Catalytic alkynylation and alkenylation of functionalized imines and further transformation of the obtained propargylic and allylic amines 01/10/2015 - 30/09/2019


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 desired 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.


Research team(s)