Amide C–N bonds activation by A new variant of bifunctional N-heterocyclic carbene

Cai, Yuxing; Zhao, Yuxin; Tang, Kai; Zhang, Hong; Mo, Xueling; Chen, Jiean; Huang, Yong

doi:10.1038/s41467-024-44756-8

“…During the past few decades, NHCs have been used as potent ligands for transition metals, − nanoparticles, and surfaces. − Such species can also serve as organocatalysts. As powerful organocatalysts, NHCs can catalyze a wide range of reactions, including annulation, − benzoin, − C–C − /C–heteroatom − bond formation, C–H and C–N activation, − stetter, − and radical reactions. , As a result, a broad range of functionalized carbocycles and heterocycles could be constructed by utilizing NHC-catalyzed transformations.…”

Section: Introductionmentioning

confidence: 99%

Mechanism, Chemoselectivity, and Stereoselectivity of an NHC-Catalyzed Reaction of Aldehydes and Hydrazones: A DFT Study

Li,

Kang,

Xiao

et al. 2024

J. Phys. Chem. A

0

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To elucidate the mechanism and origins of chemoand enantioselectivities of the reaction between aliphatic aldehydes and hydrazones catalyzed by triazolium-derived NHC, density functional theory computations have been performed. According to our calculated results, the whole catalytic cycle for the formation of dihydropyridazinones proceeds via the initial nucleophilic addition of NHC to an aliphatic aldehyde, followed by the concerted intramolecular proton transfer and C−Cl bond cleavage. Subsequent deprotonation generates an enolate intermediate. The enolate intermediate then undergoes 1,4-addition to hydrazone to construct a new carbon−carbon bond. The following ring-closure would lead to a six-membered ring intermediate, which, upon the release of NHC, affords the final product dihydropyridazinone. The computation results reveal that intramolecular proton transfer is significantly promoted by the Brønsted acid DIPEA•H + . The carbon−carbon bond formation step could determine not only the chemoselectivity but also the stereoselectivity and lead to the Sisomer product. It was found that the stereoselectivity arises from a combination of weak interactions, including C−H•••O, C−H•••N, C−H•••π, and LP•••π. NHC could enhance the nucleophilicity of the aliphatic aldehyde and facilitate further reaction with hydrazone. This work could be beneficial for the development of new catalytic strategies in the future.

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Enantioselective Relay Coupling of Perfluoroalkyl and Vinylogous Ketyl Radicals

Zhao,

Zhang,

Huang

2024

Angewandte Chemie

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β‐Chiral carboxylic acids and their derivatives are highly valuable structural motifs in the fields of asymmetric synthesis and medicinal chemistry. However, the introduction of a sterically demanding sidechain to the β‐carbon, such as an all‐carbon quaternary center, remains a significant challenge in classical polar processes. Recently, N‐heterocyclic carbene (NHC) mediated coupling reactions involving persistent ketyl radicals have emerged as a promising strategy to assemble highly crowded carbon‐carbon bonds. Nevertheless, achieving enantioselectivity in these reactions remains highly challenging. In this work, we report our recent progress in controlling enantioselectivity for relay coupling of perfluoroalkyl and persistent vinylogous ketyl radicals. We developed a chiral bifunctional NHC‐squaramide catalyst that achieves high facial selectivity in a critical bond‐forming event involving the coupling of a congested tertiary carbon radical and vinylogous ketyl radical. Chiral carboxylates bearing an all‐carbon quaternary center at the β‐position can be prepared in good yield and excellent enantiomeric excess. Results from density functional theory (DFT) calculations and nuclear Overhauser effect (NOE) experiments indicate that the N,N’‐diaryl squaramide motif adopts an unusual syn‐syn conformation, enabling hydrogen bonding interactions with the enolate oxygen, thereby rigidifying the overall conformation of the transition state.

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Enantioselective Relay Coupling of Perfluoroalkyl and Vinylogous Ketyl Radicals

Zhao,

Zhang,

Huang

2024

Angew Chem Int Ed

1

0

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β‐Chiral carboxylic acids and their derivatives are highly valuable structural motifs in the fields of asymmetric synthesis and medicinal chemistry. However, the introduction of a sterically demanding sidechain to the β‐carbon, such as an all‐carbon quaternary center, remains a significant challenge in classical polar processes. Recently, N‐heterocyclic carbene (NHC) mediated coupling reactions involving persistent ketyl radicals have emerged as a promising strategy to assemble highly crowded carbon‐carbon bonds. Nevertheless, achieving enantioselectivity in these reactions remains highly challenging. In this work, we report our recent progress in controlling enantioselectivity for relay coupling of perfluoroalkyl and persistent vinylogous ketyl radicals. We developed a chiral bifunctional NHC‐squaramide catalyst that achieves high facial selectivity in a critical bond‐forming event involving the coupling of a congested tertiary carbon radical and vinylogous ketyl radical. Chiral carboxylates bearing an all‐carbon quaternary center at the β‐position can be prepared in good yield and excellent enantiomeric excess. Results from density functional theory (DFT) calculations and nuclear Overhauser effect (NOE) experiments indicate that the N,N’‐diaryl squaramide motif adopts an unusual syn‐syn conformation, enabling hydrogen bonding interactions with the enolate oxygen, thereby rigidifying the overall conformation of the transition state.

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Amide C–N bonds activation by A new variant of bifunctional N-heterocyclic carbene

Cited by 13 publications

References 49 publications

Mechanism, Chemoselectivity, and Stereoselectivity of an NHC-Catalyzed Reaction of Aldehydes and Hydrazones: A DFT Study

Mechanism, Chemoselectivity, and Stereoselectivity of an NHC-Catalyzed Reaction of Aldehydes and Hydrazones: A DFT Study

Enantioselective Relay Coupling of Perfluoroalkyl and Vinylogous Ketyl Radicals

Enantioselective Relay Coupling of Perfluoroalkyl and Vinylogous Ketyl Radicals

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