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vanillin -> TMA-2

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phenethyl_man:
I don't believe I have seen this reaction scheme discussed on here before, but it seems like an easy route to TMA-2 using an easily accessible precursor.

Search for "2-methoxyhydroquinone" gave one article posted by Rhodium that follows a similar route, however the hydroquinone rather than an aldehyde is dimethylated and it is never formylated.

a. Dakin reaction on vanillin yields 2-methoxyhydroquinone.  I believe H2O2 under alkaline conditions will accomplish this.

b. Your choice of a phenolic ortho-formylation on 2-methoxyhydroquinone yields 2,5-dihydroxy-4-methoxybenzaldehyde.

c. Dimethylation w/DMS yields Asaronaldehyde [2,4,5-trimethoxybenzaldehyde];  plenty of representative procedures of this on rhodium.ws.

I shouldn't have to explain how to get to the target compound from there.  Anyone see any potential problems here?

Saddam_Hussein:
First, you have to subject vanillin to a Dakin reaction (H2O2/NaOH), followed by methylation of the resulting phenol. 1,2,4-Trimethoxybenzene is extracted and subsequently purified by distillation, followed by Vilmeier-Haack formylation (DMF). Total yield from vanillin is 40-50%.

You could also use TFSE.

Captain_America:
Nah, simply methylate vanillin, brominate and do a methoxid swap and you'll have the asaraldehyde...

Post 214369 (missing) (foxy2: "2 Bromination of 3,4-dimethoxybenzaldehyde", Chemistry Discourse) in methanol
Post 214376 (missing) (foxy2: "Re: 2 Bromination of 3,4-dimethoxybenzaldehyde", Chemistry Discourse) in chloroform

For 2C-T and Alephs from vanillin it might bee better to make the 6-bromovanillin a la Post 529398 (Captain_America: "5-Bromo-4-formyl-2-methoxyphenol", Novel Discourse) then swap with the methoxid and transform the -OH on para to S-R by tosylation/mesylation followed by mercaptan swap... It would of bee a nice shortcut to make the 4-alkylthio vanillin following the same strategy and then go from there, but I don't know if it would give good yields in bromination step to come, if so, then good - there is no reason going via acetoxy ester. Alternative solution would bee using a nice oxidative iodination method found by Kinetic that works on less activated substrates (maybee on 4-alkylthio-vanillin), Post 518568 (Kinetic: "Iodination of arenes with KI and H2O2", Chemistry Discourse) very simple, high-yielding and perfectly OTC, good find Kinetic.  :)

phenethyl_man:
First, you have to subject vanillin to a Dakin reaction (H2O2/NaOH), followed by methylation of the resulting phenol. 1,2,4-Trimethoxybenzene is extracted and subsequently purified by distillation, followed by Vilmeier-Haack formylation (DMF). Total yield from vanillin is 40-50%.

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Yes, I know about the Vilsmeier-Haack formylation.  The idea was to be able to use a phenolic formylation by methylating last since I don't have any POCl3 or other toxic alternative, and the Gattermann formylation seems like a nice way to poison myself. The cost to have DMS shipped by truck freight already has SWIM's funding for this project running quite low.

The route suggested by Captain_America which I had forgotten  about seems viable although I guess I will have to synth some NaOMe.

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