Propargylic and allylic amines are important building blocks for the total synthesis of complex natural products,
pharmaceuticals, and plant pesticides. In addition to their synthetic utility, some propargylic amine derivatives
display interesting biological properties.
The most direct access to these important synthetic blocks relies on the alkynylation of imines. Classical
methodologies for the preparation of propargylic and allylic amines have usually exploited the relatively high
acidity of a terminal acetylenic C-H bond to form metal acetylide reagents by reaction with strong bases. The
so-formed organometallic compounds were then able to undergo nucleophilic addition to imines to form the
products. Clearly, the strongly basic reagents employed in such reactions are incompatible with sensitive
substrates, and therefore alkyne deprotonation often had to be carried out in a separate reaction step. In
particular, highly functionalized imines, bearing one, two or even three halogen atoms in different positions have
not been investigated at all in this respect. Recently, we investigated the catalytic conversion of α,α-dichloro
aldimines to propargylic amines. None of the "classical" transition metal catalyzed alkynylations lead to the
propargylic amines. Therefore, we developed a new methodology for the efficient alkynylation of α,α-dichloro
aldimines with alkynes in the presence of a catalytic amount of indium(III) triflate giving rise to
beta,beta-dichloropropargylic amines in good yields.
The present proposal will, in the first place, make use of our newly developed indium(III) catalyzed alkynylation
to further broaden the scope of this reaction to other polyhalogenated, α-monohalo- and beta-monohalo imines.
Attempts will be made to develop alternative catalytic methods which make use of other, cheaper metals such as
copper and iron to promote this conversion. The presence of the halogen atoms in the envisaged propargylic
amines offers a unique opportunity to further elaborate these molecules and to subject them to an in depth
reactivity study. So far, the combination of an electrophilic alkyne, a nucleophilic amine and a electrophilic
dichloromethylene group has never been synthetically exploited. Since the 1,2-addition of an acetylide anion to
the imine also generates a stereogenic C-atom, the influence of the addition of chiral ligands to the catalytic
system will be investigated.