Sciencemadness Discussion Board - DMT synthesis from indole and DMAE

DMT synthesis from indole and DMAE

James Nilep - 9-1-2018 at 08:26

I’m supposing this synthesis of DMT (or DET, where instead of DMAE DEAE would be used) :
First, the indole would be converted to 3-bromoindole using the experimemtal method described in this paper: http://www.nrcresearchpress.com/doi/pdf/10.1139/v63-353
(NOTE: the experimental method using pyridine as a solvent and pyridium bromide perbromide or dioxane dibromide as a brominating agent)
Then, the dimethylaminoethanol is converted to 2-Bromo-N,N-dimethylethanamine hydrobromide using hydrobromic acid.
Finally, a Gringnard reaction (presumably using some kind of catalyst) would yield the final DMT product.

I know there are other relatively simple DMT syntheses, I’m just curious if this or a similar method could work.

[Edited on 9-1-2018 by James Nilep]

ninhydric1 - 9-1-2018 at 09:25

Sorry, this isn't the Hive.

James Nilep - 9-1-2018 at 10:08

Quote: Originally posted by ninhydric1

Sorry, this isn't the Hive.

I have seen SM used for theoritacal discussions about illegal substances, that’s why I thought posting here would be appropriate, this is definitely not meant to be a discussion about “how do I make such and such illegal compound”, rather a theoretical question about an alternate synthesis pathway.

JJay - 9-1-2018 at 10:37

I think the jury is still out on whether this thread violates the SM guidelines... if the discussion is strictly scientific, it is probably permitted, but this one is definitely borderline.

Is it actually possible to form the Grignard with dimethylaminoethyl bromide? You'd have to use an excess of HBr to brominate dimethyaminoethanol. But once you have dimethylaminoethyl bromide, can you freebase it without a lot of quaternary amine polymer forming?

Melgar - 9-1-2018 at 12:21

Can anyone think of an example of a Grignard reagent that contains a nitrogen atom? Because I can't. The ONLY case where I'd think it might be possible would be with certain heterocycles, which this obviously isn't. I'd assume that in this case, it'd just turn into a huge mess with all the alkylation going on.

OP clearly knows too little chemistry to understand why this wouldn't work, and seems to be more interested in cookery than anything. Shulgin produced DMT by trimethylating tryptamine with methyl iodide, then demethylating the quaternary amine. Seems like that'd be more likely to yield results.

James Nilep - 9-1-2018 at 12:40

I do know little about chemistry, but I understand that there would be a lot of tertiary amine polymers forming, I was curious if the rate polymerization would still allow for this reaction.
And if I’d be interested in cookery I wouldn’t be asking questions on SM

Cryolite. - 9-1-2018 at 12:46

Melgar, indole itself can form a Grignard reagent of some sort: Since it is a pyrrole, the proton that lies on the nitrogen is actually fairly acidic, and so it can be deprotonated there to give a nitrogen-centered anion. However, the C-3 carbon is also fairly acidic due to ring resonance influenced by the benzene ring, so alternatively indole can be deprotonated there as well. The one which actually happens depends on the balancing metal atom (organolithiums prefer to deprotonate at nitrogen due to the electronegativity difference, organomagnesiums deprotonate at C-3 for covalency). Thus by deprotonating indole with an alkylmagnesium bromide, an indole grignard reagent can be prepared. (this is all standard chemistry for the preparation of JWH-series cannabidinoids)

Further, tertiary amines do not react with Grignard reagents, so I don't see why the Grignard reagent derived from dimethylaminoethyl bromide wouldn't exist (although there is potential for 1,2-rearrangements here)

Although you are right, the OP here is still obviously a cook who is looking for a drug fix more than actual chemistry.

[Edited on 9-1-2018 by Cryolite.]

PirateDocBrown - 9-1-2018 at 13:14

It would be better if OP could show how far he'd gotten in his lab in in his synthesis. Then, we could all see what he may or may not be doing wrong.

JJay - 9-1-2018 at 13:20

Quote: Originally posted by James Nilep

I do know little about chemistry, but I understand that there would be a lot of tertiary amine polymers forming, I was curious if the rate polymerization would still allow for this reaction.
And if I’d be interested in cookery I wouldn’t be asking questions on SM

Actually, there would be a lot of quaternary amine polymers forming. Try cleaving the ethyl moity and you'll see what I mean.

zed - 9-1-2018 at 13:42

There are better approaches. Read.

James Nilep - 9-1-2018 at 15:06

Quote: Originally posted by PirateDocBrown

It would be better if OP could show how far he'd gotten in his lab in in his synthesis. Then, we could all see what he may or may not be doing wrong.

I don’t have the equipment, nor the intent to create DMT, but someone who is better equipped than me could try synthesising a less trippy, more legal similar compound like the propanamine instead of the ethanamine, it would certainly be interesting to see if it’s possible.

James Nilep - 9-1-2018 at 15:14

Cryolite , thanks for clearing things up a bit, not so sure about the last part. About side reactions, would this not pose a problem? https://en.m.wikipedia.org/wiki/Menshutkin_reaction

James Nilep - 9-1-2018 at 15:16

zed , I know easier approaches exist, but I’m interested in the chemistry of this particular one.

Melgar - 9-1-2018 at 20:21

Well, I guess I can see the curiosity aspect of it. I tend to be a bit suspicious of new users who immediately go straight for some unworkable drug synthesis. Really though, OP should have started with "Can DMAE be made into a Grignard reagent?" and the answer would have been a resounding "No." Instead he had to combine a bunch of disparate pieces of knowledge and go straight for a drug synthesis.

We all know that you can't get addicted to DMT. However, last I checked, prices were higher for DMT than just about any drug that's used in quantities that can be measured with a scale. So the thought was that OP was thinking he could make a fast buck, not that he was an addict.

Assured Fish - 9-1-2018 at 20:23

FFS, I know i shouldn't say anything but i cannot help myself.
James Nilep your a degenerate cook and i fucken hate you.

Forming 3 bromo indole would be a wasted effort, since the C3 position is considerably more acidic than the amine.
https://en.wikipedia.org/wiki/Indole#/media/File:Indole_anio...

So, a better route would be to prepare a grignard reagent from N,N-dimethyl-2-bromo-ethylamine and then add this to the indole.

Quote:

This sentence contradicts itself.
In my opinion, this thread is in clear violation of rules here and im surprised its still here.
The only reason i have chosen to post is because DMT is a naturally occurring substance that has been in use for thousands of years, much like ethanol. It also potentially serves as a means by which to "cure" an individual of an addiction. I find it immoral that the compound is illegal.

Melgar - 9-1-2018 at 22:00

Quote: Originally posted by Cryolite.

Melgar, indole itself can form a Grignard reagent of some sort: Since it is a pyrrole, the proton that lies on the nitrogen is actually fairly acidic, and so it can be deprotonated there to give a nitrogen-centered anion. However, the C-3 carbon is also fairly acidic due to ring resonance influenced by the benzene ring, so alternatively indole can be deprotonated there as well. The one which actually happens depends on the balancing metal atom (organolithiums prefer to deprotonate at nitrogen due to the electronegativity difference, organomagnesiums deprotonate at C-3 for covalency). Thus by deprotonating indole with an alkylmagnesium bromide, an indole grignard reagent can be prepared. (this is all standard chemistry for the preparation of JWH-series cannabidinoids)

Yeah, I tried to think of any Grignard that contained a nitrogen, and the only category I couldn't rule out was nitrogen-containing heterocycles, of which indole is a member.

Quote: Originally posted by Cryolite.

Further, tertiary amines do not react with Grignard reagents, so I don't see why the Grignard reagent derived from dimethylaminoethyl bromide wouldn't exist (although there is potential for 1,2-rearrangements here)

Although you are right, the OP here is still obviously a cook who is looking for a drug fix more than actual chemistry.

My problem with this half-baked synthesis route would be when the organobromide is formed. Correct me if I'm wrong, but organobromides DO react with tertiary amines, and thus the intermediate compound for formation of the Grignard couldn't be isolated. More likely, it'd form some sort of tar, no?

happyfooddance - 9-1-2018 at 22:17

It would be funny to see o.p. try this synth. He and everything he touched would probably stink like shit for days.

Vosoryx - 9-1-2018 at 22:27

Quote: Originally posted by Melgar

...So the thought was that OP was thinking he could make a fast buck, not that he was an addict.

Actually, I think that this shows legitimacy. We can't ever know what OP's true intentions were, but I don't think this is the case either. DMT can be easily extracted from a plant used in the ayahuasca tea. The work of synthesizing DMT in the method OP provided would be incredibly expensive and time consuming, and way harder than simply buying the plant seeds and growing them, then doing a simple extraction.

What's more, just because a person asks a question that is relating to drugs doesn't mean anything. This might be the only example they know of - especially if they (like me) learned chemistry on the internet. There is so much good chemistry information that pertains to drugs because it is such a common thing. In teaching myself chemistry, I also learned directly how to make a good handful of mind altering substances. A drug might be the only example that one can think of because of how common it's chemistry is taught, even if they have no plans on synthesizing it.

I digress, please go back to talking about chemistry I don't understand!

Assured Fish - 9-1-2018 at 23:42

Grignard reagents do not react with tertiary amines.
There is no proton present on the amine for the grignard to attack, the 2 electrons obviously come in a pair and so the resulting charge from the formation of the new alkyl group would need to be stabilized, the halide would already be ionically bound to the magnesium and the magnesium halide ion is electrophilic not neucleophilic and so it would not be able to stabilize the charge.
The only way to stabilize the charge would be if you threw some extra protons in there, which is done after addition of the grignard reagent to the substrate, Before the addition of the proton there would be 2 unstabilized positive charges that simply would not be stable on their own.

Think about it. What would be the result if a alkyl magnesium halide reagent attacked a tertiary amine?
Nothing, because it cannot happen.

Both secondary amines and primary amines can react with grignard reagents, however this occurs similar to the reaction of grignards with water where the result is a N substituted magnesium halide and the stolen proton takes the place of the former magnesium halide.
No condensation takes place, only elimination of the halide.

zed - 10-1-2018 at 13:49

Aww. This kinda stuff has mostly been tried.

The bromo material you suggest, figures to be not fun to work with, as the chloro analog, N,N-Dimethylaminoethylchloride hydrochloride is restricted, and known for its nasty qualities. Got an Org. Syn. prep for it.

http://www.orgsyn.org/Content/pdfs/procedures/CV4P0333.pdf

Further discussion on the topic.

https://www.sciencemadness.org/whisper/viewthread.php?tid=22...

[Edited on 10-1-2018 by zed]

[Edited on 10-1-2018 by zed]

Nicodem - 11-1-2018 at 11:09

DMT can be synthesized from indole and 2-dimethylaminoethanol directly in one step (DOI: 10.1021/acs.joc.5b00195). There is no need to go trough convoluted steps.

Also, direct alkylation of indole with in situ formed aziridiniums from 2-dimethylaminoethylhalides also gives DMT directly.

To use a coupling of Grignard reagents, it is the 3-indolylmagnesium that should be coupled with 2-dimethylaminoethyl bromide. It would be wasteful though, as one equivalent of 3-indolylmagnesium would be lost in order to make the aziridinum salt in situ. The regioselectivity would also not necessarily be good. A reverse coupling (a Kumada coupling, transition metal catalyzed) would not work in this case, due to acidity of indolic NH.

Besides, to prepare 3-indolylmagnesium halides it is not 3-bromoindole that is used. Instead, indole is treated with MeMgCl.

A note to others: This thread's topic obviously breaks no forum rules. Nevertheless, in future, when you feel so, report the tread so that moderators can inspect it, rather than going crazy about it in the thread itself. All this drivel makes threads difficult to read.

Melgar - 12-1-2018 at 12:16

Well, I think I know what a bunch of SM members are going to be busy doing this weekend!

AvBaeyer - 12-1-2018 at 20:28

Nicodem,

Thanks for the interesting reference. There is a good deal of ancillary chemistry buried in there upon careful reading. By the way, the direct alkylation of indole with alcohols has a long and interesting history going back at least to 1942 (Cornforth and Robinson, J. Chem. Soc. 1942, 680-682).

AvB

softbeard - 14-1-2018 at 08:26

In case anyone has trouble getting the article, I've attached the JOC article.

edit:clarity
Attachment: 3217-3222.pdf (400kB)
This file has been downloaded 1993 times

[Edited on 14-1-2018 by softbeard]