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Author Topic: Eschweiler-Clarke dimethylation of tryptamine  (Read 749 times)

Enkidu

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Re: Eschweiler-Clarke dimethylation of tryptamine
« Reply #20 on: June 23, 2011, 02:45:50 AM »
Quote from: Methansaeuretierchen on June 02, 2011, 01:02:50 AM
NaBH(CH3COO)3 or NaBH4/CH3COOH does also not work, because it does also reduce indole.
Source: Rhodium archive - several documents on triacetoxyborohydride and NabH4 in carboxylic acid media are mentioning reduction of indoles with it and some derivates.

This seems to be true. Interestingly enough, after the indole is reduced all the way to the indoline, TCCA at 0*C can probably oxidize the indoline back to indole (the tertiary amine in DMT will probably satisfy the need for TEA). See

Facile and Efficient One-Pot Synthesis of beta-Carbolines
Jian-Guo Tanga; Han Liu; Zhong-Yu Zhou; Ji-Kai Liu
Synthetic Communications Volume 40, Issue 10, 2010, Pages 1411 - 1417

A mild and efficient dehydrogenation of indolines
Ulf Tilstam, Michael Harre, Thilo Heckrodt and Hilmar Weinmann
Tetrahedron Letters Volume 42, Issue 32, 6 August 2001, Pages 5385-5387

Solid Phase Synthesis of ?- Carbolines.
Jing Xin ZHANG, Xiao Chuan TAN, Ping XIE
Chinese Chemical Letters 2000 Vol. 11, No. 11, pp. 955?956

antibody2

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Re: Eschweiler-Clarke dimethylation of tryptamine
« Reply #21 on: June 23, 2011, 03:43:06 PM »
Thanks for the refs Enkidu 8)

I've seen many of those NaBH(AcO)3 references Methansaeuretierchen is referring to, most or all of which stem from or cite Gribble. He is very spartan with the details of his reactions, in his reviews anyways. I did manage to track down one reference where he lifts his cards from his chest, a little. There is no experimental section, but some details are given below the tables. In the reductions where the indole is being reduced he is using HOAc as the solvent and reagent, and NaBH4 is added directly to the rxn, the indole already present, the STAB only being formed in situ. These conditions strike me as being much harsher than using THF as a solvent without an acid present.

I wonder if Indole would still get reduced by preformed STAB alone in THF at RT?
Is anyone aware of any way to test for the presence of indoline?

Reactions of Sodium Borohydride in Acidic Media. I.
Reduction of Indoles and Alkylation of Aromatic Amines
with Carboxylic Acids1
« Last Edit: June 23, 2011, 03:49:34 PM by antibody2 »

antibody2

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Retraction
« Reply #22 on: July 16, 2011, 04:55:10 PM »
Well after running a column on the product from this post (other ways of skiinning the cat) it would appear that it is not dmt. There were in fact two products that eluted (although showing one spot with 3:1 EtAcO:MeOH ; the 1st was a yellow oil that was not dmt (taste/smell), perhaps NMT. and the 2nd product that crystalized had a melting point much much higher than dmt > 100°C , likely tryptoline.

To be the sure, the rxn was run again and this time allowed to go to completion and the product was much purer, 100% what I believe to be tryptoline. It crystalized spontaneously in the flask and had a melting point well above 100°C. ( didn't melt on the water bath)

I am now convinced that Na(AcO)3BH proceedure on Erowid is bullroar :-\. It has been run a half dozen times and the best yield was 15%. I've spoken with others and their experience parallels my own.

 damn, sorry if I got anyones hopes up . . . NEXT!

akcom

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Re: Eschweiler-Clarke dimethylation of tryptamine
« Reply #23 on: July 20, 2011, 12:21:23 AM »
Quote
Interestingly when the STAB reduction was run in dry THF it was a very lively rxn, lots of foaming and bubbling, fun to watch. But as soon as the aqueous HCHO was added the rxn dies immediately. But it didn't matter because a large enough XS of paraformaldehyde was used in the 1st step that the rxn has mostly gone to completion before the addition of the aqueous HCHO.
I'm not quite understanding you here.  As I understand it you're isolating a crystalline (or is it an oil?) imine, then adding it to a solution of STAB in THF.  What purpose does adding the excess aq. formaldehyde serve?  If you could post your notes for this procedure (molar ratios, etc) that'd be awesome :)

edit: Should have read the STAB paper first.  I see now that it selectively reduces imines, but if you're isolating the imine from anhydrous alcohol by azeotropic distillation, you should obtain 100% conversion, negating the need to add aq. formaldehyde
« Last Edit: July 20, 2011, 12:37:25 AM by akcom »

akcom

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Re: Eschweiler-Clarke dimethylation of tryptamine
« Reply #24 on: July 20, 2011, 12:53:10 AM »
Heres a good paper on reductive amination with STAB

edit: I didn't see your comment above AB2, oh well.  It was nice while it lasted :)

A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff, R. D. Shah
Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures
 J. Org. Chem., 1996, 61, 3849-3862 DOI: 10.1021/jo960057x
Quote
Sodium triacetoxyborohydride is a general, mild, and selective reducing agent for the reductive amination of various aldehydes and ketones. 1,2-Dichloroethane (DCE) is the preferred reaction solvent, but reactions can also be carried out in tetrahydrofuran and occasionally in acetonitrile. Acetic acid may be used as catalyst with ketone reactions. Acid sensitive functional groups such as acetals and ketals, and reducible functional groups such as C-C multiple bonds and cyano and nitro groups are tolerated.
« Last Edit: July 20, 2011, 02:04:04 AM by Enkidu »

antibody2

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Re: Eschweiler-Clarke dimethylation of tryptamine
« Reply #25 on: July 22, 2011, 02:12:57 PM »
Thanks for the paper akcom. I've seen that one before. I'll try and find and post the details of the rxns I've triied, so folks will at least know what isn't working.

Dr.Methoxy

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Re: Eschweiler-Clarke dimethylation of tryptamine
« Reply #26 on: August 03, 2011, 12:54:37 AM »
Quote from: Methansaeuretierchen on June 02, 2011, 01:02:50 AM

NaBH(CH3COO)3 or NaBH4/CH3COOH does also not work, because it does also reduce indole.
Source: Rhodium archive - several documents on triacetoxyborohydride and NabH4 in carboxylic acid media are mentioning reduction of indoles with it and some derivates.
There are some other reciepes on the in the internet, where this is used to make DMT from tryptamine and aq. Formaldehyde. I think it's pure a fake. Triacetoxyborohydride is very sensitive to water and does reduce indole - no big chance to work under the mentioned conditions (RT, THF, excess CH3COOH as solvent).


Are you sure what you are claiming. I don't see why triacetoxyborohydride, a milder reagent can reduces the indone 1,2-double bond and not the NaBH4. The paper you saw that was talking about reduction with NaBH4 using acetic acid as solvent, isn't it?

Tryptamine can be dimethylated with huge eq. of aqueous formaldehyde and NaBH4 water solution. I suggest :
Add 1/5 of the formaldehyde (12 eq in total) on a tryptamine/methanol solution. Wait 30 min. Start adding dropwise the NaBH4 solution AND the rest of the formaldehyde.

Amines can also be dimethylated with Zn and aqueous formaldeyde in dioxane or water. Methanol can probably used instead of dioxane. To be tested....

Bluebottle

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Re: Eschweiler-Clarke dimethylation of tryptamine
« Reply #27 on: August 03, 2011, 02:00:22 AM »
http://www.sciencedirect.com/science/article/pii/S0040403998019042

Don't forget some base to shift the equilibrium; low pH does seem to provoke PS cyclization. It would make sense to use a great excess of zinc too.
"And now we divide both sides by zero..."

Enkidu

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Re: Eschweiler-Clarke dimethylation of tryptamine
« Reply #28 on: August 03, 2011, 07:14:43 AM »
Again. The problem is the iminium intermidiate

letters

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Re: Eschweiler-Clarke dimethylation of tryptamine
« Reply #29 on: August 03, 2011, 01:23:40 PM »
just thought id tease you guys with some synthetic spice porn, to encourage and motivate :)

-vanadium-

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Re: Eschweiler-Clarke dimethylation of tryptamine
« Reply #30 on: August 09, 2011, 12:07:00 PM »
Quote from: reckless on August 03, 2011, 12:23:15 PM
NaH2PO4,Zn, HCHO

Ok that could work but the problem is the solubility of the tryptamine. We may use dioxane as the solvent but NaH2PO4 is probably insoluble in dioxane...

Does anybody know the conditions for the cyclisation of the tryptamine ? Does it happend with diluted acetic acid at RT ?

We can dissolve tryptamine*HCl in a pH 4-5 buffer then add the formalin and reduce with Zn ? What do you think about that ?
« Last Edit: August 09, 2011, 12:12:48 PM by -vanadium- »

Enkidu

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Re: Eschweiler-Clarke dimethylation of tryptamine
« Reply #31 on: August 09, 2011, 11:20:47 PM »
Quote from: reckless on August 09, 2011, 07:06:04 PM
Why not dimethylate tryptophan and then decarboxylate?

Supposedly, N,N-dialkyl amino acids don't decarboxylate easily

Enkidu

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Re: Eschweiler-Clarke dimethylation of tryptamine
« Reply #32 on: August 23, 2011, 04:55:43 AM »
Oxidative decarboxylation is different than thermal decarboxylation. Different products and different mechanisms. Anyway, post a real citation e.i., journal (vol)iss pp.xxx-xxx or preferably a doi.
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