Sciencemadness Discussion Board

Proposed novel 6-step syntheis of 5-MeO-4-AcO-DMT

Dextrose - 1-8-2008 at 07:30

I hope this topic will be taken more seriously.

I asked Shulgin about this compound 3 years ago, and he replied the compound indeed was interesting, but the synthesis was to tedious and only one publication of a 11-step synthesis.

http://www.cognitiveliberty.org/shulgin/blg/index.html

However, after i found this Brazilian publication, i came up with this route.

Synthesis of New Indolecarboxylic Acids Related to the Plant Hormone Indoleacetic Acid IAA
J. Braz. Chem. Soc., Vol. 14, No. 1, 11-15, 2003.

Is available for free here: http://jbcs.sbq.org.br/jbcs/2003/v14_n1/02.pdf

Questions:

Would it be better to nitrate the aldehyde before condensating?
Shulgin does this in TIHKAL #32 when making 5,6-methylenedioxyindole.

HNO3/GAA should yield mostly the ortho-product as far as i have read, compared to HNO3/Ac2O.

Would it be a good idea to use H2SO4 as catalyst when nitrating?

Will the activating groups on ortho-vanillin be any problem, when preparing the indole?

An alternative could maybe be using the O-benzyl-ether of ortho-vanillin as protection group, and making the acetoxy-ester as the last step, like described here: http://psychedelichosting.info/Ionium/Rhodium/chemistry/psil... ?

The last steps from the indole to the amine, is straight from TIHKAL.

What do you think?

5-MeO-4-AcO-DMT.png - 18kB

ScienceSquirrel - 1-8-2008 at 08:23

I think you may end up with the 1-hydroxy-2-methoxy-5-nitro-nitrostyrene as the phenol is the most powerful directing group and will result in the formation of the wrong isomer at the nitration stage.

Nicodem - 1-8-2008 at 08:33

I think you should read upon electrophilic aromatic substitution and the rules governing its regioselectivity.
The nitration of 2-hydroxy-3-methoxybenzaldehyde gives the 2-hydroxy-3-methoxy-5-nitrobenzaldehyde as the main product (for example, see Bulletin de la Societe Chimique de France (1975) 2297-2306).
2-Hydroxy-3-methoxy-6-nitrobenzaldehyde has been synthesized by nitrating 2,3-dimethoxybenzaldehyde followed by -CHO group assisted selective demethylation with BBr3 (see Tetrahedron, 54 (1998) 10007-10016). It can also be synthesized from 2-hydroxy-3-methoxybenzaldehyde if using O-Ts as protection group (due to the inductive effect of the TsO group the nitration occurs at the para position in relation to the MeO group, see EP176333).

Also, the reduction of the oxamide with LiAlH4 would cause deacetylation.

Ullmann - 1-8-2008 at 11:10

Bull. Soc. Chim. France (1965), (5), 1411-17 and 1417-1423 also are worth checking as it is the first synthesis of 4-OH-5-MeO-DMT that appeared in the litterature. Julia did protect the phenol with a benzene sulfonate I remember...

There are also alot other tryptamines in the paper

Dextrose - 2-8-2008 at 04:41

Thank you for your replies, guys!

Ullmann, i haven't been able to find that paper, even the university library has problems ordering it home!
Maybe you can help me with that?

I will post an alternative approach, when i've studied your replies some more.

Thanks for the suggestion about the aldehyde, Nicodem.
I forgot to notice that Shulgin's reduction of 4-acetoxyindol-3-yl-N,N-dialkylglyoxylamides caused deacetylation!

I did take note of phenol being very dominat.

Quote:
Originally posted by Dextrose
An alternative could maybe be using the O-benzyl-ether of ortho-vanillin as protection group, and making the acetoxy-ester as the last step, like described here: http://psychedelichosting.info/Ionium/Rhodium/chemistry/psil... ?


Do you think this maybe would be possible?

The idea about possible nitrating in GAA instead of Ac2O i had from this post: http://psychedelichosting.info/Ionium/Rhodium/chemistry/4-ni...
Where there are reported good yields of nitration on the 6-position in GAA.

But yes, it is another aldehyde.


[Edited on 2-8-2008 by Dextrose]

Klute - 2-8-2008 at 08:41

It seems LiAlH4 doesn't generally cause debenzylation, so that should be possible.

A note on the phenolic nitrostyrene formation, it's possible that this reaction might take more time that with non-phenolic benzaldehydes. Thsi is the case with the corresponding aldol reactions, and I suppose by analogy the reaction times must be extended here too..

Also, the amine from the indole group might need protection during acetylation, you would need to use a hydrochloride salt of similar?

Ritter - 2-8-2008 at 09:34

One positive thing about this scheme: the starting aldehyde is commercially available & inexpensive. It is called isovanillin and is the coproduct formed in the manufacture of vanillin from guaiacol.

Nicodem - 4-8-2008 at 05:00

Quote:
Originally posted by Ritter
One positive thing about this scheme: the starting aldehyde is commercially available & inexpensive. It is called isovanillin and is the coproduct formed in the manufacture of vanillin from guaiacol.

No, isovanillin is the trivial name for 3-hydroxy-4-methoxybenzaldehyde. The trivial name Dextrose used ( ortho-vanillin) is actually correct and not just something out of his fantasy. Nevertheless, to avoid confusion it is always better to avoid nontrivial-trivial-names like this.

Dextrose - 6-8-2008 at 11:43

Even though i'm pretty doubtfull myself, i'll post it anyway for flaming purporses. :P

Would the benzyl-ether be lesser para-directing, and hopefully place the nitro group on the right position, and not be nitrated on it's own phenyl?
And the big question... would it survive all the way to the final reduction?

Cheers!

I have a third suggestion i'll sketch up soon.



[Edited on 6-8-2008 by Dextrose]

5-MeO-4-AcO-DMT-2.png - 20kB

Dextrose - 6-8-2008 at 13:30

Here's the one i find most likely to work.

5-MeO-4-HO-DMT-3.png - 16kB

Dextrose - 6-8-2008 at 13:34

...But if ethers or esters would direct the nitro-group correctly, like a sulfoxide, this would of course be the route of choice.

That would be if the pyrrol-formation is possible in any of the latter two...

[Edited on 7-8-2008 by Dextrose]

5-MeO-4-HO-DMT-4.png - 12kB

Klute - 6-8-2008 at 15:32

I would rather go through the sulfonate, I'm pretty sure the benzyl ether will get removed by LAH, and nitrated by HNO3 (you are nitrating a aldheyde, which is more desactivated that the benzyl ether..). You could just aswell leave the sulfonate on until the LAH reduction, no need of removing it straight away and thne acylating. I think LAH can cause complet removal of the sulfonate to the hydrocarbon, so you would need to remove it between the reaction with oxalyl chloride and the LAH...

What's the purpose of the dimethylsulfate during the desulfonation? That would directly alkyalte your phenol..... A typo maybe?

A little detail, i would perform the initial sulfonation with Et3N or pyridine in EDCM, not aq. KOH as you are dealing with an aldehyde. It would caus eonly minor side recation, at 0-5°C but it can always be better to have homogeneous mixtures with delicate substrates.

I'm not familiar with the indole ring, but doesn't the secondary nitrogen be prone to some acylation? Or is it unreactive du to the cyclic conjugation?

Dextrose - 6-8-2008 at 16:50

Yeah, i must admit that i also find the 3.rd the most plausible.

But 8 steps now, and it would be nice to shorten it down to 7 as you suggest.
Guess it just depends wether it's possible, and which yield you will get, when closing the ring to the indole.

The first three steps are straight from the publication quoted by Nicodem. It can also be found as patent US4643769.

The sulfonate is hydrolised with KOH to the benzaldehyde potassium salt, and further treatet with dimethylsulfate to deprotonate the salt... or what? :S I'm tired and can't think of the reaction mechanism right now.

All entries in TIHKAL with phenolic indoles, none seems to mention anything about the secondary nitrogen.

Quote:
Originally posted by Klute
I think LAH can cause complet removal of the sulfonate to the hydrocarbon, so you would need to remove it between the reaction with oxalyl chloride and the LAH...


Great thinking! :)

[Edited on 7-8-2008 by Dextrose]

Ritter - 9-8-2008 at 10:45

Quote:
Originally posted by Dextrose
...But if ethers or esters would direct the nitro-group correctly, like a sulfoxide, this would of course be the route of choice.

That would be if the pyrrol-formation is possible in any of the latter two...

[Edited on 7-8-2008 by Dextrose]


Your figured 4-hydroxy compound would not be very stable with respect to attack by oxygen. By analogy to psilocin found in mushrooms, enzymatic hydrolysis of psilocycybin gives the free 4-hydroxytryptamine which undergoes easy air oxidation to form a blue quinone derivative (3-(2-(dimethylamino)ethyl)-1H-indole-4,7-dione). This is the 'bluing' reaction that psychedelic mushroom collectors use to confirm the identity of their finds. You would either have to acetylate it or protect it as the phosphate ester as in the original Hoffmann psilocybin synthesis. Otherwise your scheme would likely result only in pretty blue junk, with the 5-methoxy group only helping to speed up the oxidation to the quinone.






[Edited on 9-8-2008 by Ritter]

Quinone.gif - 7kB

Ritter - 9-8-2008 at 11:37

IIRC, this is the final part of the scheme that Hoffman used to prepare psilocybin. The 4-hydroxyl group was esterified with dibenzylphosphorochloridate, followed by hydrogenolysis of the 2 benzyl groups to produce the final phosphate ester, which is shown in the ChemDraw as the zwitterion.

Resized to 800x615 pixels with Irfanview.

Quinone-2.gif - 27kB

sonogashira - 9-8-2008 at 13:35

Due to the problems with nitration it may be best to use the Hemetsberger reaction which is discussed in the J. Braz. Chem. Soc. article in the first post and in the attached paper producing the 4-BnO-5-MeO-6-Me-Indole ester where you want the 4-BnO-5-MeO-Indole ester. This can then be decarboxylated as described in the J. Braz. Chem. Soc. paper.

So, protect the -OH of ortho-vanillin with PhCH2Cl and react with methyl azidoacetate as described in the attached paper to get the indole precursor in pretty good yields.

Ethyl azidoacetate (which appears to work just as well) can be made from ethyl acetate ---P/Br2---> ethyl bromoacetate ---NaN3---> ethyl azidoacetate (See the J. Braz. Chem. Soc. paper for this last transformation).

Have a look at Sundberg's "Indoles" book as well which might be of interest and has been kindly provided by fractional in the References section.

Forming the 4-OAc product can be accomplished in one-pot whilst debenzylating, though it should be subjectively different from the 4-OH analog, so try both! Best of luck. Here's the paper:

Attachment: 4-BnO-5-MeO-6-Me-Indole from Hemetsberger Reaction.pdf (1.2MB)
This file has been downloaded 745 times


Dextrose - 9-8-2008 at 18:43

Thank you once again, Ritter and Sonogashira...

I have been looking at nearly every indole synthesis i could think of (7-8 kinds) for an alternative...
I hope i don't start dreaming about indoles, waking up in my bed, screaming! :D

Sundbergs book would definitly be a good read, but it seems the forum is password protected.

Dextrose - 11-8-2008 at 14:41

Quote:
Originally posted by Klute
I would rather go through the sulfonate, I'm pretty sure the benzyl ether will get removed by LAH, and nitrated by HNO3 (you are nitrating a aldheyde, which is more desactivated that the benzyl ether..). You could just aswell leave the sulfonate on until the LAH reduction, no need of removing it straight away and thne acylating. I think LAH can cause complet removal of the sulfonate to the hydrocarbon, so you would need to remove it between the reaction with oxalyl chloride and the LAH...


Did you mean "so you would not need to remove it between the reaction with oxalyl chloride and the LAH" ?

If so... maybe one could get away with this?

5-MeO-4-AcO-DMT-5.png - 15kB

Klute - 11-8-2008 at 16:33

I'm very surprised. I was sure LAH reduction of aryl sulfonates caused complete deoxygenation to the hydrocarbon.
But when checking what protective groups could be ideal here, in the excellent book "Protective Groups in Organic Synthesis Greene, T. and Wuts, P. " (a must-read!) , i see:

Quote:

Sulfonates

An aryl methane- or toluenesulfonate ester is stable to reduction with lithium aluminium hydride, to the acidic conditions used for nitration of an aromatic ring
(HNO3/HOAc)
, and to the high temperatures (200-250°) of an Ullmann
reaction. Aryl sulfonate esters, formed by reaction of a phenol with a sulfonyl
chloride in pyridine or aqueous sodium hydroxide, are cleaved by warming in
aqueous sodium hydroxide.


So it seems TsO- would be the ideal protective group, and you could keep it even through the LAH reduction. Just hydrolyze off after, and acetylate. You might want to check if some kind of transesterification can be possible, doing this in one step.

I would again suggest using the TEA or pyridine in DCM sulfonation procedure rather than the crude aq. NaOH or KOH method here.
You might want to check if you can find some mor einfo on the deprotection of an molecuel similar to this one, to insure reflux in basic solution can't be detrimental. If someone can acces the Bull. Soc. Chem. articles mentionned above, I will translate them.

I can't find the article where I saw LAH used to desoxygenate phenols via their mesylates, only one version using Pd/C and Et2NH, so I'll give myself a big slap in the head (done) (seriously :) ).

[Edited on 12-8-2008 by Klute]

Dextrose - 18-8-2008 at 14:24

Could it be more possible that a Reimer-Tiemann formylation of 2-methoxy-5-nitrophenol would yield the wanted aldehyde (and indole) ?




[Edited on 18-8-2008 by Dextrose]

2-methoxy-5-nitrophenol.png - 5kB

Klute - 18-8-2008 at 17:07

Riemmer Tiemann is a bit of a messy, low yileding procedure, and not really suitable for expensive starting substartes... I would definatively use the Mg-mediated formylation of phenols in such a case, routine >80% yields on various phenols.

But it seems this reaction wouldn't apply well to your substrate, the o-MeO group is known to inhibit mg-mediated formylation (Aldred et al, J. CHEM. SOC. PERKIN TRANS. 1, 1823-1831 (1994), availble at the ref forum).

Maybe a vilsmeyer formylation of the hydroxy-protected substrate might be better yielding. In any case, I would look for something else than a RT, which is messy, low yielding and hardly regioselective...

Cheap and dirty

meme - 18-8-2008 at 22:52

OK, I'm a little tired so with that caveat . . .

This all looks pretty hard. I think I might have a DIRTY method that would suck on the first step, but would be cheap and only 5 steps.

"Interestingly, homolytic attack by *OH on the indole nucleus affords mainly 4-hydroxyindole.

M. Julia and F. Ricalens, Contem. Rend. (C) 275, 613 (1972). "

Taken from:

Newkone, George R. Contemporary heterocyclic chemestry. John Wiley and Sons, Inc. 1982. p 76.


Maybe one could hydroxylate 5-meo-indole first, and get a mess of hydroxylated crap, which would actually have some gold (like 5-meo-7-ho). I don't like dirty reaction like this, but it would be ghetto ;) It would take some cleaning but I think DCVC (Dry Column Vacuum Chromatography) might be an easier way to clean up all the isomers, certainly cheaper than some other methods.

OK, five steps (if the first one works):


1. 5-MeO-Indole --+ 4-HO-5-MeO-Indole
2. 4-HO-5-MeO-Indole --+ 4-AcO-5-MeO-Indole
3. 4-AcO-5-MeO-Indole --+ 4-AcO-5-MeO-Tryptophol
4. 4-Aco-5-MeO-Tryptophol --+ 4-AcO-5-MeO-Indole-3-ethylbromide
5. 4-AcO-5-MeO-indole-3-ethylbromide --+ 4 aco 5meo dmt

I just wanted to throw this out while I try and think of other, cleaner, methods.

Also:

Julia, M. and Ricalens, F., Hydroxylation of N,N-Dimethyltryptamine: factors governing orientation C R Acad Sci Ser C 275, 613, 1972

sonogashira - 20-8-2008 at 05:19

meme's suggestion is interesting, but why not start from 5-MeO-DMT instead?
Here's a paper detailing the synthesis of 4-AcO-5-MeO-Indole via the nitroalkene route:

[Edited on 20-8-2008 by sonogashira]

Attachment: 4-AcO-5-MeO-Indole Synthesis.pdf (494kB)
This file has been downloaded 1697 times


meme - 20-8-2008 at 14:02

My thoughts were that 5meoDMT is more costly, and that I'd rather have loss at the beginning of a synthesis.

But it would be a two step-synthesis, come to think of it, and I bet a Chinese firm if you shopped around would get this to you at a very good price.

Heck, you could even extract it, purify the DMT, beta-carbolines, and bufotenine out of it if there was any, and start there. If one used a phalaris known to produce 5meo only, it would be free almost to make some. Yields would be awful, I bet, it is the most low tech thing ever! Grow grass, extract, free radical reaction *OH, and cleanup (hardest step by 1000 fold).

Sandmeyer - 1-9-2008 at 08:21

How many times are you gonna attach the picture of same route? ;) Imo, to make 4-subst indoles the best is to go via nitrene insertion as key step. i.e alkyl azidoacetate + aldehyde, cyclisation/nitrene insertion of the condensation product, hydrolysis, decarboxylation...

zed - 18-9-2008 at 02:59

If you started with 5-Methoxy-indole, you might be able to proceed by the method of Somei, Yamada, and Tamura. They produced 4-Benzyloxy-indole-3-carbaldehyde in good yield, from Indole-3-carbaldehyde. First Psilocin synthesis I ever saw, that actually seemed reasonably practical.

http://www.ch.ic.ac.uk/ectoc/echet98/pub/039/index.htm

Dextrose - 16-10-2008 at 09:22

Quote:
Originally posted by Sandmeyer
How many times are you gonna attach the picture of same route? ;) Imo, to make 4-subst indoles the best is to go via nitrene insertion as key step. i.e alkyl azidoacetate + aldehyde, cyclisation/nitrene insertion of the condensation product, hydrolysis, decarboxylation...


Hehe... I've been suggested so many other routes for indol-formation, but not this one though...

Can you please put up some graphics for me, please?

F.ex- the Heck-reaction - I have studied a bunch of publications with it - but i still can't figure out the reaction-mechanism directly to an indole - how the heck (:P) does this one go?

But it seems like 2-hydroxy-3-methoxy-6-nitrobenzaldehyde is commercial available, so it would be nice to find a cheap source for this item.

About the 4-hydroxylation's of the indoles... is that for fucking real? i've allways thought this to be next to impossible..!?
I just rememered that i have bunch of pure USP grade Melatonin, so that could be interesting...

[Edited on 16-10-2008 by Dextrose]

unome - 20-10-2009 at 02:13

There we go, on top of that Rhodium's pdf's include a procedure for a Hoffman degradation on an m-nitrobenzamide to the m-nitroaniline and I can think of at least one japanese paper where they found that using H3PO4 to affect cyclization of the diamine to the 4-aminoindole gave the 4-hydroxyindole, whereas sulfuric acid gave the 4-aminoindole.

In any event - using the 5-nitrobenzamide, you'd be able to reduce the nitro - form the phenylhydrazone with pyruvic acid - decarboxylate that, then form the amide, etc. Hoffman to the amine - hot H3PO4 to remove it.

Alternatively, try chain lengthening that side (ie. use salicaldehyde instead of salicylic acid - extend the chain on that side to form the phenylethylchloride and cyclize that to the benzofuran ie. an indole-type dragonFLY) or maybe put an MD on it - 4,5MDDMT should be fun:o

Attachment: Synthesis.4.nitroindole.ethylpyruvate.m.nitrophenylhydrazone.pdf (258kB)
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Attachment: MW.nitration.benzoic.acid.m.nitrobenzoic.acid.pdf (45kB)
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Attachment: Synthesis.IndolecarboxylicAcids..pdf (192kB)
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Attachment: mw.nitration.salicylic.acid.pdf (63kB)
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[EDIT - in any event, m-nitroaniline is as cheap and unwatched as anything you are likely to look at.

Also look at the last paper - where the author's use the phenylhydrazone of succinaldehydic acid (the Strecker degradation product of Glutamic acid) and cyclize it with Sulfuric acid to get indole-3-acetic acid in pretty shit yields admittedly, but then again, it is all pretty cheap.

[Edited on 20-10-2009 by unome]

Attachment: Synthesis.Indoleacetic.Acids.Glutamine.pdf (279kB)
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LabRatNW - 21-10-2009 at 19:38

Quote: Originally posted by zed  
If you started with 5-Methoxy-indole, you might be able to proceed by the method of Somei, Yamada, and Tamura. They produced 4-Benzyloxy-indole-3-carbaldehyde in good yield, from Indole-3-carbaldehyde. First Psilocin synthesis I ever saw, that actually seemed reasonably practical.

http://www.ch.ic.ac.uk/ectoc/echet98/pub/039/index.htm


Adding things to the benzene ring of indole is horrifically difficult. You need build your benzene, close the indole, alkylate.

Methyl.Magic - 14-8-2011 at 04:53

Here is my pathway. Perhaps the reaction can be done on 5-MeO-DMT :

5MeODMT-> protection -> BuLi -> O2/red-> deprotection ;)



karlos³ - 15-12-2020 at 20:01

Holy necropost!
Sorry but I had to, since here is the most relevant thread discussing this topic, the preparation of psilomethoxin.

Quote: Originally posted by zed  
If you started with 5-Methoxy-indole, you might be able to proceed by the method of Somei, Yamada, and Tamura. They produced 4-Benzyloxy-indole-3-carbaldehyde in good yield, from Indole-3-carbaldehyde. First Psilocin synthesis I ever saw, that actually seemed reasonably practical.

http://www.ch.ic.ac.uk/ectoc/echet98/pub/039/index.htm


Based on the first three one-pot steps of the 4-benzyloxyl group introduction, I found a somewhat shorter possible route to accomplish the synthesis of psilomethoxin, see the attached drawing.
Starting from 5-MeO indolecarboxaldehyde, the first reaction is clear, just as per the japanese paper.
But I found that the mannich reaction with eschenmosers salt is beneficial, as it introduces the N,N-dimethyl groups readily and is pretty high yielding.
Of course the disadvantage is the beta ketone, but that can luckily under the right conditions be reduced to the alkane with plain NaBH4.
And since I realised the opportunity for this in the NaBH4 reduction, we can one-pot add some more borohydride followed by NiCl2, which is a reducing system capable of O-debenzylation.

This makes four separate operations starting from 5-methoxyindole, when the second three and last two reactions are done one-pot.
I found that quite clever and wanted to share it on here too.
I know its not the most practical approach, but very feasible.

psilomethoxin via aminoketone from indolylcarboxaldehyde.jpg - 46kB

Edit: I just realised that I draw a 4-phenyloxy ether and not benzyloxy, I'm sorry, this is due to some properties of chemsketch....
I draw a 4-benzyl group and wanted to introduce the oxygen later(=replace one carbon with oxygen) and actually notice now for the first time that this results in a carbon missing :o
Please ignore that mistake and imagine a benzyloxy group instead, alright?

[Edited on 16-12-2020 by karlos³]

zed - 15-12-2020 at 21:55

Sorry, somehow over the course of time, the graphics have become kind of scrambled.

Psilomethoxine? Is that a thing?

karlos³ - 15-12-2020 at 22:28

Yeah that trivial name turned up somewhere in the last few years and I have to say I think it is a really good one and sounds cool.

The graphics from Dextrose? But I can view them pretty clear?

mackolol - 16-12-2020 at 04:09

One could also perform 4OH addition to the 5MeO DMT catalysed by our beloved fungus' enzymes :D It would be the easiest way.


[Edited on 16-12-2020 by mackolol]

karlos³ - 16-12-2020 at 06:14

Its even easier and cheaper if you use plain 5-methoxytryptamine for that, the mushrooms also use N-methyltransferase enzymes and can dimethylate it on their own.

mackolol - 16-12-2020 at 09:12

Although it could be toxic. Wiki states, that 4,5 dihydroxy Tryptamine is a neurotoxin (probably similar in action on serotonic receptors to the action of 6 hydroxydopamine working on dopamine receptors, just killing them).
Would n,n - dimethyl protect our neurons from that? What do you think?

karlos³ - 16-12-2020 at 09:54

Typed a long reply and lost it.
So the short answer is, no, if one of the hydroxyl is etherified, its not toxic.
Look next door I posted quite a few papers over the last half year.

Also, I heard anecdotal reports of people having doped mushroom substrate with 5-MeO DMT, and they report very distinct effects and a ca. 3x higher potency, i.e. dosages even as little as a half gram of P. cubensis being already very strong.
And they also claim its enjoyable and nice.
If you want to go the biosynthesis route, well, use mexamine instead thats much cheaper and easier to make.

However I would recommend a synthetic route, even though its a lot of steps, that is a good exercise for one synthesis skills.
And the quantities to start with don't have to be overly huge anyways.
You would likely require to use the anthony-speeter though, but its just getting the reagents thats an issue with it, the reaction itself is very simple and with Red-Al instead of LAH even very safe.
Or try the proposal of me above :P

mackolol - 16-12-2020 at 10:25

I'm pretty sure, I have seen it on Wikipedia and yes, I know it may not be the most reliable source, although 5MeO DMT is said to be metabolised mainly by cyp2d6 which demethylates it to hydroxy derivative, I thought that's mainly the parent hydroxy compound that makes it work, similar way to psilocybin -> psilocin although harder to hydrolyse.

I know that synthetic route is much more interesting and that's what we should discover, although I have a lot of different things going on in ma lab that I want to finish and this is like a massive challenge. That;s why, I prefer to make it easier just for now and to be honest I would love to even reach it to the 4OH substituted indole, which is challenging enough.

I'll look for your papers, thanks for advice, it's really easy to get the mexamine, so it may be really dope.

mackolol - 16-12-2020 at 10:33

All right, now I see, the methoxy compound is methabolised in the gut and liver and the experiments about neurotoxicity were about the compound being administered cranial. But wouldn't demethylated methabolites be absorbed in gut?

zed - 16-12-2020 at 23:04

Mexamine might be easier to obtain than Tryptamine.

I haven't cruised the net for things like that lately, but the last time I checked, Melatonin was pretty cheap in bulk. And, it is pretty easy to hydrolyse.

Better check on that....

OK. I'm Back. Melatonin. $329.00 per Kilogram.

Yeah, I know in some parts of the world, guys can't buy it.

But, in the U.S., all you have to do is slap your money on the counter. The synthetic pathways into psychedelia are difficult enough, that it isn't considered a problem.

https://www.bulksupplements.com/products/melatonin-powder?va...

OK. I checked the list. There are really a lot of places that guys can't buy Melatonin. But, it is still OK, in the U.S. and the UK?


I'll supply a link to that hydrolysis. Via a post from softbeard.
I have a hardcopy of the paper. But, softbeard has managed to to provide a live link to the actual journal article.

https://www.sciencemadness.org/whisper/viewthread.php?tid=79...

[Edited on 17-12-2020 by zed]

chemship1978 - 17-12-2020 at 00:11

Quote: Originally posted by zed  
Mexamine might be easier to obtain than Tryptamine.

I haven't cruised the net for things like that lately, but the last time I checked, Melatonin was pretty cheap in bulk. And, it is pretty easy to hydrolyse.

Better check on that....

OK. I'm Back. Melatonin. $329.00 per Kilogram.

Yeah, I know in some parts of the world, guys can't buy it.


https://www.aliexpress.com/item/4001352643390.html?spm=a2g0o...

55USD for 1kg here with free shipping to US. :)

njl - 17-12-2020 at 06:17

FYI, the listed prices on alibaba/aliexpress are more often than not either misleading or downright fake.

Tsjerk - 17-12-2020 at 07:44

Aliexpress prices are usually fine, I would trust them as long as there is some positive feedback. Usually Aliexpress sellers do about anything to get positive feedback.

karlos³ - 17-12-2020 at 11:17

In europe, we lately got the option to purchase melatonin in food grade quality from S3.
Its pretty expensive but considered I paid much more for 1g(1,3g thanks to TCI) for 5-methoxyindole than for 10g of melatonin, then it is still pretty neat to have that option for now.

Guess I'll go the mushroom route too experimentally, despite working on the synthetic method with a friend as well :)

njl - 17-12-2020 at 11:43

Melatonin is one of those things I thought was OTC everywhere since you can get it so easily and cheaply in the states. Was it Rx only before?

karlos³ - 17-12-2020 at 12:17

It is still on prescription in my country.
But formerly we weren't able to buy it as a reagent except out of country.
Inside the EU it was hard to get.
And if you buy it, from example the US, it would go to customs and that means it can potentially be sent back as importat of medications is not allowed for private persons.

I once ordered a nutritional supplement containing arachidonic acid, which I desired for certain experiments, and they hold it up and demanded so much import tax(more than I paid!) that I decided to have it sent back instead.
If I knew these asses wouldn't refund me I would have paid that money, though.... arachidonic acid is almost impossible to get inside the EU, at least in acceptable prices via nutritional supplement suppliers.

On the other hand, the expensive "herbal tea" bags I got from Peru once, only required me to pay import taxes and then I could take it back home.
Despite that the content was 1000x0,9g tea bags of mate de coca :P
They haven't looked into it, just stopped it, and then paid taxes according to the shipping leaflet on the parcel.

But they have certain buzzwords to whom they act accordingly.
If anything comes as pills or capsule, they are especially interested in it.
So, melatonin powder in bulk might get through well.... I don't know of anyone who tried that.
It could be very different though since melatonin is mostly prescription only in europe.
At least in Germany it is, and if such a parcel would be checked by customs, you would be fucked.
Either a huge fine or have it sent back... although I doubt you would get it even if you paid the huge fine, though...

So in short, melatonin is scarce in europe, too hard to get.
We want to make 5-MeO tryptamines as well.... thats why I went per anthony speeter and bought expensive 5-MeO indole instead :o
I guess we need to intensify the intercontinental relations for matters like this and have a friendly american send us bulk melatonine for an EU-wide sharing action :)
We probably have to organise such an event really....

zed - 17-12-2020 at 14:20

Ummm. In general, 4 substituted indoles have always been excessively expensive, and hard to synthesize.

5-methoxy-indoles....not so much. You should be able to make yourself a jar-full as feedstock.

Now, where I live, those little Psilocybin mushrooms, grow like weeds. They pop-up everywhere. DMT and 5-Meo-DMT, can be extracted from the local Phallerius Grasses., and if I were so inclined, I could buy the most potent Cannabis on the planet, at my neighborhood Pot-shop.

Apparently, most of the world isn't like that.

Anyway. 5-Methoxy-Indoles are available through the Fisher Indole Synthesis. From Phenyl-Hydrazones or Diazonium salts, of P-Anisidine.

Either 5-Methoxy-Tryptophol, or 5-Methoxy-Indole-Acetic Acid might be worthy targets.

Perhaps not ideal. But, synthetic pathways to Indoles, are limited, reagents are expensive or inaccessible, and...you have to start somewhere.

I know of the Speeter-Anthony, and I have heard it is reliable.

But, the required materials are fairly inaccessible here. Notably, Oxalyl Chloride. Expensive, hard to acquire, and very hard to make. The requisite reagents tend to be highly restricted.

An obstacle that might be avoided, by utilizing the Indole Acetic Acid. Simply convert the acid to the Acetyl Chloride, in situ, and react it with a suitable amine. This should yield an amide. Just utilize reaction conditions analogous to those in Tihkal's LSD procedure. This requires POCl3, but that isn't impossible to make.

Were I in the mood to play chemistry right now. Indole Acetic Acid is cheap and available. Indole might not be. And, many of the other required.... Speeter and Anthony reagents, might as well be on the moon.

Yeah, OK. I could make a lot of it, but I really lack motivation.

What can I say? I've gotten old and lazy!

[Edited on 17-12-2020 by zed]

[Edited on 18-12-2020 by zed]

karlos³ - 17-12-2020 at 15:59

Yeah well, I used the anthony-speeter, on 5-methoxy-, 5-bromo-, and plain indole, reducing the glyoxylamides with Red-Al(expensive, but easier to use), that is a very viable method, even for the halotryptamines since it doesn't result in dehalogenation unlike LAH.
I've even been told(and have the ref somewhere) that diborane in-situ prepared is an alternative to using LAH, and that is definitely very accessible too.
For completeness sake, I add the diborane reduction of indolglyoxylamides.

That makes oxalyl chloride the only remaining real hurdle for the anthony-speeter, but the advantages are that its really an idiot proof method.
My yields could be improved, but it worked free of any failure on my first trial.
And we here at the forum have the one or other guy at hand who can organise that, so this is really not an impossible task to get it.

Now, in this special case here, for psilomethoxin, we don't have as many options for the preparation of the starting material.
And we are pretty much restricted with the need to use the route via indole, almost.
The route I gave above(inspired from your ref zed) is one of the very few exceptions we have here.

Otherwise, with the need to start from the indole, what do we have left?
We can go via FC-acylation to the acetylindole, a-bromination, amination and finally reduce the ketone with borohydride... the downside is, some of these steps aren't very high yielding.
And not to forget, at that point we have already done 3-5 reactions to prepare the starting indole... so we can't afford to waste some on going a moderately yielding route.

The fischer indole is out of question too, since 3-hydroxy(or 3-acetoxy)-4-methoxy phenylhydrazine is going to yield with around a 4:1 preference the unwanted 5-MeO-6-HO indole.
No matter if you go to the tryptophol via the fischer or directly to the tryptamine, so thats not a viable choice.

So what else is left, gramine, going via the nitrile for example, maybe the 3-indolyl grignard reacted with that toxic blister agent, the mustard gas analogue, or directly with ethylene oxide for tryptophol maybe?
And surely the one or other approach I don't have in mind right now.
Mostly some greatly skill-dependant ways for the chemists.

That means the only really realistic approach, if you want to make psilomethoxin, remains the anthony-speeter.
The only potentially low yielding step at this point is the final reduction in the worst case, making that the most preferred approach.
The Marc Julia et. al. paper that even Shulgin referred to, the first full synthesis of psilomethoxin, used that method too.

And we can't really introduce the 4-hydroxy group afterwards, we definitely have almost no choice besides having to construct the indole ourselves first.
Note, this 4-hydroxy-5-methoxyindole has just as few, even fewer, options for its synthesis than plain 4-substituted indoles.
Its not easy to make, definitely another league than the simple unsubstituted or 5-substituted tryptamines who are comparably simple to make.
This is a real challenge and that is why Shulgin never made it apparently.
Even though he made the 4,5-MDO tryptamines which aren't really harder to prepare, I would say its even around the same level of difficulty, just requires one or two reactions in addition... and one or two in addition to make the benzaldehyde precursor.
But manageable.

I am attempting this with a friend and we are starting from ortho-vanillin via the "classical" route.
Tosylation of the o-vanillin, followed by nitration, followed by exchange of the tosylate with an acetyl group, followed by nitrostyrene formation and reductive cyclisation with Fe/acid reduction.
I've saved a small rest of oxalyl chloride and still have enough red-al for a few grams of the glyoxylamide left for this.

If I would have to do the first reactions, I would have started from 5-methoxy-2-nitrophenol with a VH-formylation, to skip the nitration step which I would prefer not needing to do it.
And then essentially the same, except that there is no need to go via tosylation(which is just done because the sulfonylate ester of o-vanillin nitrates selectively on the right position), we can directly acetylate the phenolic hydroxy, and after those two steps its just nitrostyrene formation and reduction to give 4-acetoxy-5-methoxyindole.

4-HO indoles are really damn hard to make, but this 4-HO-5-MeO indole(or its 4-esterified analogue) is really the icing on the cake in terms of effort thats required to make it, and sadly there are not many alternative routes existing.
Maybe one of those indole syntheses who make use of anilines or such, but else the options are pretty limited here.

Thats why I was pretty proud on my proposal above, via 5-MeO 3-indolcarboxaldehyde, its probably the shortest imaginable route to psilomethoxin with my improvements.
Although of course with the problematic downsides, of the need to introduce the 4-benzyloxy group via thallation with a toxic thallium salt, which needs to be substituted with expensive iodine, before the benzyl ether is finally attached.
Yeah, the dimethyl(methylene)ammonium chloride/iodide has to be made in at least two separate steps, or has to be bought for a way too expensive price.
And lastly, 5-MeO indole has to be bought and thats neither nonsuspicious nor very accessible, and neither cheap.
But besides that, and the not so nice yield in the final reduction to the tryptamine(but then again, good yield in the O-debenzylation with NaBH4/NiCl2), it really does not have much disadvantages.
Its uneconomical because of all the separate pre-precursor preparations though.

So, the best approach is still the classical variation, via the leimgruber-batcho variation(Nenescu? what was the rumanian chemists name? has his own indole synthesis, a different one, who invented the reductive ortho-nitro nitrostyrene cyclisation variant of the L-B indole synth).
And from the indole straight forward to the glyoxylamide and its reduction.
Thats good and solid manual crafting, not short and clever but really practical work.

Attachment: biswas1968.pdf (1.3MB)
This file has been downloaded 69 times


zed - 17-12-2020 at 18:24

Mmmm. Buy enough of it, and the price of Oxalyl Chloride is decent.

Is Sigma friendly in Europe? I no longer have relationships for exotic chemicals in the U.S..

Precurser PCl5 which is restricted by International Chemical Weapons Treaties, is a hard get.

Likewise, Phosphorus itself, is a tough get, in the U.S., and making everything from scratch is arduous.

Perhaps Oxalyl Chloride is cheaper, and more readily available, than its alternatives.

https://www.sigmaaldrich.com/catalog/product/ALDRICH/221015?...

Very reasonable price if you buy 10 Kilos. I don't know if any carrier will fly it, knowingly.

That the desired intermediate can be synthesized via the 5-Methoxy-Indole-3-Aldehyde, is not certain. Unless of course, someone has successfully done it, and provided details.

Were I to embark on attempting that synthesis, I would make about a hundred grams of 5-Methoxy-Indole to supply my experiments. It is purported that P-Anisidine Phenylhydrazone of Ethyl Pyruvate, will produce the Indole-2-carboxylic acid ester in decent yield. The 2-carboxylic acid is then be decarboxylated.

Might be a. better synthesis out there. I don't know.

It's been a while. There is often a better procedure somewhere.

I just know, I'd want a healthy supply of the critical intermediates.

[Edited on 18-12-2020 by zed]

karlos³ - 18-12-2020 at 14:53

Quote: Originally posted by zed  

That the desired intermediate can be synthesized via the 5-Methoxy-Indole-3-Aldehyde, is not certain. Unless of course, someone has successfully done it, and provided details.

Yes, it is of course just an assumption.

We know enough about aromatic thallation on the other hand.
5-MeO is activating.
It seems that for the thallation of anisole a preferance of ca. 80% para opposed to 20% ortho is expected....
I think this can't be that simple compared to the higher substituted indolylcarbaldehyde in our case, but if, then this means mostly the undesired 7-substituted analogue and in turn my idea to be of no value.
However, I've seen metallations of 3-substituted 5-haloindoles that would add on position 4-, of course those are mildly deactivating, I just mention this because from a synthetic position the 4-HO-5-x disubstitution is almost as useful.

But after thinking some more, I fear you are right.
The 5-MeO group meddles with the regioselectivity of the thallation and would give 5-MeO-7-HO probably.... damn, that sucks.

It still remains a nice approach to 4-HO tryptamines, and is thus very valuable.
The remainder of my proposed route, i.e. mannich with eschenmosers salt in special, followed by the reduction to the tryptamine remains still a valuable and very short variation, most straight forward.

And that reminds me of this, something surprising and unexpected: a friend had analysed mushrooms grown on 5-MeO DMT spiked substrate.
And they haven't contained the desired tryptamine, instead just the usual stuff and another "unknown" compound.
So this indicates that the 5-MeO substitution interfers with the 4-hydroxylase enzyme.
There is actually no short biosynthetic preparation possible for this analogue, which even Shulgin had thought to work.
This substance can only be accessed via synthetic means.

Quote: Originally posted by zed  

Were I to embark on attempting that synthesis, I would make about a hundred grams of 5-Methoxy-Indole to supply my experiments. It is purported that P-Anisidine Phenylhydrazone of Ethyl Pyruvate, will produce the Indole-2-carboxylic acid ester in decent yield. The 2-carboxylic acid is then be decarboxylated.

Might be a. better synthesis out there. I don't know.

It's been a while. There is often a better procedure somewhere.

Interesting, I would have never expected that the 2-carboxylic acid can that easily be removed, of course I knew about that fischer variation but always thought that would require more effort.
That makes the preparation of substituted indoles more accessible, good to know!
Quote: Originally posted by zed  

I just know, I'd want a healthy supply of the critical intermediates.

Yes, logical.

Since we've already decided to use the standard route, proven to work, used with success and affordable, we start with 100g ortho-vanillin.
That sound like a sufficient quantity, even half of that would probably be enough to obtain a few grams, even with intentionally lowered yield expectations.
I already wonder how much of the disubstituted indole will be available when its time to do the speeter-anthony.
But then again, the last three steps are a walk in the park, also I've started with merely above a gram of a substituted indole and still got a very nice quantity of the final tryptamine out.
So this should be the easiest part of the whole synthesis.

zed - 23-12-2020 at 19:21

Karlos, there is a more straightforward synthesis, utilizing the Azide.

Ortho-Vanillin would be the starting point. Azides are a concern, but folks are doing it.

I've got a reference. I'll go dig for it.......

https://pdfs.semanticscholar.org/ed76/3bf008c6e9ef09537f9fc8...

Page 21, Hemetzberger

As for the synthesis of Indoles via their 2-carboxylates, being decarboxylated.... The method is fairly well known.

I'm going to try to link you, to something relevant ...... https://www.google.com/search?client=safari&rls=en&q...

Click on the science madness link. I can't seem to link you directly. It is a PDF. PDFs drive me crazy. I can't seem to link to them.

As I may have stated elsewhere, the Phenylhydrazone of Acetaldehyde does not yield Indole under ordinary Fischer conditions, but when the Phenylhydrazone is passed through a tube furnace, or a flow type reactor it may. I assume the 5-methoxy-Indole might be constructed by the Fischer..... But that is not certain.

Of note. In that general paper on Indoles, there is mentioned a method of reducing Diazonium Salts to Phenylhydrazines, via Ascorbic acid. Looks like a useful technique. Ascorbic Acid, I can get by the Kilo, at minimal cost. Page 9, Scheme 7.

Diazonium Salts, form useful phenylhydrazones directly, when reacted with Dihydro-Furan. Upon cyclization, Tryptophols are produced.

Those Tryptophols, may be converted to Tryptamines, but the roads are not very familiar to me. And, in years past, the requisite reagents were fairly arcane.

[Edited on 24-12-2020 by zed]

[Edited on 24-12-2020 by zed]

[Edited on 24-12-2020 by zed]

zed - 30-12-2020 at 19:25

A link to the Hemetzberger Synthesis. Just open the PDF.

This synthesis appears to be an effective path to the Indole you wish to produce.

https://www.researchgate.net/publication/305775529_Hemetsber...

[Edited on 31-12-2020 by zed]

symboom - 30-12-2020 at 22:51

A little off topic but this about synthetic toad venom by Vice on Hamilton's pharmacopoeia (5, Meo-DMT synthysis 30 minutes in) seems ok interesting
https://youtu.be/fFXGa-Ruz_M



[Edited on 31-12-2020 by symboom]

zed - 31-12-2020 at 13:26

symboom,

Thanks for the link. Very interesting stuff on Hamilton's. Also, it led me to a Hamilton link, on the story of a Clandestine Chemist.

The gentleman in question, turned out to be an old collegue. Haven't seen young Anakin in decades. I myself, took another path. Wary of extremes, I suppose.

https://www.youtube.com/watch?v=3cvcoVPYsBE

karlos³ - 2-1-2021 at 09:43

I ditched the chance of an interview with hamilton.
Screw vice.
They should at least pay well for such a chance!
Melgar thought different, apparently(they choose him instead then after I refused).
I gave an interview for a dutch-language book about MDMA instead.
The journalist was very nice and knowledgeable and it was fun to answer his questions.

zed - 2-1-2021 at 15:19

I don't think such fame is good. Once upon a time, it might have caused beautiful young women, to jump in the sack with you. Now-a-days.... Not so much. Just attracting trouble.

Once again: https://www.researchgate.net/publication/305775529_Hemetsber...

At the moment, you can either read of download the PDF, for free. Just click.

[Edited on 2-1-2021 by zed]

[Edited on 2-1-2021 by zed]

karlos³ - 3-1-2021 at 09:02

Ortho-vanillin(or its 2-acetylated analogue) and methyl 2-azidoacetate to give the substituted a-azidocinnamic acid, which cyclises in boiling xylene to 2-carboxymethyl-4-hydroxy/acetoxy-5-methoxyindole.
Yes, that is doable and cheap indeed!

mr_bovinejony - 3-1-2021 at 09:56

What's your plan for this methyl 2 azidoacetate? I forgot to tell you I had bought some ortho vanillin for when a pathway is figured out for this

Antigua - 3-1-2021 at 09:57

https://prepchem.com/synthesis-methyl-2-azidoacetate/

Methyl chloroacetate or bromoacetate are cheap or easily made.

mr_bovinejony - 3-1-2021 at 10:25

They sure are cheap but I cant find a supplier! The patents are mostly gibberish but from what I could tell it seems like they're reacting methanol with chloroacetic acid somehow in the vapor phase

arkoma - 3-1-2021 at 10:34

Quote: Originally posted by zed  
I don't think such fame is good. Once upon a time, it might have caused beautiful young women, to jump in the sack with you.


Until you get out of bed to spend three minutes checking on your reaction. ROFLMAO.

Antigua - 3-1-2021 at 10:38

https://scihub.wikicn.top/10.1081/lft-200043689

This should blow away any doubts. Ferric chloride with 90% yield!

karlos³ - 3-1-2021 at 10:39

Quote: Originally posted by arkoma  
Quote: Originally posted by zed  
I don't think such fame is good. Once upon a time, it might have caused beautiful young women, to jump in the sack with you.


Until you get out of bed to spend three minutes checking on your reaction. ROFLMAO.

Damn I should have never mentioned that event :P

zed - 3-1-2021 at 20:40

Ummm. Reagents often being ardous to obtain, I am curious as to if requisite Chloro or Bromo, acids or esters might be synthesized from amino acids (or their esters)... via Diazotization.

Glycine is available, and dirt cheap. But perhaps I am being obtuse.

Here is an example, of what I have in mind. http://www.orgsyn.org/demo.aspx?prep=CV8P0119

OK.... I went out scouting..... Now I'm back.

Nope. Probably not gonna work. It seems the guys have tried this out before, to no avail. http://www.sciencemadness.org/talk/viewthread.php?tid=65553

[Edited on 4-1-2021 by zed]

[Edited on 4-1-2021 by zed]

zed - 24-2-2021 at 14:25

OK, I thought about it. Some of the guys have reported failure to produce Chloro-Acetic acid via Glycine Diazotization.

Since the desired intermediate, is the Ester of Chloro-Acetic Acid; might it be possible to to produce that Ester,
Via the diazotization of Glycine's Ethyl Ester Hydrochloride?

Well, maybe. I'm gonna look it up. Might not work. Might be a hydrolysis problem. Might be a solubility problem.