Decarboxylative stereoretentive C–N coupling by harnessing aminating reagent

Jeonguk Kweon, Bumsu Park, Dongwook Kim and Sukbok Chang ()
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Jeonguk Kweon: Institute for Basic Science (IBS)
Bumsu Park: Korea Advanced Institute of Science and Technology (KAIST)
Dongwook Kim: Institute for Basic Science (IBS)
Sukbok Chang: Institute for Basic Science (IBS)

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract In recent decades, strategies involving transition-metal catalyzed carbon-carbon or carbon-heteroatom bond coupling have emerged as potent synthetic tools for constructing intricate molecular architectures. Among these, decarboxylative carbon-nitrogen bond formation using abundant carboxylic acids or their derivatives has garnered notable attention for accessing alkyl- or arylamines, one of key pharmacophores. While several decarboxylative amination methods have been developed, the involvement of a common carboradical intermediate currently poses challenges in achieving stereospecific transformation toward chiral alkylamines. Herein, we present a base-mediated, stereoretentive decarboxylative amidation by harnessing 1,4,2-dioxazol-5-one as a reactive and robust amidating reagent under transition-metal-free ambient conditions, encompassing all types of primary, secondary and tertiary carboxylic acids, thereby providing access to the important pharmacophore, α-chiral amines. This method exhibits high functional group tolerance, convenient scalability, and ease of applicability for 15N-isotope labeling, thus accentuating its synthetic utilities. Experimental and computational mechanistic investigations reveal a sequence of elementary steps: i) nucleophilic addition of carboxylate to dioxazolone, ii) rearrangement to form a dicarbonyl N-hydroxy intermediate, iii) conversion to hydroxamate, followed by a Lossen-type rearrangement, and finally, iv) reaction of the in situ generated isocyanate with carboxylate leading to C–N bond formation in a stereoretentive manner.

Date: 2024
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DOI: 10.1038/s41467-024-48075-w

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