Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide ¹⁸ O-labeling

Abstract

The mechanism of umpolung amide synthesis was probed by interrogating potential sources for the oxygen of the product amide carbonyl that emanates from the α-bromo nitroalkane substrate. Using a series of 18 O-labeled substrates and reagents, evidence is gathered to advance two pathways from the putative tetrahedral intermediate. Under anaerobic conditions, a nitro-nitrite isomerization delivers the amide oxygen from nitro oxygen. The same homolytic nitro-carbon fragmentation can be diverted by capture of the carbon radical intermediate with oxygen gas (O 2 ) to deliver the amide oxygen from O 2 . This understanding was used to develop a straightforward protocol for the preparation of 18 O-labeled amides in peptides by simply performing the umpolung amide synthesis reaction under an atmosphere of .

Oxidative Amidation of Nitroalkanes with Amine Nucleophiles using Molecular Oxygen and Iodine

“…(3)). In short, all attempts to prepare,i nfer, or observe the anticipated N-iodo amines, [5][6][7] were not confirmed in our hands.I nstead, we interpret our NMR data to show that amines like allylamine and a-methyl benzyl amine form acomplex readily with NIS and precipitate,a nd these precipitates behave chemically as sources of electrophilic iodine and nucleophilic amine.F or …”

“…[5][6][7] This was the case even by directly reacting pre-formed N-bromo amines (or 15,see above) with the aci-nitronate of 1;i nf act, this generated the a-bromo analogue of 4 in good yields. [16] Having confirmed the aiodide 4 as the primary intermediate,t wo possible pathways to form the amide product 7 were considered;o ne pathway being where an oxygen molecule first reacts with 4 before the amine component, and in the other pathway the amine reacts with 4 first.…”

“…[ [5][6][7] Among such possibilities,wecurrently favor the formation of ap eroxy radical [18] 17,w hich can cyclize and expel am ono-iodine or nitrite radical to form ar eactive dioxirane intermediate (cf.E q. (3)).…”

“…[5][6][7] Herein, during the course of developing an atom-economical, direct amidation procedure of readily prepared chiral nitroalkanes, [9,10] we describe our independent findings and ultimately propose new mechanistic aspects that have general implications both in amine/halogen-based chemistry and in UmAS chemistry.…”

1,3,4-Oxadiazole and Heteroaromatic-Fused 1,2,4-Triazole Synthesis­ Using Diverted Umpolung Amide Synthesis

“…However, this was unanticipated, yet consistent with the formation of a tetrahedral intermediate hypothesized in our prior work (Scheme 1). 19 This tetrahedral intermediate was diverted from the diacyl hydrazide, directly to the heterocyclic product by intramolecular cyclization. Rather generous changes to both the α-bromo nitroalkane donor and the acyl hydrazide acceptor were tolerated, as judged by yields ranging from 43% to 81%.…”