Diastereo‐ and Enantioselective Hydrogenation of a Challenging Enamide Derived from 4‐Phenyl‐2‐tetralone: An Appealing Shortcut Towards Enantiopure cis‐2‐Aminotetraline Derivatives

Abstract

A clean, efficient, and diasteroselective (dr >95%) catalytic hydrogenation of the enamide N-(4-phenyl-3,4-dihydronaphthalen-2-yl)propionamide (2 a) using palladium on carbon is performed. This procedure provides the melatonin receptor ligand (+/-)-cis-4-phenyl-2-propionamidotetralin (cis-4-P-PDOT, 1 a) and its 8-methoxy analog. Furthermore, Rh and Ru catalyzed homogeneous asymmetric hydrogenation of the challenging racemic endocyclic enamide 2 a with several chiral phosphine ligands is studied. The best results, in terms of enantioselectivity, for both diastereomers are obtained when chiral Rh-Josiphos is used as the catalyst.

Synthesis and configuration determination of all enantiopure stereoisomers of the melatonin receptor ligand4-phenyl-2-propionamidotetralin using an expedient optical resolution of 4-phenyl-2-tetralone

“…Melting points were determined on a Buchi B-540 capillary melting point apparatus and are uncorrected. 1 H NMR (200 MHz) and 13 C NMR (50 MHz) spectra were recorded on a Bruker AVANCE 200 spectrometer, using CDCl 3 as solvent unless stated otherwise. Chemical shifts (d scale) are reported in parts per million (ppm) relative to the central peak of the solvent.…”

“…We also tried catalytic asymmetric hydrogenation of enamide 3 with different combinations of transition metals and chiral ligands. 12 Unfortunately, the trisubstituted endocyclic chiral enamide 3 proved to be a very challenging substrate, 13 and only limited enantioselectivity (64% and 76% ee for the cis and trans 4-P-PDOT isomers, respectively) was achieved. Therefore, it seemed worthwhile to develop and optimize an alternative method for the isolation of each 4-P-PDOT enantiomers.…”