Zirconium-catalyzed asymmetric Kabachnik-Fields reactions of aromatic and aliphatic aldehydes

An effective catalyst has been developed for the three-component reaction of aldehydes, anilines and phosphites in an asymmetric catalytic Kabachnik-Fields reaction to give alpha-aminophosphonates. A catalyst was sought that would give high asymmetric inductions for aromatic and, and more particularly, for aliphatic aldehydes since there has not previously been an effective catalyst developed for this class of aldehydes. The optimal catalyst is prepared from three equivalents of the 7,7 '-di-t-butylVANOL ligand, one equivalent of N-methylimidazole and one equivalent of zirconium tetraisopropoxide. This catalyst was most efficient in the presence of 10 mol% benzoic acid. Optimal conditions for aryl aldehydes required the use of 3,5-diisopropyl-2-hydroxyaniline and gave the aryl alpha-aminophosphonates in up to 96% yield and 98% ee over 11 different aryl aldehydes. The best aniline for aliphatic aldehydes was found to be 3-t-butyl-2-hydroxyaniline and gave the corresponding phosphonates in up to 83% yield and 97% ee over 18 examples. The asymmetric inductions for aliphatic aldehydes were comparable with those for aromatic aldehydes with a mean induction of 90% ee for the former and 91% ee for the latter. The best method for the liberation of the free amine from the aniline substituted alpha-aminophosphonates involved oxidation with N-iodosuccinimide.

Automated summary

An effective catalyst has been developed for the three-component reaction of aldehydes, anilines and phosphites in an asymmetric catalytic Kabachnik-Fields reaction to give alpha-aminophosphonates. The optimal catalyst is prepared from specific ligands and zirconium tetraisopropoxide, and in the presence of benzoic acid. The best conditions for aryl aldehydes and aliphatic aldehydes were identified, with comparable asymmetric inductions achieved for both types of aldehydes.