Beta-haloamines as building-blocks: The case of 2-amino-3-halo-1-oxypropanes

Beta-halo amines comprise plentiful application, mainly as synthons in organic chemistry and as anticancer agents in medical chemistry. Their activity field is broad, as they have been studied/used as building blocks for the synthesis of brain protective agents, receptor ligands for the treatment on central nervous system and peripheral disorders (stress, anxiety, depression, cardiovascular and eating disorders), but also herbicides and antioxidant lubricant additives, for instance.
The first thing a classical synthetic organic chemist comes up with about b-halo amines is that these structures may be prone to form aziridinium species, perhaps too prone to be targeted as the final product for industrial applications. In fact, these compounds are frequently reported in the literature as substrates for further elaboration towards all kinds of target compounds, being more or less stable. But very interestingly, 2-amino-3-halo-1-oxypropanes have been investigated so far and its stability has been demonstrated along the way. To qualitatively praise the limits of their stability is worthy to watch out the synthetic procedures available.

Methods towards the syntesis of 2-amino-3-halo-1-oxypropanes fall mostly into three categories: (1) ring opening of epichlorohydrin, (2) ring opening of aziridine derivatives, and (3) using L-serine as starting material.

1. Upon treatment of epihalodydrin with a nucleophilic amine through ring opening of the epoxide at the less hindered position. The synthesis of the other regioisomers requires ring opening at the more hindered position, which is unfavoured (and so needs of particular conditions).


2. Upon the old and straightforward reaction which involves the ring opening of aziridines by means of HX at the less hindered position. This option deserves further elaboration, since despite its potential, has been applied rarely, as the review quoted below points out.


3. The main path according to the literature ie starting from the naturally occurring amino acid L-serine (which interestingly includes a chiral center in its structure). There is more than one synthetic procedure according to the particular targets.

For a recent review see Tetrahedron 64 (2008) 3275-3285.