Author Topic: Question: methylating the amine in Phenylalanine  (Read 2510 times)

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java

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Question: methylating the amine in Phenylalanine
« on: June 06, 2004, 11:09:00 PM »
As in most reactions , save the reduction with sodium borohydride and Iodine, reducing the COOH in the Phenylalanine the precaution of protecting the amine group comes into play. In methylating the amine  with iodomethane , my question is then....Will the methylating of the amine affect the COOH and is this the best way to do this and what solvent and conditions would apply?  I have checked the search sources and Rhodium for the answer but not yet found it.....

Note  There are many ways to reduce the the COOH and with the amine group methylated, as it works as a protection against side reactions, the routes increase  and the need for the lithiums and  hydrides and Boron become less needed. ....java


Rhodium

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Misdirected worry
« Reply #1 on: June 07, 2004, 12:38:00 AM »
In methylating the amine  with iodomethane , my question is then....Will the methylating of the amine affect the COOH and is this the best way to do this and what solvent and conditions would apply?

Carboxylic acids are only methylated with alkyl halides under basic conditions, i.e. when it is in the form of a carboxylate salt.

The problem isn't really the presence of a carboxylic acid function, but rather that you will mainly end up with N,N-dimethyl-phenylalanine and its methiodide (i.e. the quaternary ammonium iodide) if you react phenylalanine with MeI just like that.

There are many ways to reduce the the COOH and with the amine group methylated, as it works as a protection against side reactions, the routes increase

Really? I don't know any reductions which significantly differentiates between primary and secondary amines when it comes to side-reactions.


java

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Question: methylating the amine in Phenylalanine
« Reply #2 on: June 07, 2004, 07:48:00 PM »
Rhodium ...After reading

https://www.thevespiary.org/rhodium/Rhodium/chemistry/amphetamine.methylation.html

, which did not show in my search for methylating amino groups,  I see what you mean as to the successive methylation as you stated. The article is directed to the treatment of amphetamines so would this also work for phenylalanine ?

As to the reactions that are parallel to the reduction of the COOH once the amine group has been methylated , as with the method stated above, how about the Phosphorous /Iodine environment in the reduction of the OH in ephedrine, Pseudoephedrine?  I also didn't imply that the reaction differentiated between on or the other, that you read into the question.....java

Addendum; I especially liked the one with formaldehyde, I wonder if the amino acid will be soluble in this solvent to form the formaldehyde imine  in a reflux?  then hydrogenate  with Pt. to reduce to the desired methylated amine.


Rhodium

  • Guest
several possible problems
« Reply #3 on: June 07, 2004, 09:21:00 PM »
The article is directed to the treatment of amphetamines so would this also work for phenylalanine?

Yes, that is likely. As long as the conditions are mild and you don't reduce the acid to the aldehyde in the process (something which might happen if you perform a reductive alkylation with Al-Hg/HCHO for example). Aminoaldehydes polymerizes.

As to the reactions that are parallel to the reduction of the COOH once the amine group has been methylated, as with the method stated above, how about the Phosphorous /Iodine environment in the reduction of the OH in ephedrine, Pseudoephedrine? 

Post 499398 (missing)

(Rhodium: "Aren't carboxylic acids rather inert to HI?", Stimulants)


I also didn't imply that the reaction differentiated between on or the other, that you read into the question...

Huh? Then what did you infer with the following statement? "There are many ways to reduce the the COOH and with the amine group methylated, as it works as a protection against side reactions, the routes increase" There are no less side-reactions when reducing N-Methyl-phenylalanine compared to plain phenylalanine - there is still a N-H function present.


java

  • Guest
Question: methylating the amine in Phenylalanine
« Reply #4 on: June 07, 2004, 10:43:00 PM »
Rhodium...Well that is good news,  I plan to hydrogenate using Pt , the environment should be mild enough to avoid the conversion to aminoaldehyde mentioned. Will the N,methylated phenylalanine have an easier time being reduced to an alcohol or a CH3 ? Or the established methods sodium borohydride, lithium, and the others still work the same ? Also if I chose to go to the aldehyde then OH will I have a problem with polymerization as mentioned in your reply? As to my statement of less side reactions....I stand corrected ........java


Rhodium

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evaluation of the reaction sequence
« Reply #5 on: June 08, 2004, 12:06:00 AM »
Will the N,methylated phenylalanine have an easier time being reduced to an alcohol or a CH3? Or the established methods sodium borohydride, lithium, and the others still work the same?

Should be pretty much the same. You cannot reduce the COOH to CH3 with anything less than triethylborohydride, everything else will give the alcohol. You must probably also protect the nitrogen somehow (acetylation perhaps?) before halogenating the primary alcohol, or it may polymerize (the formed alkyl halide alkylating the nitrogen of another molecule).

I believe that you will get higher yields in the end if you first reduce phenylalanine to amphetamine, and first afterwards methylate your product to meth.

Also if I chose to go to the aldehyde then OH will I have a problem with polymerization as mentioned in your reply?

Exactly. Amines and aldehydes in the same pot (or in the same molecule) will invariably form imines and depending on structure, they may continue to react from there.


Rhodium

  • Guest
Suggested route
« Reply #6 on: June 09, 2004, 03:07:00 AM »
Here is a prep of N-methyl-phenylalanine, N-methyl-alanine and other N-methylated amino acids. As the intermediate product is the N-Benzyl-N-methyl-amino acid, you have your protecting group attached which you can use to prevent side-reactions on the nitrogen. When you have reduced the carboxylic acid to a methyl group via the intermediate halide you can then remove the benzyl group with Zinc/Ammonium Formate as described in

Post 512088

(Rhodium: "Zinc/Formate: CTH Debenzylation (N-/O-/S-)", Novel Discourse)


Die Synthese optisch aktiver N-Monomethyl-Aminosäuren
P. Quitt, J. Hellerbach und K. Vogler

Helv. Chim. Acta 46, 327-333 (1963)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/n-methyl-amino.acids.pdf)

Abstract
A synthesis of optically active N-monomethylated amino acids (V) is described. It involves a three-step process, starting from optically active amino acids (I) which are converted into their benzyl derivatives (III), subsequently methylated (IV) and finally hydrogenolyzed. The reaction sequence proceeds without racemization.


java

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Alkylation of Amino Acids....
« Reply #7 on: August 08, 2004, 11:08:00 PM »
This is a post that  compliments this inquiry....thanks to Rhodium bringing it to my
 attention......java

Post 524301

(Rhodium: "NaBH(OAc)3 Reductive Alkylation of Amino Acids", Novel Discourse)