Melatonin->5-MeO-MET

[mocket]

I just wondered if people had any opinion on the prospect of reacting melatonin with paraformaldehyde then reducing with borohydride to produce 5-methoxy Methyl Ethyl Tryptamine.
The only downside is that 5MeO DET produces strangely negative effects. I THINK the M,E is the most powerful substituent for tryptamines, so it's a possible good thing...

Anyone?

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Mocket I Zulu :-)

[smiley_boy]

Its worth a try, though 5-MeO-MET (CAS # [16977-53-0] for the freebase, CAS # [74217-55-3] for the hydrochloride salt, and CAS # [19446-11-8] for the oxalate salt) doesn't seem to have much data published on it, as far as Shulgin-style human trials go.

BTW, it also goes by the abreviation "9CI".

'verdant'

twitchin' the night away...

[mocket]

I wonder if I should first reduce the melatonin to 5MeO ET using something like DiBAlH and go from there. I think that there may be more options to methylate the Ethyl amine (and will that not add a little stearic hinderence to prevent quats?)
 Also, if I have 5-OH tryptophan, is decarboxylation possible, or will the OH be affected? I ask since I imagine that (CH3)2SO4 + 5-OH typtamine would go right to 5MeO...?

_{Mocket I zulu ;-)}

[smiley_boy]

DiBALH is an excellent reducing agent; stylish, elegant and high-yielding. It has the reducing power to take off aromatic halides, reduce amides, but its steric hindrance lends itself to a great deal of selectivity (thus, it can reduce a relatively unhindered amide like melatonin, but would leave the amide moiety on something like bol-148 alone.) Its not necessarily the easiest thing to come by, but the restrictions on it are far fewer than, say, LiAlH₄.

Still though, LiAlH₄ gets the job done. If you've got the connections and guts to order it, its cheap, a little goes a long way, and its something that every formally-trained chemist has worked with at least a couple times. People generally understand how to work with it in a bench-scale situation.

Other relatively common reducing agents worth mentioning include RED-AL (all the power of LiAlH₄, now in a liquid form), NaBH₄ with an appropriate transition metal catalyst, or hydrogen gas using a catalyst like Pt or Rh.

The ethyl will add some steric hindrance, but not much.

5-HTP can be decarboxylated just fine, using heat and a ketone catalyst; that phenolic oxygen should behave jsut fine. The one drawback is that 5-hydroxy-T is not going to lend itself as easily to vacuum distillation as T does. Really, I don't know why anything would ever posses you to want to make 5-MeO-DMT.    

As far as dimethylation goes, overalkylated product can be readily dequaternized by refluxing in a little ethanolamine.

Me feelin' irie...  

twitchin' the night away...

[pulp]

smiley_boy, do you have any practical details or literature references for that dequaternization of overalkylated T with ethanolamine? thanks...

[foxy2]

pulp
THINK Shulgin

[smiley_boy]

Pulp,

Yes, take a look through TiHKAL. Look at #6 (DMT) and  #46 (5-MES-DMT) (among other things.)

The DMT entry is a fine list of the most practical procedures for dequaternization. The possibilities seem to fall into three categories:  demethylation by brute force via pyrolysis, reduction with a strongly nucleophilic reducing agent, and treating the quat salt with a strong nucleophile (and a little heat.)

Pyrolysis is used by Shulgin in TiHKAL#6, but also (among other places): Org RxN's 7, 142; 1953 (Review), and
Org RxN's 11, 317; 1960 (another review).

For reducing reagents, the extremely nucleophilic reagent LiEt₃BH ("Superhydride(R)") has been demonstrated by Shulgin in his DMT entry, and it makes perfect sense that it would be the reducing agent of choice for this situation. Also, LiAlH₄ has been used, such as in the case of Bull. Korean Chem. Soc., 20(4), 466-468;  1999, and J. Am. Chem. Soc. 82, 4651; 1960, and J. Chem. Soc. 1729; 1965. Lithium metal is used in C. R. Acad. Sci., Ser. II:  Mec., Phys., Chim., Astron., 320(10), 539-43;  1995.

As for examples of strong base, there's the refrences from TiHKAL listed, as well as J.Labelled Compd.Radiopharm. 41(12), 1127 - 1144; 1998 -- where 1,4-diazabicyclo[2.2.2]octane (a.k.a. Dabco(tm), TED, triethylenediamine) is used with great success, and again in J. Org. Chem., 50(25), 5440-1;  1985. Triethylamine is also used in Collect. Czech. Chem. Commun., 50(6), 1415-21;  1985. Sodium thiophenol is used in J. Chem. Soc. 1729; 1965, and Tet. Lett. 1375; 1966, and Hoppe-Seyler's Z.Physiol.Chem. 352, 1058-1064; 1971. The classic example of ethanolamine being used in this manner is Ber. 90, 395, 403; 1957.

Yet another approach is to treat the quaternary amine as a leaving group, and replace it with another dialkyated amine. This is nice since you can use your quaternary salt to make whatever disulstituted tryptamine you want! Here are a few references on that topic:

J. Fluorine Chem., 90(1), 29-38;  1998
Chem. Lett., (9), 893-894;  1997
J. Org. Chem., 61(10), 3228-9;  1996
Tetrahedron Lett., 36(40), 7267-70;  1995
Synlett, (5), 353-4;  1993

I hope you enjoy.

"Freebase emulsions: spot on!"

[pulp]

foxy2 and smiley_boy, thanks for your advice. Smiley_boy, very useful references, I've got some reading to do!

[mocket]

Hi,
   Well, that seems fairly detailed. So we agree that quat's are not such a problem. Now, I will have to go find some reference ;-) I'm no rocket scientist, but it looks good to me.
 Now, not wishing to keep asking dumb questions, but if SWIM was interested in the di-isopropyl varient, would IPI be the route? SWIM told me that elimination can be a problem, but I have no reference myself. My feeling is that reducing the amide to make 5MeO-ET and then going from there may be a good move. Wonder what Ethyl, Isopropyl is like...

_{mocket I zulu ;-) sez 'smoke thalidomide, not emulsion'}

[smiley_boy]

Hey there,

Elimination a problem? Well, I could see that if you're talking about a triisopropyltryptamine quaternary salt -- that might take a little more work, but that's the only what I could make sense of the concern for elimination.

Really, Sn2 alkylation of mexamine with isopropyl iodide looks pretty good - the isopropyl groups' steric hindrace keeps overalkylation from being too much of a problem (though perhaps getting that second group on there will be a bit harder.). At the same time, reductive amination looks quite good as well -- little to no risk of side reactions, its quick, and the conditions are easy. My gut reaction would certainly be reductive amination, since Shulgin's route, albeit easy, is rather low-yielding (though there's no indication that any attempt was made to improve yields, and ther are certainly other choices of solvents, reaction temperatures, and bases, that could/would dramatically affect the yield of this reaction.) Certainly an arguement could be made either way.

As far as reducing an acetamide, I'd go with a strong reducing agent like LAH or vitride (the classics), and really, you can alkylate either way. Check out  J.Labelled Compd.Radiopharm. 41(7) 585 - 594; 1998. This is a nice example of a methylation (albeit not the best yields) of a secondary tryptamine. Like you said before, the ethyl will add *a little* steric hindrance, and dequaternization shouldn't be a reall problem. Otherwise, Shulgin's classic paper J.Med.Chem. 28(7) 892-896; 1985, is a nice reductive amination of a methyl tryptamine with acetone, using catalytic hydrogenation -- its definately worth having, and undoubtably is in the collection of any hard-core Shulgin fan.

-I'm a monsta'!

[Lilienthal]

Overalkylation to tri-isopropyl-tryptamine quaternary salt is impossible under usual reaction conditions.

I think the 'elimination problem' is the HI elimination from isopropyl iodide in the presence of a base (even the tryptamine) at higher temperatures.

If I remember it right the Shulgin reaction was in an alcoholic solvent with a carbonate base - somewhat strange conditions because an alkyl iodide may not be stable under these conditions (as indicated by the poor yields).

A polar aprotic solvent would be better (DMF, acetonitrile). Since the base is needed only as an acid scavenger it can be substituted with other bases (e.g. the sterically hindered ethyldiisopropylamine). Carbonates must be used in a molar excess with good strirring to prevent the formation of water / OH- which would destroy the iodide.

Reductions of amides to primary or secondary tryptamines usually gave low yields and much byproduct in ether, THF, or a mixture of both (maybe due to solubility problems).

[Lilienthal]

And please remember (mocket):
Tryptamines + aldehydes / ketones + H+ --> beta-carbolines (Pictet-Spengler reaction).
That's the reason why reductive aminations are problematic and always give beta-carbolines, at least as a byproduct.

[mocket]

Hi,
   Sorry, HI elimination was the problem I refered to. Should have been clearer on that one! It seems, to this bee, that SWIM would do better to hydrolize the melatonin and apply the appropriate alkyl iodide.
 I seem to remember a paper concerning the melatonin extracted from coffee-wax. In this, they use NaOH + Na2S2O4 to preform the reaction. SWIM tells me that the Na2S2O4 prevents oxidation (which makes sense). Has anyone got a practical procedure for melatonin->5MeO Tryptamine?

Sorry for all these questions!

_{If I can't make it then I don't take it...}

[smiley_boy]

Yes, if hydrolysis of the alkyl iodide is the 'HI elimination' concern you were referring to, then it makes a lot more sense. Hydrolysis can occur, as our Austrian friend suggests, and it is base-catalyzed, promoted by higer temperatures and protic solvent systems (i.e. you need a source for water in the system to balance that equation.)

Actually, Shulgin uses sulfolane (tetramethylenesulfoxide) as his choice of solvent - a solvent with an extremely high pKa, but still with a strongly polar character (qualities lending themselves to the promotion of the Sn2 reaction mechanism.)

His choice of diisopropylethylamine as the proton scavenger is based on procedure developed elsewhere (I've seen it before, but I can't remember exactly which article; oh well, I'm sure its sitting in my notes somewhere.) Yes, undoubtedly its strongly nucleophilic nature combined with its steric hindrance makes it a nice choice, though it begs the question: why not use a stronger, even more basic amine like triethylenediamine instead? It also begs the question: since we're not talking about  a highly protic system, and the base used is even more sterically hindered than any of the intermediates, there aren't many obvious side-reactions that may occur -- so how does one account for the dismal yields? Since (as far as I can see) there is no offical, peer-reviewed published account in the literature of the synthesis of 5-MeODiPT, it makes it difficult to speculate as to what went on. Hmm...

The reason for bisulfite in there is not necessarily for prevention of oxidation. Actually, my guess is its acting as a protecting group. Bisulfite adds across the 2,3-double bond, resulting in an indoline sodium sulfonate salt complex, which prevents any non-reversible additions from occuring across the [temporarily defunct] 2,3-double bond; this same trick is used with indole when preparing 5-bromoindole. Just a guess.

Still though, one could alkylate melatonin, then reduce the amine. Amides are much more protic than amines, and there are numerous examples in the literature taking advantage of this in selecting reaction conditions (a deprotonated nitrogen is a stronger nucleophile than a protonated one, though certainly an adjacent carbonyl will lower electron density.)

Lilienthal,

Amide reduction gives low yields? Have you had direct experience with this, or are you referring to this literature? If so, where?

The solubity hypothesis sounds very plausible. Yes, melatonin is not always the most easy thing to dissolve, but it can be done. Its somewhat soluble in ethanol, and can be recystalized in benzene. Its not too soluble in acetone or ether, and I wouldn't be surpised if that were the case with THF, too. My guess is that another reducing agent and solvent system would be in order: since melatonin apparently is soluble in benzene, it seems a more reasonable choice of reducing agent would be vitride.

[smiley_boy]

Let's not entirely discount reductive amination as a viable synthetic procedure here. There are numerous examples in the literature of heteroaromatic ethylamines, including tryptamines, being alkylated in respectable yields. Yes, cyclization is a side reaction that may occur, but conditions can be modified to minimize this competing reaction.

Truth be told, I am partial to alkylation via nucleophilic substitution-elimination, but considering some of the successes that reductive amination has had, its worth at least considering.

[cilliersb]

Yip, Mocket.
You can Find the Synth on Rhodium's site. It utilizes Sodium Dithionite in isobutanol. A very simple procedure if you have Glassware.

[fitzhugh_ludlow]

A coup;e of q's about this.  Is the nitrogen atmosphere needed?
How do you accomplish that, glove box, or just a stream into the vessel?

Is Sodium Dithionite suspect at all?  Any common uses?

[Rhodium]

The nitrogen atmosphere is not required, it just prevents atmospherical oxygen from oxidizing the tryptamine unneccessarily - your yield will not drop with more than at most 5% without it. If you choose to use it, just blow a slow stream through the reflux apparatus during the reaction.

Sodium Dithionite is completely unsuspicious.

[pHarmacist]

Why is it a such a hassle for certain ppl when a reaction requires N2 atmosphere, simply use He, it's a noblegas as inert as N2 and can be found in baloons that kids play with. Use it. But sice its very light, it will escape the system easily, so you must have a continuus He-flow during the reaction...

"Turn on, Tune in and Drop Out"

[fitzhugh_ludlow]

Helium sounds good.  I can make funny voices too  
Found Sodium Dithionite ( AKA sodium hydrosulfite) OTC. It is  mixed only with sodium carbonate.
Can isopropanol be used instead of isobutanol?  Or some other solvent?