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Author Topic: Reductive Methylation of Primary Amines  (Read 703 times)

jon

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Re: Reductive Methylation of Primary Amines
« Reply #20 on: April 08, 2011, 11:57:49 PM »
or you can just dean stark the whole mess mebbe not.
you said reflux was a bad idea (puts foot in mouth)
« Last Edit: April 09, 2011, 12:00:08 AM by jon »

myCH3

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Re: Reductive Methylation of Primary Amines
« Reply #21 on: February 14, 2012, 12:37:11 AM »
Quote from: atara on April 08, 2011, 12:14:04 AM
It's an electrophile strength thing, I believe. IIRC:

Chloroiminium (Vilsmeier complex) > acyl chloride > iminium > aldehyde > aldimine > alkyl halide > ketone > imine

Under acidic / high temperature conditions protonation of the iminium allows it to attack the highly activated 2-position on indole. I'm not sure if a low temperature reaction will provoke a Pictet-Spengler cyclization; I'm aware it happens at reflux. The Eschweieler-Clarke reaction requires high temperatures to proceed and so it's out but novel reductants could work (even in acid) if they can reduce imines at low temperatures.

Zinc ions are Lewis acids which catalyze the alkylation of aromatic rings and so naturally a zinc-based reducing agent would probably be an issue.

So your saying hxxps://www.erowid.org/archive/rhodium/chemistry/n-methylation.zn-borohydride.html this would cause pictet-spengler cyclization to occur?  what about the experimental on the bottom of this page  hxxps://www.erowid.org/archive/rhodium/chemistry/tryptamine2dmt.html in Lilienthal's Voice. 

akcom

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Re: Reductive Methylation of Primary Amines
« Reply #22 on: February 21, 2012, 02:54:05 AM »
myCH3, the experiment on the bottom of the page does not specify tryptamine (except in the hive author's annotation, not experimental).  tryptamine will most definitely undergo pictet spangler cyclization.

myCH3

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Re: Reductive Methylation of Primary Amines
« Reply #23 on: February 21, 2012, 05:59:21 AM »
I had a feeling it was to good to be true thank you.  Trying to understand does pictet-spengler occur anytime the imine forms? or just in acidic and/or heat conditions?

akcom

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Re: Reductive Methylation of Primary Amines
« Reply #24 on: February 24, 2012, 12:42:20 AM »
There are room temperature examples of the indole pictet spengler reactions.  Water is acidic enough to catalyze the reaction, although I don't know about the rate.

myCH3

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Re: Reductive Methylation of Primary Amines
« Reply #25 on: February 21, 2013, 06:37:34 PM »
I know I am a little late in time, but I don't quite have the privilege of having journal access would someone be kind enough to upload it? 

Quote from: atara on April 06, 2011, 10:44:02 PM
It's kind of scary, but my guess would be a Strecker-type reaction with formaldehyde and sodium cyanide, followed by a reductive decyanation. Cyclisation is impeded by the fact that the imine will react with cyanide faster than it will cyclize.

Alternatively...

People have talked a lot about using ethanolamine to demethylate the trimethyltryptammonium salt. Why not do this backwards, using tetramethylammonium salts, or the tetramethylammonium precursor trimethylglycine, to methylate tryptamine? Here's a paper that says it should be possible, and in water no less!

http://pubs.acs.org/doi/abs/10.1021/ja021212u

akcom

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Re: Reductive Methylation of Primary Amines
« Reply #26 on: February 21, 2013, 08:36:15 PM »
Title: Migration of Methyl Groups between Aliphatic Amines in Water
Author: Brian P. Callahan and Richard Wolfenden*
Journal: J. AM. CHEM. SOC. 2003, 125, 310-311
DOI: 10.1021/ja021212u


I thought Shulgins procedure for demethylation of the quaternary ammonium salt was interesting.  He uses thiophenol, the procedure is found in his synthesis of 5-MeO-DALT

fishinabottle

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Re: Reductive Methylation of Primary Amines
« Reply #27 on: February 21, 2013, 11:47:00 PM »
Now thats me something interesting this article, no doubt....

Makes me wonder what other chunks might be prone to migration and think on the astonishing consequences coming out of it.

Water confined at over 220°C was what made me doubt the practicability but a quick search told me that this resolves to about 27 bar pressure, whats still just elevated pressure by definition and not too far out to handle either.

thx for this
/ORG 

Electro´S

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Re: Reductive Methylation of Primary Amines
« Reply #28 on: February 22, 2013, 05:45:24 AM »
Thanks for your Post  Antibody2!!! I hope dream something like this some day...

Here is the workup from erowid with Formaldehyde and STAB.

General procedure:

To a stirring solution of tryptamine free base (1.0g, 6.24mmol, 1eq) in THF (30ml) at room temperature were added sodium triacetoxyborohydride (5.29g ,24.96mmol, 4eq) and glacial (17M) acetic acid (0.71ml, 0.75g, 12.48mmol, 2eq). After most of the borohydride was dissolved, 37% formaldehyde aqueous solution (2.5ml ,2.53g, 31.20 mmol) was added dropwise via a syringe. Stirring was continued for 2h and LC-MS (3min) showed complete conversion of starting material (peak @ 0.94min, M+=161) to product (peak @1.01 min, M+=189). Work up proceded as described above. Column (DCM with MeOH gradient of 5 to 10% with a few drops of 5M ammonia in methanol) gave 1.05g (89%) of a white crystalline solid (DMT).

Sounds easy! and better with tryptamine 98% at less 2$ /g.

Assyl Fartrate

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Re: Reductive Methylation of Primary Amines
« Reply #29 on: February 23, 2013, 07:45:13 PM »
Under what conditions? The Birch also reduces the aromatic ring on amphetamines. It's all a matter of rates. A STAB procedure doesn't strike Assyl as "bullshit."
Someone Who Is Me

Assyl Fartrate

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Re: Reductive Methylation of Primary Amines
« Reply #30 on: February 24, 2013, 11:44:30 PM »
Can you provide the journal reference from the book? Perhaps there are some inductive effects from the carbonyls swinging around, driving the reduction forward more than would be thought obvious.
Someone Who Is Me

Assyl Fartrate

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Re: Reductive Methylation of Primary Amines
« Reply #31 on: February 25, 2013, 06:56:38 AM »
Not talking about the article itself, just the reference, so that it may be requested. Who/what does the book cite?
Someone Who Is Me

antibody2

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Re: Reductive Methylation of Primary Amines
« Reply #32 on: February 26, 2013, 05:47:18 AM »
Sorry. For what it is worth Ab2 subsequent experiments with STAB were not successful :-[  a variety of conditions were attempted, all resulting in a product that would not crystallize, was not active and was assumed to be an indoline.

Polonium

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Re: Reductive Methylation of Primary Amines
« Reply #33 on: February 26, 2013, 04:14:36 PM »
Thanks for chipping in to clarify AB2. That's a real shame but hopefully it saves someone some frustration and time. I guess we still don't / probably will never have a direct way of dimethylating tryptamine while avoiding Pictet-Spengler. Is the guy on Erowid just completely making it up, I'm curious because he even has LC-MS values. The original report is at https://www.erowid.org/experiences/exp.php?ID=61171

antibody2

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Re: Reductive Methylation of Primary Amines
« Reply #34 on: February 27, 2013, 01:24:10 AM »
Not sure Polonium, the STAB AB2 used was prepared fresh immediately prior to the experiment, formaldehyde was freshly prepared  from depolymerized paraformaldehyde. XS STAB still remained when tlc showed the rxn had gone to completion as evidenced by hydrogen evolution during the quench. The tryptamine used was the same tryptamine used to successfully prepare DET.

One thing that always bothered AB2 about the erowid write was that he said he added the 37% formaldehyde using a syringe, which implies an inert atmosphere, but if using 37% formaledhyde there is no reason to have an inert atmosphere though with all that water. Regardless an argon blanket was laid down after the STAB was prepared with no apparent improvement over running the rxn in an open flask.

AB2 was taking to another bee at Science madness who claimed a 25% yield with the same procedure, but had yet to bioassay the product ...
« Last Edit: February 27, 2013, 03:00:30 PM by antibody2 »

Electro´S

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Re: Reductive Methylation of Primary Amines
« Reply #35 on: February 27, 2013, 11:18:43 AM »
Quote from: reckless on February 23, 2013, 03:54:49 PM
Stop citing bullshit. STAB reduces indoles to indolines. (check Handbook of Reagents for Organic Synthesis Oxidizing and Reducing Agents)

Sorry man, but i don´t have any way to know (I´m not chemist)  if the procedure is right or not, all i can do is share something i got  in list of futures... And wait for Real Bees thinking about it.
So this is not the first "bad" refence from me and you can be sure it will not be the last.  ::)
« Last Edit: February 27, 2013, 11:21:32 AM by Electro´S »
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