[Ilaria]

Dear All,

Regarding the reductive amination of aldehydes with NaBH₃CN in MeOH or with NaBH(OAc)₃ in DCE, it is often said that in most cases addition of an acid catalyst (acetic acid) is not required. In addition, some advise against the use of an acid catalyst, in order to avoid aldehyde reduction (e.g. DOI: 10.1021/op0601013). Therefore, in the absence of an acid, what is the proton source for the formation of the iminium ion on which reduction takes place?

Thank you in advance!

[phth]

Adding a catalyst changes both activation energies in the same way.  Sodium can take its place or lithium.  In fact, LiAlH₄ will not reduce when a lithium sequestering reagent is used such as stoichiometric  kryptand or 12-crown-4₄.  The lone pair on nitrogen being farther away from the nucleus means that it will form a stronger bond to a metal ion compared to sp² oxygen...

[BobfromNC]

In NaCNBH3 in MeOH, the proton from the alcohol can provide a proton, but your starting amine looses a proton once the alkyl group attaches, so you ultimately are just shuffling protons around, not really creating or losing them.   You may also create a trace of NaCNBH2OMe, which would release some water to the reaction.   And when you form the imine, you release water in any case, which provides protons for future needs.   I still find that in many cases a drop of acetic acid helps the reaction, but it is case and substrate dependent.   

In the triacetoxy case, there is no need for acid, as the borohydride is already weakened so much in reducing ability.