Synthesis of Polysubstituted Piperidines by Diels-Alder Reaction of N-Alkenyl Iminiums

piperidines - Diels-Alder cycloaddition - three-component reaction

Significance

The synthesis of piperidine derivatives by the [4+2] cycloaddition of N-alkenyl iminium ion 2 with alkene dienophiles is reported. Treatment of methoxymethyl enamine 1 with TiCl₄ gave diene 2, which was trapped in situ with a range of alkenes to give iminium cycloadducts 3, 5, 8, and 10. Addition of a nucleophile (allyl silane, indole) afforded piperidines 4, 6, 7, and 9 in excellent yield with complete endo selectivity. Quenching iminium salt 10 with triethylamine generated the tetrahydropyridine 11 as a single isomer.

Comment

Piperidine structural motifs are found in a large number of natural products and pharmaceuticals. The hetero-Diels-Alder reaction is a powerful method for the synthesis of this class of compound. The current method generates an iminium cycloadduct which allows for further functionalization by addition of a nucleophile to afford highly substituted piperidine derivatives in one pot from readily available starting materials.