The Selective <i>N</i>‐Functionalization of Indoles via <i>aza</i>‐Michael Addition in the Ligand Sphere of a Chiral Nickel(II) Complex: Asymmetric Synthesis of (<i>S</i>)‐1<i>H</i>‐Indole‐Alanine Derivatives

Abstract

The selective addition of electrophilic C=C double bonds to the N–H bond of indoles is a challenging task due to the high nucleophilicity of indoles at their C3‐position. Herein, we report the successful selective intermolecular N ‐functionalization of various indoles via aza ‐Michael addition of C=C double bond of a dehydroalanine Schiff base, which takes place in the ligand sphere of a chiral Ni II complex in the presence of sodium hydride. The resulting hydroaminated Ni II complexes were isolated in 55–82 % yields with excellent diastereoselectivity ( dr &gt; 99:1) (8 examples). And the actual products of interest, namely ( S )‐2‐amino‐3‐(1 H ‐indol‐1‐yl)propanoic acids, were subsequently released from the Ni II complexes via aqueous HCl treatment of the Ni II complexes and isolated with excellent enantioselectivity (&gt; 99 % ee ). The chiral auxiliary [( S )‐BPB = ( S )‐2‐( N ‐benzylprolyl)aminobenzophenone] and Ni II ions can be easily recovered after the acidic complex cleavage step and reused for the synthesis of the starting Ni II complex. Moreover, the indole′s preference for nucleophilic attack via its N1‐ over its C3‐position was rationalized by DFT calculations.