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Insights into N-Heterocyclic Carbene-Catalyzed Oxidative α-C(sp 3 )-H Activation of Aliphatic Aldehydes and Cascade [2 + 2] Cycloaddition with Ketimines



Insights into N-Heterocyclic Carbene-Catalyzed Oxidative α-C(sp 3 )-H Activation of Aliphatic Aldehydes and Cascade [2 + 2] Cycloaddition with Ketimines



Journal of Organic Chemistry 84(10): 6117-6125



Predicting the chemoselectivity of [2 + 2] cyclizations is an important challenge in organic chemistry. Herein, we provided a valuable case for this issue. Density functional theory calculations were performed to systematically study the possible mechanisms and origin of selectivities for the N-heterocyclic carbene (NHC)-catalyzed oxidative α-C(sp3)-H activation of aliphatic aldehydes and the cascade [2 + 2] cycloaddition with ketimines. The [2 + 2] cycloaddition of azolium enolate intermediates to the C═N bond, rather than the C═O bond of ketimine, is revealed to be determined by chemo- and stereoselectivity. By comparing the energy gap between the frontier molecular orbitals (FMOs) of the two reacting parts involved in the [2 + 2] cycloaddition transition states, we propose a new strategy to determine the origin of the reaction chemoselectivity. Moreover, the local nucleophilic index can efficiently predict the active site of ketimines. Further analyses illustrate that NHC can increase the nucleophilicity of aldehydes and the acidity of the α-C(sp3)-H bond, and 3,3',5,5'-tetra- tert-butyl diphenoquinone (DQ) acts as an oxidant and promotes α-C(sp3)-H bond deprotonation. This work is useful not only for understanding the NHC-catalyzed oxidative [2 + 2] annulation but also for developing new applications of the FMO theory in organocatalytic cyclizations.

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Accession: 066715845

Download citation: RISBibTeXText

PMID: 31012584

DOI: 10.1021/acs.joc.9b00295


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