Catalytic hydrogenation of cyanohydrin esters as a novel approach to N-acylated β-aminio alcohols -: Reaction optimisation by a design of experiment approach

The catalytic hydrogenation of acyldted cyanohydrins and subsequent intramolecular migration of the acyl group to yield pharmaceutically interesting N-acyl beta-amino alcohols is shown to be a successful one-pot preparation method. The combination of a multistep DoE approach and high-throughput methodology proved to be an effective strategy for the optimisation of the reaction. With the favoured catalyst/solvent combination of nickel on alumina in dioxane, both hydrogenation and acyl group migration proceeded smoothly, giving the N-acyl beta-amino alcohols in yields (determined by GC) of up to 90% for aliphatic substrates and up to 50% for benzyhc ones, the latter being more prone to side reactions. No racemisation was found to occur at the chiral centre of an aliphatic molecule when an enantiopure cyanohydrin ester was used, though a minor decrease in ee was observed with a benzylic substrate. (c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006.