated and the residue is steam distilled. Any 1,2,3-trimethoxybenzene present passes over in the steam. The residue is acidified and extracted with ether. The ether is removed and the residue is fractionated under reduced pressure. The pure 1,3-dimethoxy-2-hydroxybenzene is obtained as white crystals that had; MP: 55-56*C
Example 2:
2-allyloxy-1,3-dimethyoxybenzene
A mixture of 154 parts of 1,3-dimethoxy-2-hydroxybenzene, 133 parts of allyl bromide and 180 parts of anhydrous potassium carbonate in 400 parts dry acetone was heated to boiling under reflux with occasional shaking for eight hours. The solvent was removed by distillation, the residue was diluted with water and extracted with ether. The ether was washed with dilute sodium hydroxide solution, the with water, dried with calcium chloride and distilled under reduced pressure on a steam bath to remove the ether and excess allyl bromide. The residual liquid was distilled under high vacuum and was obtained as an almost colorless oil that had; BP: 102*C/2mmHg, 130*C/9mmHg, nD22 = 1.5300. The yield of 2-allyloxy-1,3-dimethoxybenzene was 184 parts (95%)
Example 3:
3,5-dimethoxy-4-hydroxyallylbenzene
2-allyoxy-1,3-dimethoxybenzene (104 parts) was boiled under relflux at 75mmHg for 1 hour and was then distilled under high vacuum. 3,5-dimethoxy-4-hydroxyallylbenzene distilled as a colorless oil that had; BP: 123-125*C/2mmHg, nD21 = 1.5478. The yield was 147 parts (90%)
Example 4:
3,5-dimethoxy-4-hydroxypropenylbenzene
A mixture of 100 parts of 3,5-dimethoxy-4-hydroxyallylbenzene, 50 parts of potassium hydroxide and 200 parts of water was placed in a flask connected to a distillation assembly and heated to boiling. The clear solution soon became thick with a precipitate. When the temperature reached 100*C, it had set to almost solid. At this point 450 parts of aniline were added and the mixture distilled again. After about 100 parts of distillate were collected, the solution became thick with precipitate. This precipitate disappeared when the last bit of water was removed and the temperature began to rise. About 150 parts of distillate had been collected at this point. The distillation was continued until approximately 100 parts of aniline were collected and the temperature of boiling was 178-180*C. The hot mixture was allowed to cool and a mixture of aniline and the potassium salt of 3,5-dimethoxy-4-hydroxypropenylbenzene solidified.
Example 5:
3,5-dimethoxy-4-hydroxypropenylbenzene
The solid mass from Example 4 was dissolved in water and extracted with ether. The alkaline aqueous layer was acidified with dilute hydrochloric acid. The oil which separated was extracted with ether and the ether solution was washed with dilute hydrochloric acid, then with water, then dried. The ether was removed, the the residue was distilled to give 93 parts of 3,5-dimethoxy-4-hydroxypropenylbenzene that had; BP: 107-108*C/0.05mmHg as a colorless oil, nD27 = 1.5741.
Example 6:
Syringaldehyde from alkali metal salt of 3,5-dimethoxy-4-hydroxypropenylbenzene
The solidified mixture of the potassium salt of 3,5-dimethoxy-4-hydroxypropenylbenzene and aniline obtained when hot (178-180*C) mixture of Example 4 was cooled was covered with 300 parts of nitrobenzene and 100 parts of 1:1 sodium hydroxide solution. The resulting mixture was heated to 100-105*C with stirring for two hours, allowed to cool and diluted with water. The solution was extracted with ether and the aqueous layer was acidified. The acid mixture was extracted with ether and the ether extracted with a 21% sodium bisulfite solution. The bisulfite solution was acidified with sulfuric acid and aspirated to remove the dissolved sulfur dioxide. Crystalline syringaldehyde separated and was filtered and washed with water. Ether extraction of the filtrate and washings yielded more syringaldehyde. The total yield of crude syringaldehyde that had; MP: 109-110*C was 78 parts (84%). Recrystallization from ligroin raised the MP to 110-111*C.
Example 7:
Syringaldehyde from the isolated intermediate
195 parts 3,5-dimethoxy-4-hydroxypropenylbenzene are added to a cupric oxide mixture freshly prepared. (prepared from 1000 parts hydrated copper sulfate, 600 parts sodium hydroxide and 3000 parts water) The mix is refluxed for 8 hours. The separated red cuprous oxide is filtered and washed with water. The alkaline filtrate and washings are acidified and extracted with ether. Bisulfite purification of the ether extract should give 165 parts (90%) of syringaldehyde
Notes: The cuprous oxidation may also utilize Fehling’s or Benedict’s solutions with same results.
Example 4 and 6 may be combined to one step by allowing the temperature in Example 4 to fall to the temperature in Example 6 and continuing by adding the necessary reagents.
Example 2 may utilize with equal results in an organic solvent which is alkaline such as pyridine, dimethylaniline, aniline, etc.
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