Catalytic Hydrogenation of Cyanohydrin Esters as a Novel Approach to N-Acylated beta-Amino Alcohols-Reaction Optimisation by a Design of Experiment Approach

摘要

The catalytic hydrogenation of acylated cyanohydrins and subsequent intramolecular migration of the acyl group to yield pharmaceutically interesting N-acyl p-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 p-amino alcohols in yields(determined by GC)of up to 90 % for aliphatic substrates and up to 50 % for benzylic 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.