Nitrogen Methylations Using Diazomethane

[PrimoPyro]

I know that it is not practical to N-methylate secondary amines with methyl halides because of formation of quaternary ammonium salts, but I am wondering how would you N-methylate a secondary amine, then?

Can you N-methylate an aziridine to an N-methyl aziridine with diazomethane, CH2N2? Will any byproducts be likely? Will it wreak havoc upon the aziridine ring? (I hope not)

I know diazomethane is not fun to work with, but Im just trying to figure out/find a way to N-methylate an aziridine ring without shooting holes through it and fucking it up all to hell.

Thanks for your help.  

PrimoPyro

[PrimoPyro]

What about doing this to make the N-methyl aziridine:

It is wellknown that 1,2-aminoalcohols can be dehydrated to aziridines. If the aminoalcohol is an N-monomethyl-amine, then the aziridine formed is the corresponding N-methyl aziridine.

The compound of my desire is 1,2-dimethylaziridine. I can't find anyone that sells this compound.  

To make it, one needs to dehydrate either 1-(N-methyl)amino-2-propanol or 2-(N-methyl)amino-1-propanol. Both isomers yield the same product compound.

Now I've sat here playing with ISIS Draw for 40 fucking minutes and can't come up with a simple method for producing either of these compounds that doesn't have either conflicting/pain in the ass steps, and/or lots of steps. The best thing I've seen is this:



React propylene oxide with sodium azide to form either 1-azido-2-propanol or 2-azido-1-propanol, I don't know which would be formed, or perhaps both will. Luckily, in this case it doesn't matter.  

Reduce the azide to the amine, and alkylate with formaldehyde to prepare the N-methylamino-propanol. Then dehydrate this compound to the 1,2-dimethylaziridine.

2-methylaziridine is commercially available. A one step method going from 2-methylaziridine to 1,2-dimethylaziridine is highly desired. This amounts to a simple N-methylation. A simple N-methylation process much more desired than something like a synthesis which I outlined above, which starts with two poisonous chemicals and goes through multiple steps to get the desired product in a roundabout way.

What do you think?

PrimoPyro

[PrimoPyro]

I UTFSE and found Antoncho's posts regarding diazomethane methylations, and they have pretty much answered my questions. It is to my understanding that diazomethane should likely work very well for N-methylation of 2-methylaziridine.

PrimoPyro

[Rhodium]

Ritter posted something about the conversion of azides to N-methylamines from Synlett 1003 (2001), using either MeI or paraformaldehyde as methyl group donor to the addition compound between the azide and PMe₃.

So, first treating propylene oxide with NaN3 to form the azidoalcohol, followed by methylation with either MeI or (HCHO)_x in the presence of PMe₃ (or possibly other PR₃ compounds) gives the desired N-methylaminoalcohol, which is easily cyclized to the aziridine via the tosyl ester.

[PrimoPyro]

While reading around for more info on your previous post, I found this in March's 5th:

10-634: Formation of Aziridines From Epoxides

It is possible to prepare aziridines, which are synthetically important molecules, directly from the corresponding epoxide. Reaction of Ph3P=NPh with an epoxide in the presence of ZnCl2 gives the N-Phenyl Aziridine.

Kuhnau, D.; Thomsen, I.; Jorgensen, K.A. J. Chem. Soc., Perkin Trans., 1 1996, 1167.

As found in March's 5th, pg. 515

So one would need to use R3P=NCH3 with propylene oxide to make 1,2-dimethylaziridine.  

How does one prepare compounds of the structure R3P=NR' ? Can these be purchased in a manner that is not like pulling teeth? i.e.Are they available for purchase or must they be custom synthesized, or even worse, prepared just before use, or even WORSE, prepared in situ?

[EDIT]Im a fucking dumbass sometimes, I swear. In the picture previously posted by MYSELF in this very thread, there is shown in big pictures how organic azides react with triphenylphosphine to form the compound needed above. The only real detriment is that lightweight (small M.W.) organic azides are explosives, so the methyl azide needed is a huge pain in the ass.[/EDIT]

[EDIT#2]In the route you propose, Rhodium, you say that cyclization would easily occur with the "tosyl ester." I assume you mean the tosyl ester of the alcohol, and not an N-tosyl group. Does that mean that tosic acid would need be used to form the tosyl ester, because tosyl chloride would replace the remaining proton on the nitrogen, preventing cyclization?[/EDIT]

PrimoPyro
Will perform sexual favors for females in exchange for 1,2-dimethylaziridine. PM for details.

[Rhodium]

My suggested reaction was for the preparation of N-tosyl-aziridine, where ethanolamine reacts with two molecules of tosyl chloride, forming both the ester and the amide. The ester then cyclizes to form N-tosylaziridine (I've seen this in a patent). Not suitable for the preparation of 1,2-dimethylaziridine though. Haven't you found any aziridine hits in the US patent database?

[PrimoPyro]

Update: To answer my question: Yes Diazomethane can be used to methylate secondary amines, but only in the presence of a catalyst. Two such catalysts are BF3 (gross) and CuCN (not bad at all).

Diazomethane will not destroy the aziridine ring, but will methylate the secondary nitrogen amine to the N-methyl aziridine. Yay!  

Propyleneimine (2-methylaziridine) is commercially available, but 1,2-dimethylaziridine is not. I found another really novel (and cool) dimethylaziridine synthesis, but this is much much better because the other synt requires addition of diazomethane to acetaldehyde methylimine in the presence of ytterbium triflate.  

It is possible to purchase propyleneimine and N-methylate it with diazomethane and CuCN to 1,2-dimethylaziridine. Finally, a clear answer, I feel happy.  

Thank you, March's 5th, for the tons of answers you've given me so far. More info, and citations of all this data, to come after some sleep.  

PrimoPyro
Will perform sexual favors for females in exchange for 1,2-dimethylaziridine. PM for details.