There seems to be a considerable amount of controversy regarding the reaction time and conditions for the Sodium cyanoborohydride (SCBH) + ammonium acetate (AA) reaction.
First regarding pH control. When using SCBH in reductive amination, the pH must be maintained in the range of 6-8. When one adds the not-ketone and AA and silica gel (7-10x molar excess) the pH of the system is around 8-8.5 even before addition of SCBH. This is already too high.
The solution for this is to use Glacial acetic acid (GAA) in sufficient amounts to bring the pH down to approx. 7. This has two advantages: firstly the acid helps to catalyse immine formation and of course it maintains the pH in a range that is favourable only for immine reduction. And since the AA and GAA form a weak buffer, the pH will remain somewhat stable even after addition of the SCBH (which usually causes the pH to rise as the reaction progresses).
I also believe that one should allow the AA + ketone + Silica + GAA to pre-stir for at least 3 hours, preferrably 4-5. This allows enough imine formation and water uptake to reduce the amount of ketone in the mix (thus reducing the amount of ketone that could be reduced).
As to the overall reaction time, I believe that some people on the hive have suggested that anything in excess of 30 hours will lead to reduction of the amine to an alcohol. This is not true (nor really possible with SCBH). I think the source of this confusion arrises from the fact that most of these people do not use pH control and in the absence of this some of the starting ketone will be reduced to alcohol (and consequently the longer the reaction is allowed to progress, the higher the apparent amount of reduced alcohol by-product). It is not the formed amine that is reduced as SCBH is not capable of this reduction.
Since the MDA immine is not as stable and fast forming as the MDMA immine, this reaction does require longer reduction time. with proper pH control and enough silica gel to adsorb all the formed water, I believe that higher that 80+ % yields can be achieved.
Any thoughts on this?