Sciencemadness Discussion Board

Reductive amination without Pictet Spengler: Lilienthal's method?

megalodon - 19-6-2013 at 07:20

Hi all,

I am studying organic chemistry and the basic concepts are easy to grasp (eg, substitution vs. elimination mechanisms) but sometimes the details are a little hard to assimilate (eg, what conditions favor which)

Right now I'm studying reductive amination, in particular of arylethylamines. Here the main confounding detail is the Pictet-Spengler cyclization - how can it be minimized?

In particular, I found this procedure by Lilienthal at the Erowid Rhodium archive:
Quote:

Formalin (35%, 35 mmol) was added with stirring to a solution of holafébrine (primary amine) 3 mmol in methanol (10 ml) and the solution was refluxed for 30 min. After cooling, 400 mg NaBH4 was added slowly. After 1 h the reaction was evaporated and the mixture was extracted with CH2Cl2. Evaporation yields 85% iréhine (dimethyl-holafébrine).


I am reading through the literature cited for this procedure, but I was curious if anyone here had theoretical insight and/or practical experience with this procedure? Is it true that "Because of the aprotic, non acidic reaction and work-up conditions no cyclization to β-carbolines should occur." ? Is this the case in practice?

Thanks, and great site!

Furboffle - 20-6-2013 at 11:31

A simple wiki search could explain it for you or UTFSE. Look up the eschweiler-Clarke reaction, the pictet-Spengler reaction, and reductive amination. Learn the differences. Like why with one you get ring closure, with the other 2 you get methylations.
Or easier not that you're trying to do it or anything.... -_- just google "dmt reductive amination" plenty of shit seems to come up. Even a published article or 2

megalodon - 20-6-2013 at 12:42

I have done said research, but thanks for the advice - my head is still swimming a bit in rules and exceptions. Any thoughts on the specific procedure I had questions about?

I have tried it twice now and had no success to speak of. In both cases the end result was a small amount of rubbery, sticky substance, in the words of Douglas Adams "almost, but not quite, entirely unlike [dm]tea".

***Calculations***
3 mmol tryptamine are called for; at 160 g/mol, this is 0.48 g.

35 mmol formaldehyde, as formalin, are called for. 40% formalin is available; at 30 g/mol this gives me 2.6 mL formalin.

***Experimental ***
I.
0.520 g tryptamine were massed and added to a 50 mL RBF. 10 mL MeOH were added. 4 mL formalin were added and swirled. A condenser was added to the flask and it was gently heated for 30 minutes, the let cool. 0.445 g NaBH4 were massed and added in small portions to the liquid, causing heating and effervescence. The mixture was then let stand for 60 minutes, then heated to evaporate. Once dry, the flask was cooled. 20 mL CH2Cl2 were added and swirled. The liquid was filtered into a glass petri dish. The solid filter cake was returned to the RBF and extracted with a further 15 mL CH2Cl2. This was was filtered and combined with the first. The dish was heated gently to evaporate.

II.
0.438 g tryptamine were massed and added to a 25 mL RBF. 10 mL MeOH were added, and the mix swirled to dissolve. 2.5 mL 40% formalin were added by syringe. Small amounts of flocculent solid were observed on addition. A condenser was added and the mixture was heated on reflux for 30 minutes. 1.067 g NaBH4 were added in small portions; the later additions were much less vigorous. The cloudy lemon yellow reaction mixture was poured into a beaker to air-evaporate overnight. Fully evaporated, there was a sizeable crust of white crystals in the beaker. 20 mL CH2Cl2 were added, the mixture stirred and filtered. This was air-dried in a glass petri dish.

***Results***
In both cases, a sticky residue remained, a thin crust of rubbery yellow goo, looking somewhat like snot but sticky and tending to form fibers when pulled apart. It was a surprisingly small amount of material. Did not dissolve in ethanol or acetic acid. When heated, produces an odd smell, unlike dimethyltryptamine.



Am I missing something? I'll keep reading. Thanks again!

Furboffle - 20-6-2013 at 15:45

From what I've read THF can work much better than methanol, but regardless, all the reports seem follow the same order. Dissolve tryptamine freebase in meoh or thf, then add 2 molar eq glacial acetic acid and 4 molar eq of the borohydride. Once the borohydride has mostly dissolved then add 5 molar eq of formaldehyde dropwise then stir a couple hours. Pretty damn simple.
One thing not certain but I feel sodium borohydride maybe too harsh. It seems cyano borohydride and triacetoxyborohydride are a lot more mild and appropriate.
You should work on your clean up. You can isolate much quicker by doing it right. Once the reaction has gone to completion acidify the reaction solution. Then add dcm, discard dcm layer. Repeat once or twice. Then basify the aqueous layer, add dcm, discard aqueous layer repeat a couple times then evaporate the dcm to yield product. And if you want a really clean product recrystallize from here.

Even assuming you did everything right your purification would leave you with a dirty product.

[Edited on 20-6-2013 by Furboffle]

Furboffle - 20-6-2013 at 15:48

You've already tried so the advice is so you can at least do it a bit more accurately but you shouldn't tamper with it and if that doesnt matter at least wait till you understand what your doing or you'll kill yourself taking whatever you may have made.

megalodon - 20-6-2013 at 16:28

That is indeed a different order. I was under the impression that Lilienthal's procedure was trying to condense the imine from the aldehyde and amine (the 30 minute wait after mixing the formalin and tryptamine) followed by the reduction of the imine with NaBH4. But perhaps a different order would work.

As soon as I have sufficient material to work up, I will try what you suggest. As it was, there was really no point, especially given major questions about whether the end product was even in the ballpark. You have my assurances that there will be no bioassay without purification and characterization.

I am going to take a STAB at other reducers next :)

sonogashira - 21-6-2013 at 02:37

Are you researching the synthesis of 5-(sulfamoylmethyl)indoles?

Furboffle - 21-6-2013 at 09:26

You are doing that but the thing other stuff is necessary to carry it out. The amine will join the aldehyde, but it pushes off the double bond. You left acid out which is necessary to go in and pull the water molecule off the alpha position. Which is what creates the imine. Then the reducing agent immediately goes in and reduces the double bond before ring closure will occur forming the beta-Carbolines. Not that it doesn't happen it should be a side product but it should be fairly low.

megalodon - 21-6-2013 at 13:17

@Furboffle: Lilienthal's procedure, which I replicated, did indeed leave out an acidification step. That is why I asked if it would really work as advertised.

@Songashira: Those aren't my target molecule, but they look pretty cool. I love the variety of structure that organic chemistry provides!

Nicodem - 22-6-2013 at 02:00

Quote: Originally posted by megalodon  
@Furboffle: Lilienthal's procedure, which I replicated, did indeed leave out an acidification step. That is why I asked if it would really work as advertised.

If you want anybody to take you seriously, the first thing you should do is stop spreading nonsense. That procedure for the methylation of holafébrine is not Lilienthal's! Why would you say that? Anybody can check the Rhodium archive page where it is correctly cited and see that you just made that up.

Also, why on earth would you want to apply that procedure on tryptamine when it is obvious that it is not suitable? Why that, instead of a procedure for the methylation of tryptamine itself? It appears to me that you didn't bother reading one single article on the topic. What's more disturbing, you didn't even bother to UTFSE before opening a topic that already exists.
Quote:
I'll keep reading.

You do that.

megalodon - 22-6-2013 at 05:59

Perhaps I haven't made myself quite clear. I was not looking to be tutored on ring closure. I was not looking for general techniques for methylating tryptamine.

I was interested in a specific procedure. There is nothing on the forum about this procedure. There are no confirmations or disconfirmations of the procedure to be found on google. So, no. No such thread appears to exist.

It was described, by Lilienthal, as "Voilà, here are the PTC-killer-reactions for (di-)methylation of tryptamines", and the literature cited for the procedure is radically different from the procedure, so it's not obvious to me where the procedure came from if it is not from Lilienthal. I am reading the full archives on the deep web, and it appears that Lilienthal had some criticisms of this method actually, so his name being stuck to it may indeed be incorrect, but my attribution was not 'nonsense'.

You are sanguine with your criticism, but a simple explanation of why the procedure is inappropriate is all that is necessary, yet is lacking.

Nicodem - 24-6-2013 at 00:50

Quote: Originally posted by megalodon  
Perhaps I haven't made myself quite clear. I was not looking to be tutored on ring closure. I was not looking for general techniques for methylating tryptamine.

Exactly and I did told you that there are plenty of examples of that. There might not be so many using NaBH4 on plain tryptamine, but there are several scientific and patent literature examples of triptan drugs synthesis using formaldehyde with NaBH4. There is even a thread on using in situ made STAB on this forum. That's why I asked you, why would you want to apply a procedure used on a robust aminosteroid like holafebrine by using it on something as prone to side reactions like tryptamine. It simply does not make sense. A synthetic chemist tries to use conditions best suited to the substrate and not conditions that already a 5 min theoretic consideration shows unsuitable.
Quote:
I was interested in a specific procedure. There is nothing on the forum about this procedure. There are no confirmations or disconfirmations of the procedure to be found on google. So, no. No such thread appears to exist.

But why would anybody want to methylate such a rare and obscure alkaloid like holafebrine? Perhaps it is perfectly normal that there is no confirmation of that procedure from any other source. Yet, this does not mean that Sondengam, Hémo and Charles lied.
Quote:
It was described, by Lilienthal, as "Voilà, here are the PTC-killer-reactions for (di-)methylation of tryptamines"

And voilà, he never claims a verification on tryptamine, does he? He only provides examples of dimethylation of three other primary amines he found in the literature and suggests these might be applicable on tryptamine. The idea that these procedures are about the methylation of tryptamine came from you, not Lilienthal. This is why it is so important to keep track of the references in science. If you lose the track, you can end up loosing track of what came from your mind, what came from someone else's mind, and what came from objective and reproducible experimental work.
Quote:
... and the literature cited for the procedure is radically different from the procedure, so it's not obvious to me where the procedure came from if it is not from Lilienthal.

You are correct about the cited literature, because that reference pointer has an error. The volume is not 3, but 14 (the issue is 3). The correct reference is:
B. L. Sondengam, J. Hentchoya Hémo, G. Charles, Tetrahedron Letters, 14, 1973, 261–263. DOI: 10.1016/S0040-4039(01)95635-7 (attached)
Quote:
I am reading the full archives on the deep web, and it appears that Lilienthal had some criticisms of this method actually, so his name being stuck to it may indeed be incorrect, but my attribution was not 'nonsense'.

The "nonsense" criticism was about your attribution of a published procedure for the methylation of holafebrine to Lilienthal. That was offensive and unfair, for he only did his best to help people like you. He certainly did not plagiarize anything, utmost he made an error in the reference format.
Quote:
You are sanguine with your criticism, but a simple explanation of why the procedure is inappropriate is all that is necessary, yet is lacking.

I did not answer directly, because there is no need for it. But I did direct you to a comparison with procedures developed specifically for the synthesis of N,N-dimethyltryptamine (or chose sumatriptan or related N,N-dimethyltryptamines, if you prefer). Compare them carefully, note the differences and think about it. With some basic synthetic chemistry knowledge you should figure out the critical reaction parameters by yourself.

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megalodon - 24-6-2013 at 09:08

Quote: Originally posted by Nicodem  
Quote: Originally posted by megalodon  
Perhaps I haven't made myself quite clear. I was not looking to be tutored on ring closure. I was not looking for general techniques for methylating tryptamine.

Exactly and I did told you that there are plenty of examples of that. There might not be so many using NaBH4 on plain tryptamine, but there are several scientific and patent literature examples of triptan drugs synthesis using formaldehyde with NaBH4. There is even a thread on using in situ made STAB on this forum.


Prior to posting, I conducted a google search and a forum search for various search terms, as well as read the entire commentary of other users who had similar interests. I had read turd's STAB article. Your response doesn't really make sense unless you missed the negation which I have highlighted.

Quote: Originally posted by Nicodem  
That's why I asked you, why would you want to apply a procedure used on a robust aminosteroid like holafebrine by using it on something as prone to side reactions like tryptamine. It simply does not make sense.


That was my mistake; I had not understood what holafebrine was. This was compounded by using unusual search engines which were swamped by references to the Rhodium posting. It was further compounded by not identifying the language in question: Google Translate identifies it as Welsh, but returns a vacuous translation (holafebrine). I had guessed German. However, if you read what is written, it says "holafébrine (primary amine)". Typically, when a foreign word is followed by parentheses, the words in parentheses are a translation. Thus, I believed that this was a proposed synthesis for methylating amines. I was incorrect, and I apologize for my mistake.
Quote:

Yet, this does not mean that Sondengam, Hémo and Charles lied.


No one claimed they did. Calm down.

Quote:

Quote:
It was described, by Lilienthal, as "Voilà, here are the PTC-killer-reactions for (di-)methylation of tryptamines"
And voilà, he never claims a verification on tryptamine, does he?


I treated this remark as referring to the set tryptamines, of which tryptamine is an element. This was influenced by the misunderstanding documented above.

As I believe I noted, I agree he never claimed verification. I could find no verification or disconfirmation whatsoever. So I provided it experimentally. The reason I did it was something that turd said when STAB was proposed, and then discarded on the basis of Pictect-Spengler. To paraphrase: "Perhaps in theory it wouldn't work, but in practice it does. The analytical data are unambiguous." I noted that the usual acidification step was missing, but who knew, maybe it would work. It didn't. Now we know. You're welcome :)
Quote:

The "nonsense" criticism was about your attribution of a published procedure for the methylation of holafebrine to Lilienthal. That was offensive and unfair, for he only did his best to help people like you. He certainly did not plagiarize anything, utmost he made an error in the reference format.


You are overreacting.
Quote:

You are correct about the cited literature, because that reference pointer has an error. The volume is not 3, but 14 (the issue is 3). The correct reference is: B. L. Sondengam, J. Hentchoya Hémo, G. Charles, Tetrahedron Letters, 14, 1973, 261–263. DOI: 10.1016/S0040-4039(01)95635-7 (attached)


Thank you! I will send Erowid a message; perhaps they can append the archive. I do feel you could have brought this up earlier rather than accusing me of intellectual laziness. As you note, incorrect attribution can lead to nasty misunderstandings.

The paper is in French, which in all fairness might lead some to quit reading even had they the correct citation. Fortunately there are tools like Google Translate which can help. :)