Enhancing the Sustainability and Scalability of Transition-Metal-Free Stereoretentive Decarboxylative Amidation with Dioxazolones

Abstract

Herein, we present an investigation into the scalability and sustainability of decarboxylative amidation for constructing C(sp(3))-N bonds using dioxazolones as the amino source under transition-metal-free and ambient conditions. One of the concerns regarding the sustainability of the previously developed amidation protocol, mainly arising from the use of dimethyl sulfoxide (DMSO), was successfully addressed through reoptimization. Ethyl acetate can now serve as an effective, environmentally friendly alternative reaction medium. We also present the results of a sensitivity study of the newly optimized amidation conditions, examining parameters such as O-2 levels, concentrations, water content, and temperatures. The practicability of this stereoretentive decarboxylative amidation has been validated through multigram-scale reactions (5-50 mmol), including optically active carboxylic acids such as (S)-Naproxen.