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synthesis of DMT from IAA

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phenethyl_man:
I'm certain that I must be missing something here, but alas I will ask anyhow.. why do all the syntheses for DMT from indole-3-acetic acid listed on rhodium follow the scheme:  ester formation, aminolysis w/dimethylamine, reduction of amide.  According to the syntheses, the aminolysis step takes 48 hours and I am quite impatient.  If someone were to go this route, would the addition of an alkali alkoxide not accelerate this process tremendously?

However, my real question is why a scheme analogous to shulgin's indole/oxalyl chloride synthesis from tihkal would not work.  What I mean is simply reacting the acid with PCl3 to form an acyl halide, indole-3-acetyl chloride.  Reacting this acid chloride with dimethylamine in dry ether (as per shulgin w/glyoxlyl chloride.)  And finally, reducing the amide to the desired amine.  Yes, this is the same number of steps but I don't believe the formation of the amide from an acyl halide would take 48 hours as it does with an ester.

Also, would it be possible to simply reduce the acid to tryptophol, react tryptophol with an acid halide to displace the hydroxyl with a halogen, followed by aminolysis w/dimethylamine to displace the halogen and form the amine.

I realize all of this is obvious and straight-forward chem and they would already be established routes if they worked; therefore I am more interested in *why* these traditional methods do not work..

Nicodem:
What I mean is simply reacting the acid with PCl3 to form an acyl halide, indole-3-acetyl chloride.

I guess indole-3-acetyl chloride is not really what you would call a stable acid chloride. It would very likely polymerize by acylation at the activated indole ring, most probably at the nitrogen. If you look at the structure of 'indoleoxalylchloride' you can see that the aromatic ring is highly deactivated and the ring is enough depleted of electron density to be inert to acylation. At least this is how I see it.

Also, would it be possible to simply reduce the acid to tryptophol, react tryptophol with an acid halide to displace the hydroxyl with a halogen, followed by aminolysis w/dimethylamine to displace the halogen and form the amine.

I guess (again) you could do that but I suspect the yields would be low. First because of more steps needed and next because alkylhalogenides are not very reactive and the harsh conditions need would cause some elimination side reaction especially because of the indole ring favoring it by conjugation. The reaction of 'bromosafrole' at least is known to give not the best of the yields.

hest:
Also, would it be possible to simply reduce the acid to tryptophol, react tryptophol with an acid halide to displace the hydroxyl with a halogen, followed by aminolysis w/dimethylamine to displace the halogen and form the amine.

--- End quote ---

Im quite sure this synth s on rhodium site.
My personal eksp. with it was a bit low yeald (50-60%)
I'ts some years ago, and there are (ofcourse) no rekord of the eksperiment, so you have to stick with it.
The route from IAA works greath, nice xtaline (with sometimes is hard) product.
The oxalylchloride route is also quite easy to work with, depending on wath's kind of chemicals you have on hand.
And dont bee impatient with chemistry. It is one of those think that takse the time it want's (oposite sex)

phenethyl_man:
I guess it's not that I'm impatient but rather that I have a lot of projects going on and only one hot-plate/stirrer which I don't like to have tied up for 2 days..  Then if I were to screw up the reduction of the amide I'd have to break something.

Thanks hest.. now that you mention it I went looking again and found that synth on rhodium hidden in all the references in the "Psychedelic Chemistry" book under the "5-Methoxy-DET BSC 1062(1962)" entry:

".. Dissolve 3 g of the tryptophol in 140 ml ether and stir at 0ø. Add dropwise 1.8 g PBr3 in 30 ml ether and let stand sixteen hours at room temperature. Decant the ether and wash the precipitate with ether. Wash ether with water, NaHCO3 and water, and dry, evaporate in vacuum the ether to get the bromide (recrystallize-ethanol). 2 g of the bromide and 1.5 g piperidine (or equimolar amount DEA, etc.) in 65 ml methanol and heat in sealed tube fifteen hours at 100ø (or let stand room temperature twenty-four hours). Evaporate in vacuum to get the 5-methoxy-dialkyltryptamine .."


ah well, so this appears to be even more time-consuming..

I also stumbled upon another reference from the same book that uses the methyl ester aminolysis and which states only 12 hours are required; but there's no f'ing way I'm adding the ester drop-wise over 12 hours (no addition funnel).


"Alternatively, dissolve 220 g 4-benzyloxy-3-indoleacetic acid (or equimolar amount other indoleacetic acid) in 2 L absolute methanol and reflux six hours in the presence of 20 g Dowex 50x8 sulfonic acid resin. Filter (decolor with carbon if desired) and concentrate below 35ø until precipitation starts; then cool to precipitate and filter to get 200 g of the methyl ester. Add 200 g of the ester to 600 ml 40% aqueous methylamine over twelve hours with vigorous stirring. Filter, wash precipitate with water and dry to get 187 g of the N-methyl-acetamide (reflux two hours in 500 ml benzene to remove unreacted ester). 24 g of the acetamide in 300 ml tetrahydrofuran is added dropwise to 10 g lithium aluminum hydride in 300 ml tetrahydrofuran; reflux ten hours, cool to 15ø and add dropwise with stirring 50 ml ethyl acetate. Reflux two hours and proceed as above to get 15 g (II) or analog."


nicodem;  ah, yes bromosafrole does react very slowly (or so I've heard).. however, in shulgin's methylone patent (US9609603), shulgin reacts the piperonyl halo-propiophenone w/methylamine in sulfolane.  He only achieves a 32% yield but that is only after a *mere ten minutes* reaction time. 
I'm curious if it is the solvent that is accelerating this reaction or is it the prescence of a carboxyl group on the aliphatic chain that causes such effects..  should it be the solvent, I really need to get my hands on sum sulfolane..

Nicodem:
If time is more of an obstacle than obtaining chemicals than I would propose a coupling agent as an alternative. If you have access to coupling reagents like DCC, CDI or similar than maybe you could prepare your amide directly from IAA and anhydrous dialkylamine. I only worked with DCC once, but I remember it as a fast and easy condensation reaction (but it was for an ester formation). Besides you could also enrich The Hive with a write up of a new method if it works. See the thread Post 527262 (n00dle: "LSD vs peptide coupling", Tryptamine Chemistry).

nicodem;  ah, yes bromosafrole does react very slowly (or so I've heard).. however, in shulgin's methylone patent (US9609603), shulgin reacts the piperonyl halo-propiophenone w/methylamine in sulfolane.

Yes, alpha-bromo-ketones can react in ten minutes, but they are considerably more activated than plain alkylhalogenides. There is a huge difference in the reactivity between chloroacetone and 1-chlopropane, for example. If you ever worked with chloroacetone or phenacylbromide you would know they so reactive to make you go cry in tears 8) . However I think that using sulfolane for that already activated halogenide is a bad choice. UTFSE for Kinetic's posts on the methods for various cathinones synthesis for better yielding alternatives.

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