Author Topic: 3,4,5-trimethoxy-BA for 3,4-dimethoxy-BA question.  (Read 3756 times)

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amine

  • Guest
3,4,5-trimethoxy-BA for 3,4-dimethoxy-BA question.
« on: November 16, 2003, 01:04:00 PM »
If one were able to obtain a 3,4-dimethoxybenzaldahyde.
Could one brominate the 5th carbon similar as is done with vanillin, and yeild a 3,4-dimethoxy-5-bromobenzaldahyde,

This followed up by a reflux with Sodium Methoxide to  possibly yield a 3,4,5-trimethoyxbenzaldahyde.

Would this work?

hest

  • Guest
Yes
« Reply #1 on: November 17, 2003, 12:23:00 AM »
Yes it will work. But the OH group in vaniline is much more activating, so better yeald and cleaner produt will bee obtained wit the bromination of vaniline.

Rhodium

  • Guest
Veratraldehyde brominates in 6-position
« Reply #2 on: November 17, 2003, 02:55:00 AM »
No it will not.

In the case of vanillin, the phenol group is ortho-directing (the para position is taken), causing the electrophile to add in the 5-position. In 3,4-Dimethoxybenzaldehyde (veratraldehyde) para-directing forces are predominant, causing the electrophile to add para to the 3-methoxy (the position para to the 4-methoxy is taken), forming the 6-substituted product.

With bromine as the electrophile, the end product is thus 6-Bromo-3,4-Dimethoxybenzaldehyde (or more properly named 2-Bromo-4,5-Dimethoxybenzaldehyde). For details of the reaction, see

Post 214369 (missing)

(foxy2: "2 Bromination of 3,4-dimethoxybenzaldehyde", Chemistry Discourse)

amine

  • Guest
ah thanks rhodium, I'm assuming you can react...
« Reply #3 on: November 17, 2003, 01:53:00 PM »
ah thanks rhodium, I'm assuming you can react the 2-bromo,4,5-dimethoxybenz. with Sodium Methoxide and get the tma2 precursor?

Rhodium

  • Guest
Indirect 6-Methoxylation of Veratraldehyde
« Reply #4 on: November 18, 2003, 10:01:00 AM »
You might have to go through the corresponding benzoic acid or benzoate ester for the synthesis to be successful, see the following document on a similar analog:

Post 465752 (missing)

(Rhodium: "6-Bromo- to 6-Methoxy-piperonylic acid", Novel Discourse)


Another alternative is this more advanced reaction procedure, followed by methylation:

Aromatic hydroxylation. Hydroxybenzaldehydes from bromobenzaldehydes
via reaction of in situ generated, lithiated -morpholinobenzyl alkoxides with nitrobenzene

Achintya K. Sinhababu, Ronald T. Borchardt

J. Org. Chem. 48, 1941-1944 (1983)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/bromo2hydroxy-benzaldehydes.pdf)

Yet another alternative is to start with vanillin and turn it into 2,4,5-trimethoxybenzaldehyde using this procedure:

None

(https://www.thevespiary.org/rhodium/Rhodium/djvu/245-meo-ba.from.vanillin.djvu)

The same procedure can very likely be used on 3,4-dimethoxybenzaldehyde with the only modification being that the amounts of dimethyl sulfate/base amounts are to be cut in half in the second step (after the dakin oxidation of the aldehyde to the phenol ester), as there is only one free phenolic group to be methylated.

Here are the pertinent procedures from that article:

1,2,4-Trimethoxybenzene

Vanillin (30g) in 1M potassium hydroxide (175 ml.) was treated at 40°C with hydrogen peroxide (30 mL 30% H2O2 diluted to 100 mL with water). The solution was stirred without further heating until it had cooled to 20°C (ca. 1.5 h) and the oxidation product was methylated by stirring with successive portions of alkali (4x100 mL 20% caustic soda) and dimethyl sulfate (4x30 mL). The trimethoxybenzene separated as an oil and was extracted into ether and dried (MgSO4). Evaporation of the solvent gave the trimethoxybenzeme (20g, 60%) as an oil, which was used directly in the formylations described below. The same product has also bees prepared by Thiele acetylation of p-benzoquinone, followed by hydrolysis and methylation and dimethyl sulphate [JCS 1165 (1954)].

2,4,5-Trimethoxybenzaldehyde

(a) 1,2,4-Trimethoxybenzene (17.0g) in dimethylformamide (50 ml.) was treated with a cooled mixture of phosphoryl  chloride (20 g.) in dimethylformamide (50 mL), and the resulting solution was warmed at 40°C for 1 h. It was then poured into water (500 mL), basified by addition of excess of 10% caustic soda, and the liberated aldehyde extracted with ether, washed with water, and dried (MgSO4). Evaporation of the ether gave an oily solid which was crystallised from chloroform light petroleum to give the trimethoxybenzaldehyde (18.0g, 90%) as needles, mp 112°C (lit. 114°C). The same product was also obtained in 95% yield by substitution of N-methylformanilide for dimethylformamide in the above preparation.

(b) 1,2,4-Trimethoxybenzene (17.0g) in methylene dichloride (60 mL) was cooled to -70°C, and stannic chloride (17 mL) followed by dichloromethylmethyl ether (10 mL) was added slowly at -70°C. The red mixture was stirred for a further 15-30 min. at room temperature before being poured into ice and water. The organic layer was separated, the aqueous layer extracted with more methylene dichloride, and the combined extracts washed with water, saturated sodium hydrogen carbonate, again with water, and dried (MgSO4). Evaporation of the solvent under reduced pressure gave a yellow oil which slowly solidified and was crystallised from chloroform to give the aldehyde as needles, mp 112°C (15g, 75%).


Bonus Preparation: A High-yielding (75%) Benzaldehyde -> Benzyl Cyanide Synthesis

2-Benzyloxy-4,5-dimethoxybenzyl Bromide

2-Benzyloxybenzaldehyde (1.0g) was stirred in diethylene glycol dimethyl ether (20 mL) with sodium borohydride (0.5g) at 20°C. After 1 hr. the excess of borohydride was decomposed by addition of solid carbon dioxide, the mixture diluted with water, and the product extracted with ether (2x20 mL) and washed with water (5x10 mL). After drying (MgSO4) the ether was evaporated to give the benzyl alcohol (0.9g, 89%) as an oil which was used directly.

The crude benzyl alcohol (2.0g) in dry ether (40 mL) was treated with phosphorus tribromide (2 mL). After 10 min. the pale red solution was poured on crushed ice (100 g), and the organic layer separated, washed with sodium hydrogen carbonate solution, then with water, and dried (MgSO4). The pale green oil remaining after evaporation of the ether was extracted with boiling light petroleum (bp 60-80°C) and gave the desired benzyl bromide (2.2 g, 90%) as needles, mp 86°C.

If hydrochloric acid was used to decompose the excess of borohydride, and the product extracted as above, a white solid was obtained, which on crystallisation from benzene-light petroleum (bp 60-80°) afforded 2,2'-dibenzyloxy-4,4',5,5'-tetramethoxydiphenylmethane (0.76 g.; 80%) as needles, mp 116°C. The same product was also obtained in 80% yield on treatment of the crude alcohol with thionyl chloride in ether.

2-Benzyloxy-4,5-dimethoxybenzyl Cyanide

The foregoing benzyl bromide (10.0g) in dimethylformamide (100 mL) was stirred at 200 with dry sodium cyanide (5.0 g.) for 15 hr. The pale yellow solution was diluted with water (2 L) and the product extracted with benzene (3x100 mL). The extracts were washed with a little water, dried (MgSO4), and evaporated to dryness. The residual oil solidfied on scratching, and was recrystallised from chloroform-light petroleum (bp 60-80°C) to give the cyanide (8.0g, 94%) as needles, mp 90°C.