Cobaloxime catalyzed carbene insertion into N–H bonds: a streamlined route to α-amino esters with mechanistic insights

Abstract

The efficient construction of carbon–nitrogen bonds is fundamental to the synthesis of pharmaceuticals, agrochemicals, and natural products, particularly for α-amino esters. Transition-metal-catalyzed carbene insertion into N–H bonds offers a powerful approach due to its efficiency and selectivity, but has predominantly been developed using noble metal catalysts. Although, select base metals have been explored, cobalt catalysts remain scarce. Herein, we report an N–H insertion reaction to form α-amino esters catalyzed by a cobaloxime catalyst, using diazo compounds as the carbene precursors. With low catalyst loading, primary, secondary, and (hetero)aromatic amines all react smoothly (up to 97%). While comprehensive mechanistic studies suggest a cobalt alkyl ylide intermediate dominates these reactions, we observe small contributions of a carbene radical. This approach can be applied in the late-stage functionalization of various N-containing bioactive molecules, highlighting its potential synthetic application.