Titanium Chloride: Reducing Oxime to Amine

[gravenewworld]

Ahhh! Titanium Chloride!

So I was at work today and I was told I had to reduce an oxime using titanium chloride and sodium borohydride. Now let me tell you this reaction is NASTY. There was so much toxic gas, bubbles, foam, and heat given off (and this was on roughly a 100mg scale). Titanium chloride is pretty nasty stuff to work with, so do any of you expert o chemists have any milder ways to reduce an oxime to an amine?

 

[movies]

Uhh...LiAlH₄? Not really "milder," but a lot better than using TiCl_x. You can also use BH₃, I think, but it's probably going to be pretty slow. LAH reduction of an oxime is generally slower than that of a ketone. Also, I thought that those TiCl_x conditions used NaB(CN)H₃. I imagine if you are working in industry that reagent is frowned upon though. It might temper the reactivity a bit though.

Better conditions would probably be Zn⁰/AcOH (this would be the one that I would try first). I think you can achieve this transformation with Pt/H₂ as well, but heterogeneous Pd won't work because the catalyst is poisoned by the product amine. Pt catalysts don't get poisoned as readily.

Good luck!

 

[chem_tr]

Yeah, radicalic hydrogen is the best. Isn't sodium borohydride alone (in dilute alcoholic solution, for example) is sufficient in reduction? You might cool the solution to say, 0°C, to reduce its vigorous nature, and quench it with diluted HCl after slowly bringing the medium to room temperature. Maybe the titanium chloride/borohydride combination is responsible for the vigorous reaction, due to a possible synergistic effect. What do you think on this?

 

[movies]

If anything, I think you would get the N-hydroxyl amine from a NaBH₄ reduction.

 

[gravenewworld]

Well I go back to work tomorrow. I think am going to try the zn AcOH method. That one sounds good. I will let you know how it turns out.

 

[gravenewworld]

Ok I actually found a paper on Sci Finder that has a procedure for oxime reduction using Zn and acetic acid. The work up however is very tricky (the work up the paper suggests) and I always end up getting low yields. Do you have any suggestions for how to go about working up the reaction? The paper suggests doing the reaction by adding Zn to a suspension of oxime in acetic acid and stirring for 30 min. Work up is filtering through celite, evaporating off the solvent, neutralizing residue w/ concentrated ammonia, adding DCM, and washing with brine. The problem is that I alway seem to get a low yield. The paper claims to have gotten 90+ % yield on a reaction very similar to mine. So would there be any other work up methods I could try?

 

[movies]

Maybe try neutralizing with 1N NaOH instead of ammonia. How many times did you extract the aqueous layer with DCM? You might try a different organic solvent too, I have had good luck with amines and ethyl acetate.

You might also try a direct extraction after you filter through celite. Add some DCM and then add 1N NaOH and extract the aqueous layer a few times. The NaOH ought to neutralize all the acetic acid and the acetate junk should stay in the aqueous layer. This should work provided you don't have loads and loads of AcOH. You might also want to add a little NaOH to your brine to minimize protonation of your amine.

Do you have any idea how soluble the amine is in water?

Are you sure the reduction step went to completion before you worked it up?

 

[gravenewworld]

I extracted the DCM layer several times but still seem to get a low yield- ~10%. I know the reaction has occurred because I monitored it by LC/MS and TLC. I will try the work up you suggest. The reduced oxime seems to be relatively soluble in water. I will let you know how it turns out.


-Thanks again.

 

[movies]

You extracted the DCM layer, or you extracted the aqueous layer with DCM?

 

[gravenewworld]

Sorry, extracted the aqueous layer.

 

[movies]

Hmmm...DCM is usually a good solvent for amines, but maybe you need to try some others, especially if your amine is significantly water soluble.