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

ABSTRACT: We report an organocatalyst that combines a triazolium N-heterocyclic carbene (NHC) with a squaramide as a hydrogen-bonding donor (HBD), which can effectively catalyze the atroposelective ring-opening of biaryl lactams via a unique amide C-N bond cleavage mode. The free carbene species attacks the amide carbonyl, forming an axially chiral acyl-azolium intermediate. Various axially chiral biaryl amines can be accessed by this methodology with up to 99% ee and 99% yield. By using mercaptan as a catalyst turnover agent, the resulting thioester synthon can be transformed into several interesting atropisomers. Both control experiments and theoretical calculations reveal the crucial role of the hybrid NHC-HBD skeleton, which activates the amide via H-bonding and brings it spatially close to the carbene centre. This discovery illustrates the potential of the NHC-HBD chimera and demonstrates a complementary strategy for amide bond activation and manipulation.

SUBMITTER: Cai Y

PROVIDER: S-EPMC10786861 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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

Cai Yuxing Y Zhao Yuxin Y Tang Kai K Zhang Hong H Mo Xueling X Chen Jiean J Huang Yong Y

Nature communications 20240112 1

We report an organocatalyst that combines a triazolium N-heterocyclic carbene (NHC) with a squaramide as a hydrogen-bonding donor (HBD), which can effectively catalyze the atroposelective ring-opening of biaryl lactams via a unique amide C-N bond cleavage mode. The free carbene species attacks the amide carbonyl, forming an axially chiral acyl-azolium intermediate. Various axially chiral biaryl amines can be accessed by this methodology with up to 99% ee and 99% yield. By using mercaptan as a ca ...[more]

PMID: 38216571

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Project description:N-Heterocyclic carbene (NHC) Au(i)-catalyzed organic synthesis has recently been receiving increasing attention, especially with the activation of alkynes. In contrast, counteranions, being widely problematic in Au(i)-catalyzed transformations, are commonly considered as innocent partners and are not respectably included in a computational model. Herein, we report density functional theory (DFT) investigations of the Au(i)-catalyzed cyclization of propargylic amides to exploit the mechanistic effect of several counteranions to shed some light for further future developments. Among the counteranions used in this study, NTf2 -, ClO4 -, TsO-, TFA-, TfO-, MsO-, and SbF6 -, both the cyclization and protodeauration step favor the 5-exo-dig product over the 6-endo-dig product when the alkyne moiety is terminated with hydrogen. These anions reveal a crucial influence on the energy profile through lowering the barriers of the reaction. Mechanistically, the results obtained from all counteranions show that the protodeauration is slower than the cyclization. By using an energetic span model, the results clearly indicate that the rate-determining state is the protodeauration step for all counteranions, and thus protodeauration is the turnover-limiting step. The turnover frequency (TOF) results for the formation of the 5-exo-dig product show cyclization reactivity in the order of MsO- > TFA- > ClO4 - > NTf2 - > TfO- > TsO- ≫ SbF6 -, whereas an order of TFA- > MsO- > NTf2 - > TfO- ≈ ClO4 - > SbF6 - ⋙ TsO- is calculated for the protodeauration, suggesting that SbF6 - and TsO- are disfavored due to their slow protodeauration. In this regard, and for the 6-endo-dig pathway, our conclusions demonstrate an order of TfO- > TFA- > MsO- > NTf2 - > ClO4 - > TsO- ⋙ SbF6 - for the cyclization and TFA- > TsO- > MsO- > TfO- > NTf2 - > ClO4 - ⋙ SbF6 - for the protodeauration, advocating that the anions SbF6 -, NTf2 - and ClO4 - are unlikely partners for the 6-endo-dig pathway because of their slow protodeauration. Finally, the findings here advise that any engineering of the counteranion to increase the efficiency of catalytic system would be more effective on the protodeauration step rather than the cyclization step.

Dataset Information

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

Publications

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

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