[collin_det]

Hello.

It should be a classical thing to make N-methyl amines, using BOC and reduction, but I cant find much about the experimental procedures. I have found an article where they use 5 eq. BOC anhydride in their abstract to a protected amine, but nothing about their work up. So I dont know if I should cleave an tert butyl ether after the reduction or will it remove the BOC under the reduction also?

It should also be possible to make the N-ethyl from an amide, made by using acetyl chloride and reduction, but I dont know how efficient these methods are? compared to, maybe just deprotonate the amide using NaH and then attack by bromoethane.

Any experience will be highly appreciated.

Thanks in advance.

[Dan]

A more common method is reductive amination of an aldehyde. For example, methylation can be achieved by treating the amine with formaldehyde in the presence of a reducing agent - normally sodium cyanoborohydride or hydrogen/palladium. I have methylated and butylated several secondary amines this way. The intermediate imine can also be isolated if required - in cases where you are attempting to make a secondary amine this may be necessary since the secondary amine product could react further in a one-pot procedure, though probably relatively slowly, to give a tertiary amine.

This is generally preferable to S_N2 with alkyl halides, which is a method that often suffers from overalkylation and can give tetraalkylammonium salts.

[collin_det]

Thanks for your reply.

I will consider reductive amination, but I just find them hard to do, as the imines are hard to get sometimes. But maybe I should try to do it in situ as you described, with paraformaldehyde and sodium triacetoxy borohydride. Maybe in cold methanol.

Thanks.

[Doc Oc]

You can't do a reductive amination with Boc, it's impossible.  You can't assume that it's possible because you can do it with an amide, that's comparing apples to oranges.  Amides and carbamates are different and they each have their unique properties and uses.  They aren't always interchangeable.

That being said, N-methylation even by reductive amination is not terribly easy.  When I tried with formaldehyde and NaBH(OAc)₃ I got double methylation.  I went an alternative route and did reductive amination with benzaldehyde first to get the benzylamine, then another reductive amination with formaldehyde.  Deprotection of the benzyl group will yield the N-methylamine.  I know it sounds circuitous, but believe me, you will not get good yield from the formaldehyde/NaBH(OAc)₃ procedure.

[collin_det]

Thanks for your answer.

I would not do a reductive amination on the BOC protection. I would reduce it to yield the N-methyl compound. LiAlH4 or red al.

For the amide I would consider using BH3 - THF (reflux). That would be an easy way to make alkylated amines if it works.
If I was going to use the aldimine, then I would attack with methyl iodide or another methylating agent. I think that would be the most easy thing?

I have just tried on my aniline to first make the amide and then deprotonate it with NaH and then attack with MeI, but it dosent seem to work, so I will try different things.

Oh I saw that I wrote 5 eq. BOC anhydride in the start topic. I meant of course red al. Sorry for the confusion. But thanks for the info regarding the sodium triacetoxy borohydride.

[Doc Oc]

You still won't be able to do the reaction with Boc.  It wants to break apart into CO₂ and methyl butene, that's why you can't do it, not because the reagents are wrong.  The carbonyl of a carbamate is remarkably insensitive to reaction, Boc-protected amino acid esters can be reduced to primary alcohols using LAH and the Boc remains unaffected.

I've heard from people (and read in the literature) that if you do the NaH/MeI procedure with an amide that the order of addition is absolutely critical.  I was considering going this route for one of my projects, I'll see if I can find those papers again.