I just found this today looking for improvements in preparation of meta-methoxy-benzaldehyde.
It turns out that a nitro-BA (crude product obtained from nitration) can bee reduced to amine with NaHSO3 (!), diazotized and decomposed into m-OH-BA - all this in one pot!
This is especially cute since aminobenzaldehydes are very very picky substances and polymerize very readily - all preps i've seen thus far involve acetal protection (such as
Patent GB884765
- BTW, acetal survives diazotization despite pH<7 - as well as several preps on Orgsyn).
Moreover, it wasn't entirely clear (to me, that is
) as to how well diazo group would beehave towards the aldehyde moiety.
Well, bees, here's the xperimental from
Patent GB232392
:
15 parts by weight of benzaldehyde are nitrated in the usual way with a mixture of nitric and sulphuric acids at as low temperature as conveniently possible, and the nitration mixture poured on to ice, the oil well washed with water and dilute soda, and with water again until neutral. The mixture of o- and m-nitro-benzaldehydes thus obtained is then stirred thoroughly in parts water containing sufficient sodium hydrosulphite for the complete reduction of the nitro bodies; about 96 parts will be necessary. The heat generated by the reaction causes the temperature to rise even to boiling point.
This may be allowed to continue for about quarter of an hour, when the reaction will abate; then as quickly as possible, the entire reaction product is cooled down, and the amino-benzaldehydes are diazotised. For this purpose, about 200 parts concentrated hydrochloric acid, or 120 parts 50% sulphuric acid are added, that is to say, sufficient to combine with the amines, with the nitrite to be added, and with the excess of hydrosulphite and its oxidation products contained in the liquid. About 43 parts of sodium nitrite are necessary, and this is preferably added in the form of a concentrated solution. The diazo solution should be pale red in colour.
If the cooling of the amino body took too long, a deeper shade is obtained, and a smaller yield of the final product.
Towards the end, the diazotisation proceeds slowly; when it is complete, it is decomposed by dropping it into a boiling solution of about 90 parts concentrated sulphuric acid in 400 parts water, through which a lively current of steam is passing, the salicyl aldehyde and anthranil distill over, and the m-hydroxybenzaldehyde remains in the solution.
The aldehydes are collected by extraction from their solutions. In the case of salicyl aldehyde, it must be separated from the anthranil by solution in alkali separated from the insoluble anthranil and subsequent precipitation by acid.
Now, ain't that sweet? Instead of those tedious routes from bromo- aldehydes that require either 24hrs reflux or strictly unhydrous conditions, we now have a procedure that gives us a hydroxy-substituted aldehyde in under 4hrs, with all the reagents being dirt cheap and accessible.
Ir remains to bee seen how well this route works on methoxy-subst'd BA's (such as veratraldehyde, nitration of which is described on OrgSyn).
But that's not all yet, here's another improvement to the method. As it appears from
Patent US2622078
, if one adds some ketone (like acetone) to the pre-diazotization mixture, the rxn proceeds w/better yields of cleaner products - moreover, the temp can bee increased thus speeding up the rxn.
It is interesting to note that the trick works equally well independently on what methods are used to diazotize the amine, whatever it is, and whatever is the pH of the reaction!
And, in addition to all that, the patent clearly states that if one adds yet more acetone to the post-diazotization mixtr, the diazonium salt crashes out! Another patent says that to effect this not only acetone may bee used, IPA (as well as butanol and amyl alcohol) will do the trick.
And the isolated solid salt can bee reacted directly w/MeOH to produce methoxylated aldehyde!
It can't bee said with certainty that such a method would work on hydroxylated diazonium salts (like the one that can bee made from vanillin) - but if it would, it'd certainly make life so much easier, since those dihydroxyaldehydes are a real bitch to isolate fro aq solutions - that is, unless you evap all water in vacuo and Soxlet the remains as Uemura did
In any case, this seems to bee a superior route to m-MeO-BA, from which one would arrive at m-MeO-PEA which is a reported aphrodisiac (yeah, i know that the o-methoxy was reported to bee a fraud, but meta- hasn't been bioassayed yet
. And the N-methylated amphetamine is certain to bee interesting).
Another yet more interesting application for this would start from p-tolualdehyde - well, you know what i mean, don't you?
Tell me if you like the idea, bees
Antoncho