Post by: Nescafe on September 15, 2014, 11:33:38 AM
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.
Post by: Dan on September 15, 2014, 02:53:06 PM
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?
Post by: Nescafe on September 15, 2014, 08:39:38 PM
Post by: Dan on September 16, 2014, 02:57:42 AM
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.
Post by: Nescafe on September 17, 2014, 08:28:32 AM
Post by: Dan on September 17, 2014, 10:35:58 AM
Post by: Nescafe on September 17, 2014, 03:36:56 PM
Post by: discodermolide on September 18, 2014, 12:25:33 AM
Post by: Nescafe on September 18, 2014, 12:52:04 PM
Post by: discodermolide on September 18, 2014, 01:57:59 PM
Perhaps a higher boiling ether may be worth trying. I assume the LAH quality is ok?
Post by: Nescafe on September 23, 2014, 12:02:41 PM
Post by: Nescafe on September 29, 2014, 03:34:20 PM
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.
Post by: Dan on September 30, 2014, 04:08:53 AM
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?
Post by: Nescafe on September 30, 2014, 02:05:21 PM
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.
Post by: Dan on October 01, 2014, 03:29:48 AM
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.
Post by: Nescafe on October 01, 2014, 03:18:28 PM
Post by: Nescafe on October 02, 2014, 01:29:27 PM
So can you please explain to me exactly what your suggestion is post reaction. Qunch and then load onto an amberline column flush with ethanol/water and then 2M ammonium hydroxide to elute my amine out?
Post by: Dan on October 02, 2014, 03:49:13 PM
Yeah BH3THF is a no go the major spot by MS is basically my SM - 2 protons which makes me speculate that I have made an alkene, although I am not sure where or how exactly so I will have to make the LAH work.
Unlikely to be a dehydrogenation, this would be an oxidation using borane.
How many equivalents of BH3 did you use? Maybe it could be this aminoborane:
![[*:1]CN([*:2])B](https://www.chemicalforums.com/SMILES/2331481dfb0d317eb43c.png)
Not sure that would survive MS though. If it is, then it worked and just needs decomposing to the free amine. Repeated concentration from methanol should do the job (trimethyl borate is volatile), but the acidification followed by ion exchange will also work if not.
Quote
So can you please explain to me exactly what your suggestion is post reaction. Qunch and then load onto an amberline column flush with ethanol/water and then 2M ammonium hydroxide to elute my amine out?
Yes, exactly.
Post by: Nescafe on October 02, 2014, 04:43:03 PM
Based on LCMS it could very well be it as the mass matches the specie you suggested perfectly.
I tried azeotroping with MeOH and no luck. I left it stirring in acetonitrile with a bit of sodium bicarbonate hoping that will free the amine. Not sure if it was a good idea but I was in a rush to leave.
Thanks for the advice, still surprised how MeOH did not help release it.
Post by: Dan on October 02, 2014, 05:08:49 PM
This is all assuming that it is actually the aminoborane, it might not be.
Post by: Nescafe on October 02, 2014, 05:38:35 PM
I just cant see what else it could be, I have drawn out a number of other possibilities but the only thing that matches the mass is the borane specie you suggested. And like you said dehydrogenation is unlikely.
I like the idea of making the ammonium salt if the bicarb does not do it.
Adding a total of 3.5eq definitely moved the reaction along but made things difficult at the end.