Regio‐ and Enantioselective Synthesis of 1,2‐Diamines by Formal Hydroamination of Enamines: Scope, Mechanism, and Asymmetric Synthesis of Orthogonally Protected Bis‐Piperazines as a Privileged Scaffold

Abstract

AbstractWe have previously reported the first formal hydroamination of enamines for the synthesis of chiral 1,2‐diamines. Here, we describe: (i) the discovery, optimization, and substrate expansion of this reaction; (ii) a novel and straightforward protocol for the “click‐type” synthesis of enamines in quantitative yield utilizing sodium sulfate in a dual role as an ancillary and dehydrating agent without the need for workup or purification; (iii) the application of this methodology to the first enantioselective synthesis of orthogonally protected 1,1′‐(1‐(4‐fluorophenyl)ethane‐1,2‐diyl) piperazines, a scaffold for rapid lead optimization in drug discovery; (iv) a computational investigation into the mechanism and rationalization of the enantioselectivities of the reaction.