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Abstract The challenging transamidation of unactivated tertiary amides has been accomplished via cooperative acid/iodide catalysis. Most crucially, the method provides a novel manifold to re‐route the reactivity of unactivated N,N‐dialkyl amides through reactive acyl iodide intermediates, thus reverting the classical order of reactivity of carboxylic acid derivatives. This method provides a direct route to amide‐to‐amide bond interconversion with excellent chemoselectivity using equivalent amounts of amines. The combination of acid and iodide has been identified as the essential factor to activate the amide C−N bond through electrophilic catalytic activation, enabling the production of new desired transamidated products with wide substrate scope of both unactivated amides and amines, including late‐stage functionalization of complex APIs (>80 examples). We anticipate that this powerful activation mode of unactivated amide bonds will find broad‐ranging applications in chemical synthesis.
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Transition‐Metal‐Free Activation of Amides by N−C Bond Cleavage
Abstract The amide bond N−C activation represents a powerful strategy in organic synthesis to functionalize the historically inert amide linkage. This personal account highlights recent remarkable advances in transition‐metal‐free activation of amides by N−C bond cleavage, focusing on both (1) mechanistic aspects of ground‐state‐destabilization of the amide bond enabling formation of tetrahedral intermediates directly from amides with unprecedented selectivity, and (2) synthetic utility of the developed transformations. Direct nucleophilic addition to amides enables a myriad of powerful methods for the formation of C−C, C−N, C−O and C−S bonds, providing a straightforward and more synthetically useful alternative to acyl‐metals.
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- Award ID(s):
- 1650766
- PAR ID:
- 10127393
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- The Chemical Record
- Volume:
- 20
- Issue:
- 7
- ISSN:
- 1527-8999
- Page Range / eLocation ID:
- p. 649-659
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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