A New Method of Synthesis of 6-Substituted Piperidine-2,4-diones from Homoallylamines

Mono- and dihomoallylamines serve as convenient precursors for the preparation of 6-substituted piperidine-2,4-diones. This transformation is based, on the one hand, on a simple and well-known halocyclocarbamation reaction proceeding by the addition of a source of cationic halogen to the N-Boc-protected homoallylamines and, on the other, on a new enolate-isocyanate rearrangement that proceeds by the action of strong bases on bromocyclocarbamates. A set of racemic dihomoallylamines were prepared by the allylboration of nitriles or primary amides with triallylborane and enantiomerically enriched N-Boc-1-phenyl-3-butenylamine was synthesized by the addition of (–)-AllB(Ipc)2 to the corresponding silylimine. Chiral precursors containing a carboxylic ester group were synthesized from (S)-allylglycine and-alanine. The reactions of N-Boc derivatives with NBS smoothly produced the corresponding bromocyclocarbamates either in the form of a single diastereomer or as an isomeric mixture. All these bromourethanes were cleanly transformed into 6-substituted piperidine-2,4-diones in good yields via the formation of intermediate cyclic enolates, which was confirmed by the direct synthesis of enolate 12 and its transformation into dione 8 in a series of kinetic experiments. Based on the experimental results, a mechanism for the new enolate-isocyanate rearrangement is proposed.