reductive amination with triacetoxyborohydride

I haven't got much to add!
The problem with toluene is that low boiling amines (NH3, MeNH2, etc) tend to evaporate off during the long reflux, or at least concentrate in the trapped water ( no aq layer btw, the water is eliminated as it forms so you have a sometimes milky homogeneous phase). Besides using a very arge excess of the amine, i haven't worked a way out of this... Maybe using the amine salt and slowly dripping trietylamine at RT, then refluxing would be ok. For low boiling reflux, you can use pet ether as a solvant, i forms a ~5% azeotrope with water, i've used it for condensations and the pot temp never went over 60°C. If I distilled the pentane fraction, or used pur pentane, the temp would be even less. I could take a few hours more though.

Have you considered the Ti isoproxide route? The "regular" grade isn't that expensive, and the reaction is said to work well with delicate substrates...

solo, as stated in the other papers (i mean this one), the authors use Ammonium Chloride and Methylammonium Chloride along with Triethylamine (ratios: Substrate:Amine Salt:Triethylamine:Ti(OIPr)4:NaBH4 1:2:2:2:1.5) stirred for ~10hrs, then adding NaBH4 and stirring for 8hrs.

so, here's the solution to your problems

Klute, where did you read about the subequimolar amounts of Ti(OIPr)4 being used? i'd love to see that, since the Ti(OIPr)4 isnt really that cheap (2kg=7.5mol=150EUR)

[Edited on 29-3-2008 by stoichiometric_steve]

I´m interested in your pictures .

If you try "my" procedure, you can use much more toluene of course to make the mixture easier to stir.
Also you can use THF or 1,2-dichloroethane as solvent.
There is an article where they use propionic acid and THF and when I remember correctly, they get a solution.
Acids with higher molecular weight than acetic acid give a higher stereoselectivity in the reductions.

Here goes:


- The setup (oven dried, cooled under Ar)



-The enamine (aniline and N,N-diethylbenzoylacetamide in toluene, cat. TsOH and Dean Stark, removal of most of the toluene):



-NaBH4 (dried over KOH overnight):



-GAA+ anhydrous toluene (3A MS), added via syringe:



-Paste obtained near the end of the addition:



-After adding anhydrous toluene:



-Addition of the enamine:







-After 24H stirring at RT (notice fine cristalline solid):



-After addition of conc HCl dropwise (quench of the exces hydride, and decomposiiton of the amine-borane complex):



Didn't take any more pictures after.... After stirring at RT for 30min, adding conc. NaOH until most of the solids/emulsion had dissolved gave a clear aq. and dark orange/brown organic layer, which was washed with water and extracted with dilute HCl, aq. washed with toluene, basified and amine extracted, washed, dried, and cristillized from HCl/IPA in ~70% yield.

Indeed, I think adding a little water first can't do any harm. The reaction with STAB will be a little less vigorous I suppose.


The carbonyl compound I used is the N,Ndiethylamide of benzoylacetic acid, made by reacting excess ethyl benzoylacetate and diethylamine in presence of cat. NaH at high temps and subsequent removal of ethanol formed.

One could think that with a primary amine and a ketone an imine would form, but b-ketoester and b-ketoamides always form stable enamines, the double bond formed being conjugated with the carboxyl. Apparently, it isn't just a mixture of enamine and imine tautomer, but only the enamine at all times. Hence, the reduction must be run with 1 eq. of GAA or simialr to form the iminium salt...

Yes, the slurry was definitively easier to stir after adding the enamine, but I did add at least an equal volume of toluene (the imine took a few seconds to correctly dilute itself in the mixture, while in solution it was instantaneous). There was a little H2 evolution at first, but it quickly came to a stop.

I only hav acces to a kitchen oven at home, and am very reluctant at putting chemicals in it The KOH seems good for my purposes, I was thinking of using P2O5, but I prefer keeping non-acidic conditions to avoid any H2 evolution if a grain of NabH4 falls on the P2O5 for some reason...

Quote:

Originally posted by Klute I only hav acces to a kitchen oven at home, and am very reluctant at putting chemicals in it The KOH seems good for my purposes, I was thinking of using P2O5, but I prefer keeping non-acidic conditions to avoid any H2 evolution if a grain of NabH4 falls on the P2O5 for some reason...

This looks like a much better approach than adding the hydride to solvents: you hydride it entirely dry, aswell as your steup, and introducing dry solvents via syringe minimizes any contact with atmospheric moisture.. You really are the STAB Guru

I'm also considering trying to reduce the enamine with NaBH4 in AcOH, but adding the hydride to the enamine with 1 eq of GAA: of course, the reductant is NaBH4 here, not STAB, but at least all 4 hydrides can be used. Now that I knwo that STAB works for this particuliar substarte, i will try the NaBH4 (which is used in an enamine reduction procedure).

Apparently, with a similar substrate, using NaBH3CN with the carbonyl and the amine in MeOH gives only the alcohol, even though the enamine is readily formed, but preforming the enamine and reducing it it with NaBH3CN gives the expected product.

The Zn/GAA procedure has been pretty dirty and low yielding, but it could be du to the crude amide (I'm going to try it out with a cleaner amide).