Sciencemadness Discussion Board

Gamma Amino Butanal from GABA

Cooper_Panda - 2-1-2021 at 13:02

Hello all!

I am trying to synthesize gamma amino butanal from gamma amino butryric acid.
From the reaction mechanism of the Bouveault–Blanc reduction, it looks like the aldehyde could be generated by first synthesizing an ester of GABA, then using a 50% stoichiometric quantity of sodium.

[img]https://en.wikipedia.org/wiki/Bouveault%E2%80%93Blanc_reduction#/media/File:Bouveault-Blanc_Reduction_Mechanism.png[/img]

The attached paper describes good yields and mild conditions using ester dissolved in hexane with 4.5mol alcohol and 4.5mol sodium. The paper uses a 15um sodium dispersion, where the high surface area allows for the mild conditions.

Rather than trying to get finely milled sodium, I was thinking I could use eutectic NaK liquid. And as I said, based on the reaction mechanism having 4 discrete steps, using 2.5mol NaK and 2.5mol alcohol seems like it could generate a decent yield of aldehyde.

Does anyone have any thoughts or experience with this?

Thanks!

Attachment: Bouveault Blanc reduction Na-15 (419kB)
This file has been downloaded 284 times

myr - 2-1-2021 at 13:23

The sodium would react with the amine to make the amide salt: you would need to protect it first if you want to start with GABA.

mr_bovinejony - 2-1-2021 at 15:00

I have nothing to add but I'm interested in this reaction too for 4-chlorobutanal. Could the amine be protected with a tosylate group?

Cooper_Panda - 2-1-2021 at 15:23

That reaction doesn't seem favored. Most references to the direct amidation of an ester describe harsh reaction conditions and long reaction time.

I actually intend to methylate the amine, but wanted to see if I could get the primary amino butanal first before investing more time and money into first methylating the amine group. FYI I intend to follow the dimethylation of the primary amine to the tertiary product as in this paper: https://www.erowid.org/archive/rhodium/pdf/eschweiler-clarke...

So maybe I should plan on first forming the tertiary amine from gaba, then the ester, then the aldehyde. The tertiary amine should be incapable of forming an amide in the reaction mixture.

unionised - 3-1-2021 at 08:28

Setting aside the question of making it; how are you going to store it?
The amino group will react with the aldehyde group.

https://en.wikipedia.org/wiki/Aminoaldehydes_and_aminoketone...

clearly_not_atara - 3-1-2021 at 14:48

Aldehydes react faster than esters in nearly all reductions, so you'll get a mixture of products. The exceptions are reduction with DiBAl-H and Cp2ZrHCl, which are hard to come by. You could go via an intermediate alcohol if you protect the nitrogen, or you can try N-chlorination of pyrrolidine.

Cooper_Panda - 4-1-2021 at 00:30

Quote: Originally posted by unionised  
Setting aside the question of making it; how are you going to store it?
The amino group will react with the aldehyde group.

https://en.wikipedia.org/wiki/Aminoaldehydes_and_aminoketone...



Generating the tertiary amine group seems neccessary to prevent self condensation, then. As I said, my hope was to prove the concept of the half reduction before spending time on methylating the GABA.


Quote: Originally posted by clearly_not_atara  
Aldehydes react faster than esters in nearly all reductions, so you'll get a mixture of products. The exceptions are reduction with DiBAl-H and Cp2ZrHCl, which are hard to come by. You could go via an intermediate alcohol if you protect the nitrogen, or you can try N-chlorination of pyrrolidine.


That makes sense and has been my biggest concern with this "half reduction". But I've been hoping to lean into the cheapness of the reagents here. The most expensive and inconvinient of which is sodium. A mixture of aldehyde and alcohol should not be a problem, even if the yields are low.

Cooper_Panda - 4-1-2021 at 00:35

My plan was not to isolate the aldehyde, but if its formed in low yields along with a lot of alcohol, maybe it's worth trying to form the acetal and isolating it

Σldritch - 4-1-2021 at 23:52

Not to familiar with that reaction but can you not just form the lactam and reduce that? Looking at the mechanism the extra charge on oxygen should help it stick to the sodium surface. Still it a gamble though.

karlos³ - 5-1-2021 at 06:18

Quote: Originally posted by unionised  
Setting aside the question of making it; how are you going to store it?
The amino group will react with the aldehyde group.

https://en.wikipedia.org/wiki/Aminoaldehydes_and_aminoketone...


Usually as the acetal, it is even sold in that form.

Cooper_Panda - 5-1-2021 at 23:52

Quote: Originally posted by karlos³  
Quote: Originally posted by unionised  
Setting aside the question of making it; how are you going to store it?
The amino group will react with the aldehyde group.

https://en.wikipedia.org/wiki/Aminoaldehydes_and_aminoketone...


Usually as the acetal, it is even sold in that form.


Does the prospect of self condensation (amine attacking the aldehyde either to form a cyclical compound or to form an 8 carbon long compound with an amide at the center) concern you?

clearly_not_atara - 6-1-2021 at 11:12

Self-condensation will occur and in fact is nearly inevitable; this isn't a concern because it is reversed under the conditions of acetalization. The bigger concern is step-growth oligomerization of 1-pyrroline, or reduction of this to pyrrolidine, which is a highly active catalyst for aldol condensations. Aldol condensations are not reversible in HCl@MeOH and thus prevent you from isolating the acetal.

Cooper_Panda - 19-1-2021 at 17:56

Quote: Originally posted by clearly_not_atara  
Self-condensation will occur and in fact is nearly inevitable; this isn't a concern because it is reversed under the conditions of acetalization. The bigger concern is step-growth oligomerization of 1-pyrroline, or reduction of this to pyrrolidine, which is a highly active catalyst for aldol condensations. Aldol condensations are not reversible in HCl@MeOH and thus prevent you from isolating the acetal.


Does this oligermization occur with a tertiary amine group as well? ie n,n dimethylamino butyric ester?