A Modified System for the Synthesis of Enantioenriched N -Arylamines through Copper-Catalyzed Hydroamination

Abstract

Despite significant recent progress in copper-catalyzed enantioselective hydroamination chemistry, the synthesis of chiral N-arylamines, which are frequently found in natural products and pharmaceuticals, has not been realized. Initial experiments with N-arylhydroxylamine ester electrophiles were unsuccessful and, instead, their reduction in the presence of copper hydride (CuH) catalysts was observed. Herein, we report key modifications to our previously reported hydroamination methods that lead to broadly applicable conditions for the enantioselective net addition of secondary anilines across the double bond of styrenes, 1,1-disubstituted olefins, and terminal alkenes. NMR studies suggest that suppression of the undesired reduction pathway is the basis for the dramatic improvements in yield under the reported method. A Modified System for the Synthesis of Enantioenriched N-Arylamines through Copper-Catalyzed HydroaminationSaki Ichikawa, Dr. Shaolin Zhu, and Prof. Dr Stephen L. BuchwaldDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, United StatesAbstractDespite significant recent progress in the copper-catalyzed enantioselective hydroamination chemistry, the synthesis of chiral N-arylamines, which are frequently found in natural products and pharmaceuticals, has not been realized. Initial experiments with N-arylhydroxylamine ester electrophiles were unsuccessful and, instead, their reduction in the presence of copper hydride (CuH) catalysts was observed. Herein, we report key modifications to our previously reported hydroamination methods that lead to broadly applicable conditions for the enantioselective net addition of secondary anilines across the double bond of styrenes, 1,1-disubstituted olefins, and terminal alkenes. NMR studies suggest that suppression of the undesired reduction pathway is the basis for the dramatic improvements in yield under the reported protocol.A modified systemAn efficient method for the preparation of enaptioenriched N-arylamines was developed by making key modifications to a previously reported hydroamination. The reaction is mediated by a copper(I)-hydride (CuH) catalyst, and wide range of olefins and N-arylhydroxylamines are compatible under the optimized conditions. Key to the successful development of this method was the addition of tBuOH and PPh3 to the reaction mixture. Keywords: hydroamination; copper; enantioenriched N-arylamines; asymmetric synthesis