Author Topic: "OTC" racemethorphan synth idea  (Read 3195 times)

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  • Guest
"OTC" racemethorphan synth idea
« on: June 06, 2004, 06:50:00 PM »
Well, here's a skeletal synth idea for racemethorphan/raceorphanol, which I had one night. I'd like to know what the experienced chemists at the hive think of its chances for success, based on their experience and knowledge.

Basically, this is a theoretically OTC synth, in that it is possible, though not exactly practical, to produce all the required precursors from scratch.

The heart of this synthesis is a mannich reaction followed by an intramolecular grignard/barbier addition.

1. p-methoxyphenethanal and methyethanolamine HCl are reacted mannich-style with an excess of cyclohexanone to give the first intermediate (whose name is too long for me to attempt)


Mannich reaction ("c1cc(OC)ccc1CC=O.CNCCO.O=C1CCCCC1>>c1cc(OC)ccc1CC(N(C)CCO)C2CCCCC2=O")

2. The resulting alcohol is converted to an alkyl halide with HCl or HBr, then heated with zinc or magnesium to perform an intramolecular addition to the carbonyl group of the cyclohexyl ring.


Organometallic reaction ("c1cc(OC)ccc1CC(N(C)CCBr)C2CCCCC2=O>>c1cc(OC)ccc1CC2C3CCCCC3(O)CCN2C")

3. Finally, the last ring is closed with an intramolecular Friedel-Crafts alkylation, probably using concentrated sulfuric acid on the last product. As this operation will remove much ring strain, and the hydroxyl is both tertiary and very close to the aromatic ring, it will likely require only very mild conditions to dehydrate.


Endgame ("c1cc(OC)ccc1CC2C3CCCCC3(O)CCN2C>>c12ccc(cc1C43C(C(C2)N(CC3)C)CCCC4)OC")

All of these steps seem not terribly unrealistic, although perhaps the intramolecular barbier reaction may be somewhat uncommon. I have still to search for some lit refs to back me up.

Now, OTC I said, so here is some offhand ideas how the aforementioned precursors could be produced:

The methylethanolamine would be made by hofmann rearrangement of acetamide in ethanol to give ethyl N-methyl carbamate, which could then be alkylated under alkaline phase-transfer conditions with ethylene chlorohydrin, then hydrolyzed. The ethylene chlorohydrin would be produced by slowly distilling a mixture of ethylene glycol with sulfuric acid, salt, and catalytic sodium acetate.

The p-methoxyphenethanal could by produced by performing an aldol condensation of anisaldehyde with ethyl acetate, followed by hydrolysis, amidation of the cinnamic acid with urea, and hofmann rearrangement in ethanol to yield an unsaturated urethan, which could be hydrolyzed to give a phenethanal. Alternately, the same process could be performed substituting acetonitrile for the ethyl acetate and skipping the amidation. Perhaps also one could ozonate p-methoxyallylbenzene to arrive at the p-methoxyphenethanal directly.

Most likely, one would simply buy these precursors. But home production is feasible.

Well, any thoughts? I look forward to the barbecue ;D


  • Guest
Perhaps Lego ist just stupid
« Reply #1 on: June 06, 2004, 07:30:00 PM »
Do you want to alkylate the aromatic ring with the hydroxyl group of the cyclohydrocarbon?
It seems that the hydroxyl group is pointing away from the aromatic system, no matter how you rotate this molecule, so it seems as if the system would rather react intermolecular and not intramolecular.


  • Guest
A good point
« Reply #2 on: June 06, 2004, 09:31:00 PM »
However, there are two points to consider:

1. According to Chemsketch's 3d viewer, in fact the hydroxyl can point towards the ring (the hive applet does not do conformational optimization)

2. In fact, a carbocation is what alkylates the ring. Being that this is a tertiary alcohol, it will be very easily converted to its ion. This makes the whole point moot, since the ion could attack backwards or forwards...

At least, that's what I think...  :)


  • Guest
« Reply #3 on: June 16, 2004, 12:43:00 PM »
This would never have occured to Pimpo, but it sounds in parts feasible! The p-methoxyphenylacetaldehyde is highly unstable and should therefore maybe be substituted with its bisulfite compound or the p-methoxyphenylglycidic acid methyl ester (compare

Post 510895

(Pimpo: "discussion + article", Methods Discourse)
). According to this article the Grewe cyclization of the hydroxy compound is feasible.
The main problem Pimpo sees is that probably the grignard intermediate would lead to elimination of ethene?:

  CH3                  CH3
  |                    |
R-N-CH2-CH2-Mg-X --> R-N-Mg-X  + CH2=CH2