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Author: Subject: n,n-dimethyltryptamine by Eschweiler-Clarke methylation of tryptamine
organometallic
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shocked.gif posted on 27-8-2008 at 14:09
n,n-dimethyltryptamine by Eschweiler-Clarke methylation of tryptamine


On an anonymous imageboard I sometimes peruse, there is a user who claims to have synthesized DMT via an Eschweiler-Clarke methylation of tryptamine, while somehow avoiding Pictet-Spengler ring closure. I paraphrase:

To the formic acid and tryptophan solution, add 37% formaldehyde in water, dropwise. Continue reflux for 8 hours. Extract once with naptha to remove traces of turpentine from a previous stage and discard this extraction. Basify to ph 10.5, do second naptha extraction. Cool this naptha extract overnight in a freezer, filter out and dry DMT.

"As for why this method favors methylation over ring closure, the main thing is it occurs in the presence of a hydride source. What decides if there's ring closure or methylation is whether the electrons of the indole double bond or the hydride get to the imine first, respectively, so you basically want to make hydrides as available as possible to snatch the imine away from the indole's electrons." And this is done with a large excess of formic acid, which acts as a hydride source apparently, although I personally do not understand how. Would someone briefly explain this?


"The ratio of Formic Acid:Tryptamine:Formaldehyde was 7:1:3. by mass"

and then...
"http://www.bluelight.ru/vb/showthread.php?t=375993

according to that link, tetrahydrobetacarboline (which is a synonym for Tryptoline) may be a potent dopamine neurotoxin, in the same way MPP+ is, aka one dose and poof, parkinsons. While this route seems to produce mainly DMT, some tryptoline is almost CERTAINLY also being made and getting carried over to the final product, so a decent purification scheme needs to figured.

The melting point of the crystals recovered was ~46 degC, while that of tryptoline and tryptophan are both >200degC.

Yes, I realise that this post is horribly sketchy and detritus-style.

My question is simply, what are your thoughts on this? It seems somewhat revolutionary..




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[*] posted on 27-8-2008 at 15:33
dimethyl trip


If you are aware of the mechanism of the EC and the PS reactions you will realize that you cannot avoid the PS process. No way...
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[*] posted on 28-8-2008 at 08:13


Anyone else please confirm/deny this?
"you cannot avoid the PS process"




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[*] posted on 28-8-2008 at 08:44


Quote:
Originally posted by organometallic
Anyone else please confirm/deny this?
"you cannot avoid the PS process"


Compare the reaction conditions with the ones stated in the Wiki article on the P-S rxn:

PS.jpg - 24kB




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[*] posted on 28-8-2008 at 09:05


Quote:
Originally posted by organometallic
On an anonymous imageboard I sometimes peruse, there is a user who claims to have synthesized DMT via an Eschweiler-Clarke methylation of tryptamine, while somehow avoiding Pictet-Spengler ring closure.

You read too much fiction.
Try reading scientific papers instead.
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[*] posted on 29-8-2008 at 04:05


What Nicodem said...
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[*] posted on 6-9-2008 at 21:08


Unlike Benzaldehydes, Acetophenones usually don't react with nitromethane to form nitroalkenes. However, it was discovered recently, that when ethylenediamine is used as the condensation catalyst, this reaction does occur. The diamine reacts simultaneously with both the Ketone and Nitromethane, and brings the reactive intermediates into close proximity to one another. Then Viola! The Nitro-olefin is formed.

What does this have to do with DMT?

Read on.

Via the mannich reaction.....Acetophenone reacts with formaldehyde and Dimethylamine to form 3-Dimethylamino-Propiophen-1-one.

Use O-nitroacetophenone (Org. Syn.) as your starting material
and react the resultant O-Nitro, 3-Dimethylamino-Propiophen-1-one....with Nitromethane via ethylene diamine, and you instantly have a direct precursor to DMT.

A simple reduction will reduce the nitro-styrene to an aldoxime,
while simultaneously reducing the O-nitro group to an amine.

Without further ado, the aldehyde and amine react to form the indole ring. And, bingo. DMT.

Will it work? Dunno. Just an odd dream I had. Maybe Barium has some input.

Edit 1: Organic Syntheses, Coll. Vol. 3, p.305 (1955); Vol. 23, p.30 (1943).
β-DIMETHYLAMINOPROPIOPHENONE HYDROCHLORIDE
[Propiophenone, β-dimethylamino-]

From acetophenone, easy and in high yield.

Edit 2: Organic Syntheses, Coll. Vol. 4, p.708 (1963); Vol. 30, p.70 (1950).
o-NITROACETOPHENONE
[Acetophenone, 2'-nitro-]

[Edit by Ramiel - quadruple posting for the new record. I relent because you posted references <i>etc.</i> please be aware of the edit feature in future.]

[Edited on 7-9-2008 by Ramiel]
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[*] posted on 6-9-2008 at 22:24


Haha quadruple posts, and they were all supposed to be one. Edit button works by the way :P
Thanks for your input and all though.
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[*] posted on 6-9-2008 at 23:06


Ah, I'll try that. When I open another window, to cut something out....to paste into my post, I return to find my stuff has been erased. New here. I suppose I'll get the hang of it.
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[*] posted on 7-9-2008 at 04:44
acetophenone + diamine + formaldehyde


The reaction of acetophenone and derivatives with a N,N-diamine (not N,N'-diamine) and formaldehyde has long been known. It has even been described in detail in one of the earliest volumes of Organic Reactions (your β-DIMETHYLAMINOPROPIOPHENONE HYDROCHLORIDE reaction) and is the subject of many patents, such as that of the not so widely used today pridinol (patent is in German). This will work (the less water in the medium the better); however, the nitromethane (nitroaldol/Henry) part looks as having poor prospect, even with ethylenediamine mediation.
Ethylenediamine was used as the acetate by Barton as promoter of the Henry reaction with benzaldehydes.
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[*] posted on 7-9-2008 at 04:50


Quote:
Originally posted by zedAcetophenones usually don't react with nitromethane to form nitroalkenes. However, it was discovered recently, that when ethylenediamine is used as the condensation catalyst, this reaction does occur.


Will you please attach this paper or at least give a reference for it?

The reduction to indole with Fe/GAA is well known and is demonstarted in some of the papers from this thread
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[*] posted on 7-9-2008 at 06:00


The reference I have seen is to a similar reaction of nitromethane with a ketone. I'll see if I can dig it up.

Boy, stuff gets buried fast.

A year or two back, folks were fairly skeptical about such reactions. They were considered hard to pull off. I remember the ethylene diamine reference...because a researcher reported it as working, and his premise as to why it worked, seemed to make sense.

I've scanned the web a little, and at the moment, I'm finding other reagents that are claimed to effect the condensation between ketones and nitroalkanes. Still, I think I'd bank on ethylene diamine first. I'll work on it.
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[*] posted on 26-9-2008 at 06:14


K gots some questions on this that could use answering...

Most importantly --- is Tryptoline really a dopamine neurotoxin? (Could someone point towards some references?) There is little information on the compound on the 'net and the wiki says nothing about it. Think I read earlier actually that it's found naturally in some foods as well but I'm not sure of the authenticity of that.

Also, would Formic acid be a suitable reducing agent if other alkylating agents (such as methyl iodide for instance) were used instead of formaldehyde? The pictet-spengler reaction seems to require an aldehyde to take place.

Also, how much chance is there for the pictet-spengler reaction to happen? Are there ways to prevent such cyclizations? If any DMT would be formed it could be filtered off in liquid form since tryptoline's boiling point is that much higher.

Thanks in advance
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[*] posted on 2-8-2010 at 19:05


Yup! Nitromethane will definitely react with Propiophenone, in a Henry-type condensation. Whether or not, it will produce a usable intermediate with O-Nitro-Beta-Dimethylaminopropiophenone....Well, that remains to be seen.

Tamura, Sato, and Oda, report that under the influence of NH2CH2CH2N(CH3)2, Nitromethane may be readily condensed with ketones to produce Nitro-olefins.

J. Org. Chem. 1986, 51, 4368-4375 Facile Synthesis of Allylic Nitro Compounds by N,N-Dimethylethylenediamine-Catalyzed Condensation of Aliphatic and Alicyclic Ketones with Primary Nitroalkanes.

The Alpha Nitro-Alkene, formed from the condensation of Propiophenone and Nitromathane, may however isomerize to a product that might be inappropriate for indolization. Hard to say.

Under the conditions the authors employed, regular Propiophenone condensed with Nitromethane to produce a Nitro-Olefin that isomerized to C6H6-CH(CNO2)CH=CH2.

What O-Nitro-Dimethylaminopropiophenone, might do under these reaction conditions is difficult to project.

If the condensation can be achieved, and if the Nitro-Olefin can be captured in a favorable isomer.....Then Bingo! Upon reduction it should yield Dimethyltryptamine.

O-Nitro-C6H5-C(=C-NO2)CH2CH2N(CH3)2 +H2-------->DMT

Don't know if it's been tried.




[Edited on 3-8-2010 by zed]
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[*] posted on 3-8-2010 at 00:35


In my experience, the Mannich reaction on ortho-nitroacetophenone did not work under the conventional conditions under which plain acetophenone reacted normally (amine hydrochloride, 35% formaldehyde, ethanol reflux - essentially the conditions as described at Org. Synth.). I did not use dimethylamine though (this was years ago, but if I still remember correctly I did try with diethylamine as well). The starting ketone was recovered almost quantitatively (I think there has been a few % of conversion to the desired aminoketone, but I do not remember much about it any more). I can't remember where, but I recently read a case where o-nitroacetophenone was said to fail some other reaction where enolization is also required. On the other hand, there are at least two papers where this ketone is used successfully used in a Mannich reaction, so perhaps it is just a matter of adding more HCl, using paraformaldehyde or whatever other detail... I have not checked what exactly, because I latter gave up on that synthesis but here are two references if someone else wants to check: the o-nitroacetophenone Mannich reaction with piperidine is described in Archiv der Pharmazie, 316 (1983) 707-712, while with dimethylamine/paraformaldehyde in Angewandte Chemie IE, 46 (2007) 4489-4491.

The altered reactivity could also prevent any successful Knoevenagel condensation with nitromethane via the method in that JOC paper. Though, it should be noted that o-nitromandelonitriles also cyclisize to the corresponding indoles upon hydrogenation (one example: Journal of Labelled Compounds and Radiopharmaceuticals, 24 (1987) 637-643). It should be easier to prepare the cyanohydrin from 3-dialkylamino-ortho-nitropropiophenones than the nitromethane condensation product.




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[*] posted on 3-8-2010 at 11:29


Thank you Nicoderm,

I'll check those Mannich reactions out, on my next visit to the library.

I have considered the route via the cyanohydrin, but for the moment, I am against it.

Messy stuff, Cyanide. Makes me nervous.

Of course, at the moment, the entire enterprise is a "Thought Experiment". A hypothetical romp. Currently dependent upon how folks fared during those Mannich Experiments you quoted.

Piperidine in Archiv der Pharmazie, 316 (1983) 707-712,
Dimethylamine/paraformaldehyde in Angewandte Chemie IE, 46 (2007) 4489-4491.





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[*] posted on 3-8-2010 at 14:59


Did you see this?
https://www.hyperlab.info/inv/index.php?s=&act=ST&f=...
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[*] posted on 3-8-2010 at 20:47


Ummm. Transmethylation of tryptamine via a betaine. Sounds like a good idea. But, does it work? That someone smoked the product of such an experiment, and they felt it got them "high", is not entirely convincing evidence. I wouldn't dismiss the claim out of hand, because it is possible.

But, I'd be a lot more impressed, if a product was isolated, and melting point information was recorded.

Even if they only succeeded in producing N-Methyl-tryptamine in good yield, that would really be quite an achievement.
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[*] posted on 3-8-2010 at 22:48


Given the abundance of this substance in nature and the relative ease of isolation is it really worth the effort?Conversion to the 4hydroxy compound via fenton/udenfriend would be more interesting.



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[*] posted on 4-8-2010 at 11:37


Yes, I believe it's worth the effort. A simple, high yielding, fairly non-hazardous route to N,N-Dialkyl tryptamines would be welcomed by many. The guys in Big Pharmacy are surely interested.

Folks have been pounding away at synthesizing Tryptamine derivatives for a long time, and from a lot of different angles. A lot of progress has been made in various areas, but a straightforward slam dunk hasn't arrived yet.

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[*] posted on 4-8-2010 at 12:37


Not sure if already explored, but maybe you can try a tryptophan double methylation, followed by decarboxylation.
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[*] posted on 22-12-2010 at 08:37


I'm resuming this topic to ask your opinion on this variation of the Eschweiler-Clarke reaction, applied to tryptophan dimethylation: http://www.sciencemadness.org/talk/files.php?pid=86049&a...
Has anyone tried it yet? Do you think that the slight change in mechanism could actually avoid the Pictet-Spengler cyclization?

BTW, this is my first post here, hello all =)
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[*] posted on 22-12-2010 at 15:06


Quote: Originally posted by McLovin382  
Most importantly --- is Tryptoline really a dopamine neurotoxin? (Could someone point towards some references?)


If you are looking for an MPTP --> MPP+ type neurotoxin, tryptoline is not, unless it is methylated in vivo. However, the product of the pictet spengler condensation of N-methyltryptamine with formaldehyde could produce a toxic metabolite if the ring is then enzymatically dehydrogenated (by MAO) to the pyridinium.

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