Enantioselective modular synthesis of α-aryl-α-heteroaryl aminonitriles with parts per million organocatalyst loading: mechanistic investigation for stereochemical origins

Abstract

Heteroaromatic installation and peripheral modifications are the most common reactions in the pharmaceutical industry. However, the synthesis of biologically important aminonitrile-functionalized heteroaromatics remains unexplored. Although nucleophilic aminonitrile introduction and Strecker reaction under enantioselective catalytic conditions enable facile access to chiral aminonitriles, these approaches largely disfavor substrates with highly steric substituents on the imine carbon atom, thus affording limited products. Herein, we report an efficient and versatile method that combines the traditional methods to generate α-aryl-α-heteroaryl-aminonitriles. This methodology exhibits a broad scope and can form bonds even when using low-reactive Friedel–Crafts nucleophiles through a mild and practical protocol. It should be highlighted that the catalyst loading could be reduced to parts per billion, giving rise to phenomenal turn-over-number (TON) and turn-over-frequency (TOF) values. Interestingly, different stereochemistries between the pyrrole and indole adducts were obtained with the same (R)-derived chiral phosphoric acid catalysis. Computational studies have indicated that this unpredicted stereoreversal is due to the coordination system between iminonitriles and catalysts, helping us understand the origin of the stereochemical outcome of the traditional Friedel–Crafts reaction.