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

Abstract

The stereoselective synthesis of several secondary propargylamines by 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 the CuSO4/NaI or CeCl3ꞏ7H2O/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 absolute relative configurations of each of the obtained propargylamines, previously unknown in the literature, were attributed by comparison of the 1H-NMR experimental chemical shifts with those theoretically predicted via the DFT-GIAO method.