A Mechanistic Study of Umpolung Amide Synthesis, the Straightforward Synthesis of 18O-Labeled Amides, and the Development of Catalytic Umpolung Amide Synthesis

Abstract

Johnston and coworkers recently reported a novel amide bond forming reaction wherein the amine acts as the electrophile and the carbon donor acts as the nucleophile (Umpolung Amide Synthesis). In the following study, the mechanism through which this reaction occurred was investigated by evaluating potential oxygen sources that could be responsible for the formation of the amide carbonyl. Using a series of 18O-labeled nitroalkane substrates, it was determined that the reaction could proceed through two distinct pathways: 1) an aerobic pathway, where oxygen from the air acts as the oxygen source and 2) an anaerobic pathway, where a nitro to nitrite isomerization occurs to allow the nitro group to act as the oxygen source. Once the mechanism had been evaluated, a simple protocol was developed for the direct formation of 18O-labeled amides using 18O-labeled gas. This discovery also led to the development of a method for the formation of doubly-18O-labeled peptides and an oxygen-catalyzed version of Umpolung Amide Synthesis.