[Nescafe]

Hello,

I was wondering if it was possible to reduce NON-substituted lactams to amines. I find in literature that you can do it with substituted amines but nothing on non-substituted lactams. I am guessing this is because the reducing the nonsubstituted lactams will end up opening the ring?

Cheers,

Nescafe.

[Dan]

By a non-substituted lactam do you mean a lactam with an NH (cyclic secondary amide)? e.g. 2-Pyrrolidinone pyrrolidine?

That's very well precedented, usually done with BH₃ or LAH. You should be getting 1000s of hits for that reaction, which database are you using?

[Nescafe]

Yes, exactly as you say a secondary lactam/cyclic secondary amide. Well I was on scifinder and got a lot of hits but not one that showed BH3 or LAH right off the bat and with good yields. Hmmm I thought they would be very popular routes, is there a chance the ring could open?

[Dan]

is there a chance the ring could open?

Probably depends on ring strain (size and substitution), but generally speaking it shouldn't. I remember a few years ago a colleague claiming to have some issues with a 7-membered lactam opening, but I don't remember the details. You can do a search for that reaction as well.

You can search specifically for NH lactams if you draw in the NH in your search (and maybe use a "lock atoms" tool or similar). I generally use Reaxys for these sort of searches - I find the free substitution sites and atom mapping tools easier to use.

[Nescafe]

I tried LiAlH4 in THF for 24hrs and see only SM... Hmmm, any ideas? It is a 7-membered secondary lactam

[Dan]

A lot of literature preps reflux with LAH or borane·THF - did you try that?

[Nescafe]

Its refluxing now, I found it a bit odd that there was literally no product and only SM. But I understand it could be due to the stability of the amide and the requirement of heat to accelerate the reaction. Are these reactions Microwave friendly or is LiAlH4 and MW a no go?

[discodermolide]

A MW will only increase the rate of heating. Stick with the normal reflux.

[Nescafe]

Well I heated for about 6hrs so far at 70C and still see SM, I am a bit surprised. I ordered BH3.THF just to have an alternative.

[discodermolide]

Are you seeing any product?
Perhaps a higher boiling ether may be worth trying. I assume the LAH quality is ok?

[Nescafe]

No product after 72hr reflux with LAH. A colleague also tried the same reaction and same result with a different batch. Litertaure shows that with lactams tertiary lactams proceed easily but there is less simple procedures for secondary lactams. I am going to try BH3.THF

[Nescafe]

So after trying a fresh batch of LAH reaction works beautifully, BUT, I have tried two ways to get my product and have failed to get anything more than a 15% yield and I know it is not the reaction itself but my product getting stuck during the filtration procedure.

First I tried an aqeous work-up which was a bad idea since my cyclic amine is really polar and would not come out of the water layer

Next I tried the first portion of this http://chemwiki.ucdavis.edu/Reference/Lab_Techniques/Quenching_reactions/Lithium_Aluminium_Hydride

Now I am considering diborane or retrying BH3THF or retry LAH but this time use Rochelle's salt, any ideas?

Thanks in advance!

Nescafe.

[Dan]

Can you be a bit more specific about exactly what you did?

A Rochelle's workup won't help you if you can't extract the product from water.

You may be able to use ion exchange (this works well for cleaning very polar amines after boron-based reductions, but I've never tried with Al). Quench the reaction, acidify with HCl and then load onto a short column of strongly acidic resin (e.g. Dowex, amberlite etc.). Elute the resin with a solvent in which the impurities are soluble (I tend to use water and ethanol) until the eluent leaving the column is neutral. Now elute with 1-2 M aqueous ammonia. Amines will be present in the first few ammoniacal fractions.

What happened with borane.THF?

[Nescafe]

If I do as you say and use water ethanol would not my water soluble product elute from the column? I basically have a cyclic secondary amine that is really polar.

BH3THF there were like four spots, it was a bit of a mess but I might try it again and monitor it this time.

LAH reaction is clean as it gets just having work up issues

First time I did an acidic work up and tried extracting with EtOAc. Everything just stayed in the water layer. I vaced off the aqeous and tried a celite filtration but everything just got stuck including my product. Second time I just quenched the solution with 0.3mL of water, 0.1mL of 10% NaOH, then added 1mL of water and diluted with ether, added some magnesium sulfate and let it stir for 15 mins. Next I concentrated it under vacuo and ended up with a nice salt that was easily filtered. I rinsed with MeOH to get my product pass the filter but I guess I did not rinse enough and most of my stuff was stuck behind on the filter paper.

[Dan]

If I do as you say and use water ethanol would not my water soluble product elute from the column? I basically have a cyclic secondary amine that is really polar.

No, any amines will remain bound to the resin until they are displaced in the ammonia elution step.

I used to work with polyhydroxylated pyrrolidines and piperidines, some of with would not even dissolve well in methanol they were so polar, and this was the routine purification. It's quite crude and relies on a clean conversion in the reaction because it will not separate amines from each other, it just separates amines from non-amines.