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

Herein, we present an investigation into the scalability and sustainability of decarboxylative amidation for constructing C­(sp3)–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 O2 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.本研究针对无过渡金属、常温常压条件下以二噁唑酮（dioxazolones）为氨基源构建碳(sp³)-氮键的脱羧酰胺化（decarboxylative amidation）反应的可扩展性与可持续性展开探究。此前开发的该酰胺化反应工艺因使用二甲基亚砜（DMSO）而存在可持续性方面的隐患，本次研究通过重新优化成功解决了这一问题，现已采用乙酸乙酯作为高效且环境友好的反应介质替代溶剂。此外，本研究还针对优化后的酰胺化反应条件开展敏感性研究，考察了氧气含量、底物浓度、含水量及反应温度等参数。本研究通过5–50 mmol级的多克规模反应验证了该立体保留型脱羧酰胺化反应的实用性，所涉及的底物包括(S)-萘普生[(S)-Naproxen]这类手性羧酸。