Synthesis of Allene Substituted Nipecotic Acids by Allenylation of Terminal Alkynes

The relative reactivities of several secondary amines serving as hydride donors in propargylic amines undergoing a [1,5]-hydride transfer reaction to yield the respective terminal and 1,3-disubstituted allenes were studied. For this study, a two-step procedure was employed. At first, the synthesis of propargylic amines via the Cu^I-catalyzed aldehyde-alkyne-amine reactions (A³ coupling) was accomplished. The obtained propargylic amines were subsequently transformed to the desired allenes under CdI₂ or ZnI₂ catalysis. As a result, among the various secondary amines employed, differing in steric bulk, electronic nature, and conformational properties, allyl(tert-butyl)amine was found to be the best hydride donor for the synthesis of terminal allenes. For the synthesis of 1,3-disubstituted allenes, the propyne derivatives containing either a allyl(tert-butyl)amine or a 1,2,3,6-tetrahydropyridine unit in propargylic position performed best. Finally, with the developed procedure, nipecotic acid derivatives containing an N-allenyl substituent were synthesized with good yields using either ZnI₂ as catalyst for the preparation of 1-substituted or CdI₂ for the synthesis of 1,3-disubstitued allenes.