Preparation of N-Aryl Amides by Epimerization-Free Umpolung Amide Synthesis

Abstract

Amide synthesis is one of the most widely practiced chemical reactions, owing to its use in drug development and peptide synthesis. Despite the importance of these applications, the attendant effort to eliminate waste associated with these protocols has met with limited success, and pernicious α-epimerization is most often minimized but not eliminated when targeting challenging amides (e.g., N-aryl amides). This effort has focused on what is essentially a single paradigm in amide formation wherein an electrophilic acyl donor reacts with a nucleophilic amine. Umpolung amide synthesis (UmAS) emerged from α-halo nitroalkane reactions with amines and has since been developed into a method for the synthesis of enantiopure amides using entirely catalytic, enantioselective synthesis. However, its inability to forge N-aryl amides has been a longstanding problem, one limiting its application more broadly in drug development where α-chiral N-aryl amides are increasingly common. We report here the reaction of αfluoronitroalkanes and N-aryl hydroxyl amines for the direct synthesis of N-aryl amides using a simple Brønsted base as the promoter. No other activating agents are required, and experiments guided by mechanistic hypotheses outline a mechanism based on the UmAS paradigm and confirm that the N-aryl amide, not the N-aryl hydroxamic acid, is the direct product. Ultimately, select chiral α-amino-N-aryl amides were prepared with complete conservation of enantioenrichment, in contrast to a parallel demonstration of their ability to epimerize using the conventional amide synthesis alternative.

Nitroalkanes as Thioacyl Equivalents to Access Thioamides and Thiopeptides

“…[28] The Johnston group further expanded their UmAS concept to an extensive range of chiral nitroalkanes and amines. [29][30][31][32][33][34] Inspired by this body of work and our own amidation studies with the Hayashi group, [35] we herein show the synergistic combination of readily available chiral nitroalkanes with amines and elemental sulfur provides a direct and efficient method to form thioamides and thiopeptides in excellent yields (Fig. 1d).…”

Recent Advances in Carbon‐Nitrogen/Carbon‐Oxygen Bond Formation Under Transition‐Metal‐Free Conditions

“…Apart from the above-mentioned typical synthetic approaches, alternative TM-free strategies for amide bond formation using new substrates or catalysts have also been reported. Thus, this section mainly focuses on these strategies including an umpolung amide synthesis (UmAS) strategy, [74] carbonyl generation via rearrangement of highly reactive nitrile imines, [75] photo-induced decomposition of 1,4,2-dioxzaol-5ones, [76] and CÀ X (X=C, N and Br) cleavages. [77] In 2022, Johnston group discovered the UmAS strategy for Cs 2 CO 3 -promoted amidation between α-fluoronitroalkanes (128) and N-aryl hydroxylamines (129) without additional activating reagents (Scheme 24a).…”

“…In 2022, Johnston group discovered the UmAS strategy for Cs 2 CO 3 ‐promoted amidation between α‐fluoronitroalkanes ( 128 ) and N ‐aryl hydroxylamines ( 129 ) without additional activating reagents (Scheme 24a) [74a] . Haloamino nitroalkane (HANA, 130 ) was proposed as an active intermediate, which could be further transformed into the amide products ( 131 ) with the elimination of cesium nitrate (CsNO 2 ).…”

New Acetamide Derivatives of the COX-II Inhibitors-A Brief Review

“…Today in the modern methodology used in the preparation of the amide using green chemistry, the synthetic procedure includes the reaction carried out in conditions water [25], microwave [26], ultrasound [27], electro synthesis [28].…”