[Archer]

Does anyone know of a relatively simply procedure for mono-N-methylation of amino acids, particularly alanine?

This substance (in each enatiomer) is commercially available but is prohibitively expensive for the synthesis that I am conducting and, potentially, I would like to prepare other N-monoalkylated alanine derivatives which are not commercially available.

Thanks in advance for any guidance.

[TwistedConf]

Have you done a lit search?  What are your ideas?

This is just a selective secondary amine synthesis...  so you have several common options.

[Archer]

There are many options for the preparation of secondary amines which I have successfully achieved in the past but amino acids are the very devil to work with in my opinion .  Their reactivity is different to, for example, amines or related aminoketones. Where possible I have avoided amino acids throughout my career for that reason (rightly or wrongly) as there is often a way around having to use them unless one is attempting stereoselective synthesis which is my aim here.

Most of the methods I have found employ N-protection and the use of sodium or potassium hydride and iodomethane. I don't particularly like working with metal hydrides as it requires dry reaction conditions which are not readily available where I work. The toxicity of iodomethane makes it unfavourable too.

There is a paper which describes an aqueous method of preparation but this is also not ideal for my purposes as aminoacids are difficult to remove from water and to find their isoelectric point for the next step of my reaction.

Really I was just wondering whether anyone who works or has worked with amino acids in organic synthesis had any favorite methods which are quick and dirty but get the job done.

My alternative is to do the N-methylation as the last step  in my reaction (when it is no longer an amino acid) but I was hoping for a convergent synthesis to keep yields slightly higher.

[Dan]

How about this? I guess this is "the paper" you are referring to? You could change the isolation method - it seems the reaction is quite clean.

[Archer]

That's the one, in typical Tet. Lett. Style they don't provide an actual full synthesis, they simply state that they were isolated "by traditional methods".

As I have never really worked with them I am not familar with these traditional methods of amino acid isolation.

[Dan]

Yeah, it is terrible that they do not at least provide a reference for purification.

As I have never really worked with them I am not familar with these traditional methods of amino acid isolation.

Me neither, but this information should not be too difficult to find. Ion exchange resins are probably the way to go if you don't like the idea of derivatising for non-aqueous purification. I do not have the sufficient experinece with amino acids to recommend a resin though.

[Doc Oc]

Can you elaborate on what you're trying to do?  Exactly what derivative of alanine are you referring to?  Is the amine in a peptide bond or is it the free amine?  The acid isn't free, right?  It's some kind of ester?  Alkylation will be very different depending on those variables.

If it's an amide or carbamate of some sort, a metal hydride followed by alkylation with MeI is the most common method.  If you use a dispersion of sodium hydride you can get away with a little moisture.  Methyl iodide isn't bad as long as you use it in a properly ventilated hood.  The main issue with this method is that the hydrides are known to racemize the stereocenter to varying degrees, depending on the starting material.  Sometimes just a 5% loss, sometimes complete loss.

If the amine is free, the only way to guarantee mono-alkylation is via reductive amination.  I have colleagues that found success with this method, but I personally didn't.

Org. Lett., 2005, 7 (19), pp 4111–4112
DOI: 10.1021/ol051441w

One of my current co-workers has had strange success in using substoichiometric amounts of the MeI and doing a traditional alkylation with free amines.  You may be interested in trying that at a small scale just to see if it works.

[Archer]

Can you elaborate on what you're trying to do? 

Org. Lett., 2005, 7 (19), pp 4111–4112
DOI: 10.1021/ol051441w

Thanks for the reference, that looks like something I could attempt quite easily.

I am trying to make aminoketones so ultimately the N-protected amino acid chloride will be reacted with a Grignard reagent at low temperature to make the ketone.

Presently I am brominating the ketone and reacting with an alkylamine to make these but it is not stereospecfic and unsuitable for certain substrates (i.e. valine type derivatives)

 The main issue with this method is that the hydrides are known to racemize the stereocenter to varying degrees

It had not occured to me to think about racemisation! This would be a blow if total loss occurred. If the ee is quite high then I can probably resolve with mandelic acid or something similar. I guess I will have to look at all the options and see which gives the highest isolatable yeild of the desired enantiomer on a simple substrate and work from there.

Thanks for your help.

[BobfromNC]

You can also make the formamide of the amine and reduce.

Almost all of these methods have the possibility of racemization, so you would be best to try both R & S and check to see if they give equal but opposite products, or try chiral chrom. or NMR, or add another stereocenter to look for diastereomers.   

But if the amine is protected as a Boc, or coupled as an amide, that is far easier to N-methylate than the amino acid.  Boc amino acids are usually cheap and readily available, at least for naturally occuring ones. 

Bob