Minisci-Type Alkylation of N-Heteroarenes by N-(Acyloxy)phthalimide Esters Mediated by a Hantzsch Ester and Blue LED Light

A synthetic method that enables the Hantzsch ester-mediated Minisci-type C2-alkylation of quinolines, isoquinolines and pyridines by N-(acyloxy)phthalimide esters (NHPI) under blue LED (light emitting diode) light (456 nm) is described. Achieved under mild reaction conditions at room temperature, the metal-free synthetic protocol was shown to be applicable to primary, secondary and tertiary NHPIs to give the alkylated N-heterocyclic products in yields of 21-99%. On introducing a chiral phosphoric acid, an asymmetric version of the reaction was also realised and provided product enantiomeric excess (ee) values of 53-99%. The reaction mechanism was delineated to involve excitation of an electron-donor acceptor (EDA) complex, formed from weak electrostatic interactions between the Hantzsch ester and NHPI, which generates the posited radical species of the redox active ester that undergoes addition to the N-heterocycle.

Automated summary

A synthetic method for the Hantzsch ester-mediated C2-alkylation of quinolines, isoquinolines, and pyridines using N-(acyloxy)phthalimide esters (NHPI) under blue LED light has been described. The metal-free protocol provides alkylated N-heterocyclic products with high yields and can be carried out at room temperature. The introduction of a chiral phosphoric acid enables an asymmetric version of the reaction with high enantiomeric excess values. The reaction mechanism involves the excitation of an electron-donor acceptor complex and the addition of a radical species to the N-heterocycle.