Remote C(sp3)−H Acylation of Amides and Cascade Cyclization via N‐Heterocyclic Carbene Organocatalysis

The direct functionalization of inert C(sp3)−H bonds under environmentally benign catalytic conditions remains a challenging task in synthetic chemistry. Here, we report an organocatalytic remote C(sp3)−H acylation of amides and cascade cyclization through a radical‐mediated 1,5‐hydrogen atom transf...

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Published in:Angewandte Chemie International Edition 2022-04, Vol.61 (15), p.e202116629-n/a
Main Authors: Li, Qing‐Zhu, Zeng, Rong, Fan, Yang, Liu, Yan‐Qing, Qi, Ting, Zhang, Xiang, Li, Jun‐Long
Format: Article
Language:English
Subjects:
Acylation
Amides
Carbamates (tradename)
Carbenes
Catalysts
Computer applications
Cyclization
Cyclization Reactions
C−H Functionalization
Enantiomers
Hydrogen atoms
Isoquinolinone
Ketones
Methane - analogs & derivatives
Methane - chemistry
NHC Organocatalysis
Nitrogen
Radical Acylation
Reaction mechanisms
Substrates
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Summary:The direct functionalization of inert C(sp3)−H bonds under environmentally benign catalytic conditions remains a challenging task in synthetic chemistry. Here, we report an organocatalytic remote C(sp3)−H acylation of amides and cascade cyclization through a radical‐mediated 1,5‐hydrogen atom transfer mechanism using N‐heterocyclic carbene as the catalyst. Notably, a diversity of nitrogen‐containing substrates, including simple linear aliphatic carbamates and ortho‐alkyl benzamides, can be successfully applied to this organocatalytic system. With the established protocol, over 120 examples of functionalized δ‐amino ketones and isoquinolinones with diverse substituents were easily synthesized in up to 99 % yield under mild conditions. The robustness and generality of the organocatalytic strategy were further highlighted by the successful acylation of unactivated C(sp3)−H bonds and late‐stage modification of pharmaceutical molecules. Then, the asymmetric control of the radical reaction was attempted and proven feasible by using a newly designed chiral thiazolium catalyst, and moderate enantioselectivity was obtained at the current stage. Preliminary mechanistic investigations including several control reactions, KIE experiments, and computational studies shed light on the organocatalytic radical reaction mechanism. An N‐heterocyclic carbene catalyzed remote C(sp3)−H acylation of amides was developed, and also combined with a cascade cyclization. Over 120 functionalized δ‐amino ketones and isoquinolinones with diverse substituents were synthesized in up to 99 % yield under mild conditions. Preliminary mechanistic investigations shed light on the organocatalytic radical reaction mechanism.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202116629