康 · 学术 | Reaction of the Day No. 1746

A Convenient Conversion of Amides to Ketones

Amy J. Su, Andrew W. Chen, Chunge Li, Nick R. Wierich, Brenda Wu, Clare L. Phelps, Todd J. Martínez, and Noah Z. Burns*

Department of Chemistry, Stanford University, Stanford, California 94305, United States;

—JACS,2026, doi: 10.1021/jacs.6c15781

Recommended by Depei Meng _ MC4

KEY WORDS: Skeletal editing, Nitrogen deletion (反应类型), C(=O)─C(sp3) (成键类型), amides (原料), ketones (产物).

ABSTRACT: Amides are classic motifs for further functional group transformations because of their abundance and well-established syntheses. Herein we describe a general route to ketones from secondary amides through direct nitrogen deletion, preserving the remainder of the structural scaffold. The transformation proceeds through rapid oxidation of hydrazides, which are accessed via N-amination of the parent amides. Our protocol employs simple, commercial reagents in a wet organic solvent, open to air. This method can be performed in one pot and translates smoothly to gram scale, demonstrating a unique retrosynthetic logic toward ketone targets.

Established amide transformations and amide-to-ketone reactions relevant to this work

Precedent for ketone formation from hydrazides, and general conditions for hydrazide synthesis from amides

Screening of oxidants in pursuit of standard reaction conditions and application to one-pot and gram-scale reactions

Substrate Scope

Mechanistic studies

Summary and Comments

In summary, Prof. Noah Burns’ group have achieved a general intramolecular conversion of secondary amides to ketones via hydrazides. Our protocol uses common commercial reagents in wet solvent, open to air. This method exhibits convenience, scalability, and practicality. It is operationally straightforward and remarkably clean. Numerous functional groups are tolerated in this transformation, suggesting compatibility with late-stage functionalizations of complex compounds. In essence, we have described a coupling approach to ketones from amines and carboxylic acids utilizing classic amidation techniques as the inherent retrosynthetic logic. Extension of this methodology to more elaborate ketone targets such as macrocycles and peptides is currently ongoing.

总地来说，美国斯坦福大学Noah Burns教授课题组实现了二级酰胺通过酰肼向酮的通用分子内转化。该方案使用商业化试剂，在湿溶剂中、空气氛围下进行，具有便捷、可放大和实用的特点。操作简单且反应非常干净，耐受多种官能团，适用于复杂化合物的后期官能团化。本质上，该方法描述了一种从胺和羧酸出发构建酮的偶联策略，以经典酰胺化技术作为内在的逆合成逻辑。目前，将该方法拓展至大环和肽等更复杂酮目标的工作正在进行中。