Enantioselective Synthesis of α-Bromonitroalkanes for Umpolung Amide Synthesis: Preparation of tert-Butyl ((1R)-1-(4-(benzyloxy)phenyl)-2-bromo-2-nitroethyl)carbamate

Lim, Victoria T.; Tsukanov, Sergey V.; Stephens, Amanda B.; Johnston, Jeffrey N.

doi:10.15227/orgsyn.093.0088

Cited by 7 publications

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References 12 publications

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“…Bromonitromethane is a versatile reagent used in the preparation of nitroheterocycles, nitrocyclopropanes, α-functionalized terminal nitroalkanes and, to a limited extent, 1,3-dipolar cycloaddition products . Advances in the synthesis of enantiopure amines, amides, and peptides have increasingly relied on the reagent, , which was commercially available at a reasonable cost for many years.…”

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confidence: 99%

Resolving Bromonitromethane Sourcing by Synthesis: Preparation at the Decagram Scale

et al. 2022

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The accessibility of bromonitromethane has declined in recent years, limiting its viability as a reagent for chemical synthesis. The reinvestigation and optimization of a variety of preparations, and the development of safe operating principles, are described. The reproducible protocol described here leverages the effectiveness of hydroxide for nitromethane bromination while respecting its incompatibility with the product it forms. This careful balance was achieved at scales up to 56 g, resulting in a reproducible procedure that provides straightforward, sustainable, and affordable access to this critical reagent.

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confidence: 99%

Resolving Bromonitromethane Sourcing by Synthesis: Preparation at the Decagram Scale

et al. 2022

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Preparation of Benzyl(( R )‐2‐(4‐(benzyloxy)phenyl)‐2‐(( tert ‐Butoxycarbonyl)Amino)Acetyl)‐D‐Phenylalaninate Using Umpolung Amide Synthesis

2018

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

2022

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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.

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Enantioselective Synthesis of α-Bromonitroalkanes for Umpolung Amide Synthesis: Preparation of tert-Butyl ((1R)-1-(4-(benzyloxy)phenyl)-2-bromo-2-nitroethyl)carbamate

Abstract: Graphical abstract

Cited by 7 publications

References 12 publications

Resolving Bromonitromethane Sourcing by Synthesis: Preparation at the Decagram Scale

Resolving Bromonitromethane Sourcing by Synthesis: Preparation at the Decagram Scale

Preparation of Benzyl(( R )‐2‐(4‐(benzyloxy)phenyl)‐2‐(( tert ‐Butoxycarbonyl)Amino)Acetyl)‐D‐Phenylalaninate Using Umpolung Amide Synthesis

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

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