Diastereoselective Synthesis of Secondary Propargylamines Exploiting CuI-Based Promoters and Determination of Their Relative Configuration by DFT-GIAO Conformational Analysis

The stereoselective synthesis of several secondary propargylamines by the copper-promoted A³-coupling reaction of aliphatic and aromatic aldehydes with phenylacetylene and (R)-(+)-phenylethylamine is here reported. Two different synthetic methodologies have been investigated in this study, involving CuSO₄/NaI and CeCl₃·7H₂O/CuI promoting systems. The reported methodologies were compared in terms of efficiency, diastereoselectivity, and toxicity, both showing advantages with respect to the current methodologies. The relative configurations of each of the obtained propargylamines, previously unknown in the literature, were assigned by comparison of the ¹H NMR experimental chemical shifts with those theoretically predicted via the DFT-GIAO method.