Eschweiler-Clarke dimethylation of tryptamine

[Locked]

1mol tryptamine
5mol 88-90%formic
2.2mol formaldehyde

Almost straight from page 323 of organic reactions 5. Is there any reason to believe that this wont work?

The indole nitrogen should be resistive to this reaction, I think. Any collective wisdom on this?

[timecube]

I thought Pictet-Spengler Cyclization was the main problem?

http://pubs.acs.org/doi/abs/10.1021/jo01018a011

[Vesp]

yep, and I believe that a decent amount of discussion has gone on about this -- though, perhaps not about exactly the same thing -- hopefully you can find some of the stuff on the board. If so, feel free to link it here.

[Naf1]

here is a quote from zz-zhuchila;

"I don't know concerning oxylic acid/formaldehyde, but eshweiler-clark methylation (CH2O + HCOOH), is not applicable to tryptamines as it would produce a carboline derivative(-CH2- making a cycle between tryptmine nitrogen and position 2 of indole). That i have read on some drug forum, not though sure about that.."

[Locked]

Thanks everyone.

I guess there is always platinum oxide, hydrogen and formaldehyde. Or Shulgin's diformyl route. Or practice the new school acid tech with coupling reagents and dimethylamine(EDIT2->for clarity, from 3-Indoleacetaldehyde, which could be used with other reducing agents as well).

Shulgin's looks the least pleasing.

EDIT->http://127.0.0.1/talk/index.php/topic,380.0.html

http://127.0.0.1/talk/index.php/topic,680.0.html

EDIT3->or with the alcohol, not aldehyde. The aldehyde can be used with other reductions.

EDIT4->tryptophan to alcohol + tosyl chloride then dimethylamine in triethylamine looks slick and high yielding. Cheap-ish, too.

[Locked]

I am retarded. Sorry about edit 2.

Anyway, this would be an awesome practice for the big acid game by using the coupling reagents on indole acetic acid. One reduction from glory!

EDITSOMEMORE->Yeah, just nix all 2-4 because the reduction of the ester of IAA doesn't seem like fun to get indole 3 ethanol. Anyone know the yeast tech for doing that? Seems cooler then hydrides or sodium metal.

ANDMORE->Could Indoleacetic acid be run one pot in a hydrogenator with dimethylamine and Pt? Otherwise, the tryptophan decarb->tryptamine Frifelder Pt C=O->DMT seems like the cheapest, easiest, (depending on decarb tech)highest yielding route.

[timecube]

I would think that indole-3-acetaldehyde and dimethylamine could be used in place of P2P and methylamine in a Hg/Al amalgam reduction and proceed in a similar way.  The amalgam would reduce the enamine into the amine and remove water to shift the equilibrium favorably.  The quantities and conditions needed would of course take some trial and error.

[Sedit]

I would worry that it might start reducing the indole as well.

[Locked]

Yeah, Sedit, I'm still worried that Pt will reduce the indole double before the formaldehyde alkalation, too.

So we are down to indole-3-ethanol and tosyl chloride with dimethylamine... Yeah, otc at wallmart...

EDIT->and that might not even work unless one adds pyridine to complex the tosylchloride. Otherwise, I fear for the indole N. I don't know...

[Sedit]

I jutthink more focus should be brought on protection of the nitrogen indole and it will save all the hassles people have looking for a direct root that won't mess with the indole.

[Enkidu]

Supposedly Al/Hg works on indolic substrates, but I haven't seen any experimental data.

[Locked]

Actually, p-Toluenesulfonyl chloride is freakin perfect! Battle ones way to tryptophol(3-indole ethanol) then cheap as shit tosyl both the alcohol and the indole nitrogen. Dimethyl amine will not swap with it there, only the alcohol. Then zinc and hcl? That is if the tertiary amine doesn't do something funky.

3-indole ethanol has options, but tryptamine and protecting groups? Both are n...

Or am I missing an easy one from tryptophan?

[timecube]

I would worry that it might start reducing the indole as well.

Supposedly Al/Hg works on indolic substrates, but I haven't seen any experimental data.

Shulgin uses both Al/Hg and catalytic hydrogenation to form alpha,N-dimethyl-T from indole-3-acetone and MeNH2 without any apparent issues, although I'm not sure how the enamine will compete with the indole double bond.

http://www.erowid.org/library/books_online/tihkal/tihkal08.shtml

[Enkidu]

then cheap as shit tosyl both the alcohol and the indole nitrogen.

tosyl chloride will not react with the indolic nitrogen, unless it is first deprotonated with a strong base.

[Locked]

Then tosyl chloride and trophanol is a winner, I hope. Seems cool at least. Some note dropper might take a swing at it soon.

EDIT->The palladium on carbon can run with the same hydrogenator, just after perfecting adam's cat, like hell I want to go messing about with making another with a different $ metal. Also Shulgin states shit yields which would probably get even more shit with dimethylamine, but who knows what level of water removal or tech he used. That description in tihkal is lacking and there are a lot of variations.

[Bluebottle]

Also, just a side thought, the dihydrotryptamine could be useful, as if the indole ring were no longer aromatic, there would be no cyclisation, and the EC dimethylation would progress smoothly (or other aldehydes/ketones, like acetone, although steric hindrance might get in the way of that, I remember having read a paper on that, doesn't seem too bad) . The dihydrodialkyltryptamine could then be oxidised with MnO2 as in Rebek's lysergic acid synthesis.

edit - steric hindrance

[Methansaeuretierchen]

Eschweiler-Clarke does not work at all. Picted-Spengler would be the main-reaction.

Also Al/Hg does not work (or with ~20% yields). The indole gets reduced.
Source: Somewhere in Tihkal I think.

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).

BH3*THF or NaBH4/H2SO4 or NaBH4/I2
Does also not work. The indole gets also reduced very fast under normal conditions.

NaBH4/MeOH . Does work (!!!), but does reduce aldehydes faster than imines/enamines form. It has to be very cold and a large excess of NaBH4 and aldehyde are neccessary. For DET it may work good because ethanal seems to get reduced slower than formaldehyde. See http://127.0.0.1/talk/index.php/topic,1600.0.html somewhere near the end of the topic.

Pd/C. Does also work. But needs high pressure of H2. Does sometimes overdo it's job when the catalyst is too strong.
Source: Tihkal

Reduction agent of choice: Sodium cyaboborohydride.
Source: Rhodium archive

Untested by me but very interesting: Zinc borohydride, potassium borohydride and Zn/NaH2PO4
Zincb orohydride because it's known to perfom very well for dialkylations of amines, potassium borohydride because it less active and smoother than NaBH4 and Zn/NaH2PO4 because it's known to alkylate amino acids and alkylamines in high yields.

Zn/NaH2PO4 and formaldehyde does also work for tryptophane.... but dimethyltryptophane is very hard to ripped of CO2 and extremely toxic. Try it yourseld.

[Enkidu]

Also Al/Hg does not work (or with ~20% yields). The indole gets reduced.
Source: Somewhere in Tihkal I think.

I am quite interested in seeing the reference, because I have wondered about that many times. According to Posideon at TC, an aluminum amalgum will not reduce the indole. I also did research and I believe that I came to the conclusion that it would not reduce the indole, but of course, I could be wrong.

[antibody2]

According to this paper, sodium cyanoborohydride is NOT the method of choice, it results in a complex mixtures of products that are difficult to separate. Not to mention having cyanide in your waste steam.  It also states that use of aqueous HCHO and NaBH4 results in beta Carbolines as the major product.

"Characterization of the synthesis of N,N-dimethyltryptamine by reductive amination using gas chromatography ion trap mass spectrometry.
Brandt SD, Moore SA, Freeman S, Kanu AB.
Source
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK. s.brandt@ljmu.ac.uk

There are literature references for alkylations using STAB with aqueous HCHO that claim high yields. I've attached that paper by Magid. However Antibody has been unable to reproduce the yields claimed (87%) with STAB and aqueous HCHO even using a large XS of STAB. Turd over at Science Madness is also mentioned having a hard time reproducing those yields. We're both getting yeilds in the 15-25% range.

So Antibody agrees, the post on the internet claiming STAB yields with aqueous HCHO of 87% is either incorrect or missing details.

Another experiment where the imine was formed in anhydrous EtOH with paraformaldhyde first, then isolated, and reduced with STAB in dry THF, then followed by the addition of aqueous HCHO, worked much much better. The resulting product had one spot on EtAcO/MeOH/NH4OH TLC with an rf (rf 0.5) identical to DMT extracted from MHRB, visulaized using Ehlrich reagent. When Antibody has had a chance to run a column on the product and do a bioassay she will post a full write-up. But get this, the product is crystalizing ON ITS OWN!!!!

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.

@ Enkidu - I've also attached a paper where a similar compound is reduced using activated Al, see example 3

[antibody2]

Here is the abstarct from the 1st ref in my pervious post

Abstract
The present study established an impurity profile of a synthetic route to the hallucinogenic N,N-dimethyltryptamine (DMT). The synthesis was carried out under reductive amination conditions between tryptamine and aqueous formaldehyde in the presence of acetic acid followed by reduction with sodium cyanoborohydride. Analytical characterization of this synthetic route was carried out by gas chromatography ion trap mass spectrometry using electron- and chemical-ionization modes. Methanol was employed as a liquid CI reagent and the impact of stoichiometric modifications on side-products formation was also investigated. Tryptamine 1, DMT 2, 2-methyltetrahydro-?-carboline (2-Me-THBC, 3), N-methyl-N-cyanomethyltryptamine (MCMT, 4), N-methyltryptamine (NMT, 5), 2-cyanomethyl-tetrahydro-?-carboline (2-CM-THBC, 6) and tetrahydro-?-carboline (THBC, 7) have been detected under a variety of conditions. Replacement of formaldehyde solution with paraformaldehyde resulted in incomplete conversion of the starting material whereas a similar replacement of sodium cyanoborohydride with sodium borohydride almost exclusively produced THBC instead of the expected DMT. Compounds 1 to 7 were quantified and the limits of detection were 28.4, 87.7, 21.5, 23.4, 41.1, 36.6, and 34.9 ng mL(-1), respectively. The limits of quantification for compounds 1 to 7 were 32.4, 88.3, 25.4, 24.6, 41.4, 39.9, and 37.0 µg mL(-1), respectively. Linearity was observed in the range of 20.8-980 µg mL(-1) with correlation coefficients > 0.99. The application holds great promise in the area of forensic chemistry where development of reliable analytical methods for the detection, identification, and quantification of DMT are crucial and also in pharmaceutical analysis where DMT might be prepared for use in human clinical studies.