Redox-Neutral Umpolung Synthesis of α-Functionalized Amides

α-Heteroatom-substituted amides are useful as both targets and intermediates but are challenging to synthesize via conventional enolate chemistry. Herein, we describe a general and unified umpolung procedure to prepare α-heteroatom-functionalized secondary amides with various heteroatom-based nucleophiles under redox-neutral conditions. This transformation is a formal oxidation state reshuffle process from -N to -C in the hydroxamate, thereby achieving the umpolung α-heterofunctionalization of carbonyl groups without external oxidants. Regulated by the reshuffle mechanism, functionalization exclusively occurs at the α-position of the hydroxamate and precisely affords the α-functionalized amide with reliable predictability even in complex settings. Density functional theory studies support that soft enolization enabled by Mg<sup>2+</sup>/DIPEA combination is essential to facilitate the formation of the α-lactam intermediate. This represents the first general protocol to prepare α-functionalized secondary amides.

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Publication Details

Journal
JACS Au
Published
2024-10-26
DOI
https://doi.org/10.1021/jacsau.4c00767
Citations
8
Primary Topic
Advanced Synthetic Organic Chemistry
Type
article
Field-Weighted Citation Impact
2.00

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article

Redox-Neutral Umpolung Synthesis of α-Functionalized Amides

Yuan‐Ye Jiang, Rui Wang, Wenbo Liu, Shaokang An et al.
8 citations
JACS Au
Advanced Synthetic Organic Chemistry
2.00
article

Redox-Neutral Umpolung Synthesis of α-Functionalized Amides

Yuan‐Ye Jiang, Rui Wang, Wenbo Liu, Shaokang An, Yi-Xuan Xin
article en
8 citations

Abstract

α-Heteroatom-substituted amides are useful as both targets and intermediates but are challenging to synthesize via conventional enolate chemistry. Herein, we describe a general and unified umpolung procedure to prepare α-heteroatom-functionalized secondary amides with various heteroatom-based nucleophiles under redox-neutral conditions. This transformation is a formal oxidation state reshuffle process from -N to -C in the hydroxamate, thereby achieving the umpolung α-heterofunctionalization of carbonyl groups without external oxidants. Regulated by the reshuffle mechanism, functionalization exclusively occurs at the α-position of the hydroxamate and precisely affords the α-functionalized amide with reliable predictability even in complex settings. Density functional theory studies support that soft enolization enabled by Mg<sup>2+</sup>/DIPEA combination is essential to facilitate the formation of the α-lactam intermediate. This represents the first general protocol to prepare α-functionalized secondary amides.

JACS AuVol. 4(11)
Sun Yat-sen University (CN), Qufu Normal University (CN)
Qufu Normal University, National Natural Science Foundation of China, Sun Yat-sen University, Basic and Applied Basic Research Foundation of Guangdong Province
Openalex Percentile: Top 14%
Advanced Synthetic Organic Chemistry
2.00
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Redox-Neutral Umpolung Synthesis of α-Functionalized Amides — Yuan‐Ye Jiang, Rui Wang, et al. · JACS Au (2024) | TGRS Research Map | TGRS