Synthesis of 2,5-dimethoxybenzaldehyde

[foxy2]

Synthesis of Some Benzodipyrones, Potential Photochemical DNA Crosslinking Agents
John N. Marx, Pill-Soon Song, and Patrick K. Chui
Journal of Heterocyclic Chemistry 12(1), 417 (1975)

2,5-dimethoxybenzaldehyde (V)
To a solution of 1.06g (7.65 mmoles) of hydroquinone dimethyl ether and 2.69g (23 mmoles) of dichloromethyl methyl ether in 30ml of methylene chloride under nitrogen was added 5.78g (30 mmoles) of titanium tetrachloride.  The dark red mixture was refluxed for 48 hours.  Water was then added and the solution washed with dilute sodium bicarbonate and then water, dried, and the solvent removed to give a solid residue which gave a major blue fluorscent spot by tlc for V and a very minor green one for IVd (2,5-dimethoxyterephthaldehyde).  Crystallization from ethanol gave 0.59g (3.55 mmoles, 46%) of V, mp 50-52°C.

Use of hydroquinone under these conditions gave only tars.

[Kinetic]

Now that is interesting...

A couple of bees have expressed concern about the toxicity of the 'usual' Lewis acid catalyst, SnCl₄, for formylations with dichloromethyl methyl ether. I had wondered whether TiCl₄ would work, and this proves it! I'm sure titanium is less toxic than tin.

Maybe the even more eco-friendly SiCl₄ would also work? It seems quite likely, but if anyone tries it, remember to clean your syringe thoroughly as soon as you've used it.

[slappy]

Dichloromethyl methyl ether is nasty, nasty stuff... at that point, you are not even concerned about the toxicity of the SnCl4.

SiCl4 would most likely not work.

[Rhodium]

Synthesis and Resolution of 2,5-Dihydroxyphenylalanine
A. Neuberger

J. Biol. Chem. 43, 599-605 (1948)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/25-dihydroxyphenylalanine.pdf)

Experimental

2,5-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 AlCl₃ (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-methoxyphenol³ 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 H₂SO₄. 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 N₂, 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