Cu-Catalyzed Enantioconvergent Synthesis of N-Alkyl Amides from Racemic Alcohols
Abstract
Enantioconvergent amidation of racemic alcohols offers a powerful retrosynthetic disconnection to convert abundant, readily accessible alcohol feedstocks into chiral N-alkyl amides, while streamlining access to valuable enantioenriched primary amines. However, a mechanistic framework that can integrate efficient C(sp3)–O bond cleavage with enantioselective amidation has remained understudied. Herein, we report the enantioconvergent deoxygenative amidation of racemic alcohols through a Cu-catalyzed radical relay. β-Scission of oxidant-derived electrophilic alkoxy radicals was leveraged as a radical-umpolung event, producing nucleophilic methyl radicals that effectively activate alcohol substrate-derived xanthates. Computation-guided optimization revealed that increasing xanthate electrophilicity facilitates methyl-radical addition and improves reaction efficiency. The transformation accommodates a variety of alcohols and amides with high enantioselectivity, and the reaction conditions are compatible with medicinally relevant functional groups, heterocycles, and pharmaceutical frameworks. Synthetic applications of this protocol streamline access to enantioenriched β-amino alcohols and biologically active primary amines, circumventing the need for enantioenriched alcohol precursors. Mechanistic studies revealed that polarity matching favors the capture of electron-deficient carbon-centered radicals by electron-rich CuII–amidates. Under catalytic conditions, however, the greater acidity of electron-deficient amides facilitates transmetalation, accelerating the formation of CuII–amidate and enhancing coupling efficiency.
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BibTeX
@misc{vu2026cucatalyzed,
title = {{Cu-Catalyzed Enantioconvergent Synthesis of N-Alkyl Amides from Racemic Alcohols}},
author = {Jonathan Vu and Eve Yuanwei Xu and Tanner S. Schubert and Matthew J. Metzger and Yongxian Li and Robert S. Paton and Yuyang Dong},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010339/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010339/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Cu-Catalyzed Enantioconvergent Synthesis of N-Alkyl Amides from Racemic Alcohols
AU - Jonathan Vu
AU - Eve Yuanwei Xu
AU - Tanner S. Schubert
AU - Matthew J. Metzger
AU - Yongxian Li
AU - Robert S. Paton
AU - Yuyang Dong
PY - 2026
DA - 2026/10/13
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010339/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010339/v1
AB - Enantioconvergent amidation of racemic alcohols offers a powerful retrosynthetic disconnection to convert abundant, readily accessible alcohol feedstocks into chiral N-alkyl amides, while streamlining access to valuable enantioenriched primary amines. However, a mechanistic framework that can integrate efficient C(sp3)–O bond cleavage with enantioselective amidation has remained understudied. Herein, we report the enantioconvergent deoxygenative amidation of racemic alcohols through a Cu-catalyzed radical relay. β-Scission of oxidant-derived electrophilic alkoxy radicals was leveraged as a radical-umpolung event, producing nucleophilic methyl radicals that effectively activate alcohol substrate-derived xanthates. Computation-guided optimization revealed that increasing xanthate electrophilicity facilitates methyl-radical addition and improves reaction efficiency. The transformation accommodates a variety of alcohols and amides with high enantioselectivity, and the reaction conditions are compatible with medicinally relevant functional groups, heterocycles, and pharmaceutical frameworks. Synthetic applications of this protocol streamline access to enantioenriched β-amino alcohols and biologically active primary amines, circumventing the need for enantioenriched alcohol precursors. Mechanistic studies revealed that polarity matching favors the capture of electron-deficient carbon-centered radicals by electron-rich CuII–amidates. Under catalytic conditions, however, the greater acidity of electron-deficient amides facilitates transmetalation, accelerating the formation of CuII–amidate and enhancing coupling efficiency.
ER -