3-methyl-2,5-diMeO-benzaldehyde

[Antoncho]

Hey, guys, watch this.

May i humbly note that not only this

Patent US3236898

remarkable beecause of the insight into that  completely enigmatic so far ground - 3-smth-2,5-diMeO-phenethylamines (Shulgin in PiHKAL #160 says that "...This 2,3,5-orientation of the methoxy groups on the aromatic ring is far and away the most difficult tri-substitution pattern known to chemists.  There just isn't any simple way to put it together.  " - and in fact no such compound was ever bioassayed to an active level).

It's also remarkable 'cause the 1st stage of the chemistry is very neat - it is a hydroxymethylation - which usually gives very poor yields, but in this case (and, no doubt, also possible w/a variety of substituents) and w/some tricks, it is quite high-yielding. The methylation of the phenolic hydroxyl is performed w/out purification of the intermediate:



Or the following variation (it's a well-known rxn, although a different variation than i've seen bee4 - what's its name, pray tell me?):




The benzyl alcohol can then bee oxidized to aldehyde w/SeO2 like this:



- but, well, i guess, we know some more appealing methods - like w/Fe(NO3)3,

or one can always directly make nitrile from it and reduce it to the PEA, as described in

https://www.thevespiary.org/rhodium/Rhodium/chemistry/pea.benzyloh.html

Antoncho


P.S. How does one prepare 2-something-4-MeO-phenol?

P.P.S. How well a 'usually' oriented 3-something -4-MeO-phenol would beehave under the same conditions? Would two different isomers - on both sides from the phenolic hydroxyl - form?

[foxy2]

Patent US3846501

   
Those who give up essential liberties for temporary safety deserve neither liberty nor safety

[Mountain_Girl]

Were you being sarcastic Foxy ?

Abstract: US3846501
 
Alkoxy substituted hydroxy aromatic compounds may be prepared by reacting a hydroxy aromatic compound with an alcohol and hydrogen peroxide in the presence of a catalyst system comprising hydrogen fluoride and carbon dioxide.
 

[Antoncho]

.... yesss', liquid hydrogene fluoride in a significatly larger qtty than the starting phenol - under pressure in an autoclave!

Apart from that, the procedure is indeed nice

actually, when i thought about possible ways to make such a phenol a thought of Reimer-Tiemanning p-MeO-phenol and reducing the 2-OH-5-MeO-BA to the corresponding toluene immediately crossed my mind - but how such a reduction can bee effected? Is there an easy and one-stage way to do that at all?

Another possibility is to perform a Baudisch reaction on anisole - see

Post 276654 (missing)

(PrimoPyro: "Ephedrine To MDMA: Another Roundabout Possibility", Chemistry Discourse) for more details (but what direction the substitution will take place? Can anyone tell?), reduce the nitroso to amine and Sandmeyer it to a halide ro smth else. Yess, a long, tedious route...


well, anyway. i guess for you hi-end bees purchasing such a phenol from a chem supplier won't bee a problem, and for us the ghettoists such a synth will always bee only a dream - so why ramble    



Antoncho

[poix]

The 'Serotonin Receptor Affinities of Psychoactive Phenalkyamine Analogues' article in JMC 1980, 23, 294-299 has some experimental section on 2,5-dimethoxy-3-methyl benzaldehyde and 2,5-dimethoxy-3-bromo benzaldehyde as well as serotonin affinities of the two aminopropane drugs.

The sad things is that they score only 5.33 +-0.06 for the Me analogue and 5.27 +-0.03 for the bromo one on the pA2 value. DOM has an affinity of 7.12+-0.07 and so the affinity of 2,5-dimeo-3-Me-A is more than 60 time less than DOM, even less active than mescaline (5.65+-0.10)!

Maybe the rat stomach fundus doesn't fully compare with human 5-HTP and these compound will show to be active or maybe they aren't at all. They may be active in some other way, non psychedelic one, but only human trial will tell us.

Anyway if someone is still interested for the experimental section I can scan it.

Edit: The article has been posted in

Post 453729

(Rhodium: "Phenylalkylamine Serotonin Receptor Affinities", Serious Chemistry) /Rhodium

[yellium]

Affinities aren't everything. There's a JMC article where a number of 2,5-dimeo-4-alkyl-amphetamines (could also be phenethylamines) are compared, and after the alkyl chain is longer than 4 carbon atoms, affinities are more or less the same. Which is not in agreement with biological data. Ditto for R=tert-butyl.

So there's only one way: make'em and taste'em.

[Rhodium]

Here is a full route to 3-Methyl-2,5-dimethoxybenzaldehyde:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/methyldimethoxybenzaldehydes.html