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Issue 15, 2019
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Mechanistic investigation-inspired activation mode of DBU and the function of the α-diazo group in the reaction of the α-amino ketone compound and EDA: [DBU-H]+-DMF-H2O and α-diazo as strong N-terminal nucleophiles

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Abstract

Density functional theory (DFT) calculations have been carried out to disclose the effective activation mode of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and the function of the α-diazo group for the DBU-catalyzed reaction of the α-amino ketone compound and ethyl diazoacetate (EDA). Different from the previous result proposed by Zhao et al., an unexpected activation mode of DBU is identified. Our results suggest that DBU as a base and catalyst preferentially activates the α-amino ketone compound by the formation of DBU·[DBU-H]+-DMF-H2O or DBU·[DBU-H]+-DMF, whereas DBU as a nucleophile first activates EDA. Moreover, we found a dramatic electronic turnover of the α-diazo group, which converts from a weak electrophile to a strong nucleophile under the DBU·[DBU-H]+-DMF-H2O and DBU·[DBU-H]+-DMF-catalyzed conditions via a through-space charge migration. Additionally, water molecules can improve the activity of the [DBU-H]+-DMF catalyst and profoundly accelerate the electronic turnover process of the diazo group. On the basis of this novel activation mode of DBU, we disclosed three main pathways. The preferential DBU·[DBU-H]+-DMF-H2O co-catalyzed mechanistic scenario involves four major processes: deprotonation, C–N bond formation, stepwise H-shift, and internal N-protonation. The second nucleophilic C–N bond formation process is the rate-determining step. Moreover, non-covalent interactions, secondary orbital interactions, and electrostatic interactions are responsible for the different origins of [DBU-H]+-DMF-H2O and [DBU-H]+-DMF co-catalyzed C–N bond formation cases. Moreover, we found that DBU and DMF not only act as a base and solvent, but also as a critical catalyst to promote the whole reaction. Water acts as an anchor, stabilizer, and catalyst to improve the catalytic activity of DMF and DBU. Remarkably, our findings on the activation mode of DBU and the effective role of α-diazocarbonyls will prove to be useful in improving the efficiency and in providing guidance for further experimental investigations.

Graphical abstract: Mechanistic investigation-inspired activation mode of DBU and the function of the α-diazo group in the reaction of the α-amino ketone compound and EDA: [DBU-H]+-DMF-H2O and α-diazo as strong N-terminal nucleophiles

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Publication details

The article was received on 05 May 2019, accepted on 06 Jun 2019 and first published on 10 Jun 2019


Article type: Research Article
DOI: 10.1039/C9QO00602H
Org. Chem. Front., 2019,6, 2678-2686

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    Mechanistic investigation-inspired activation mode of DBU and the function of the α-diazo group in the reaction of the α-amino ketone compound and EDA: [DBU-H]+-DMF-H2O and α-diazo as strong N-terminal nucleophiles

    L. Zhu, H. Yuan and J. Zhang, Org. Chem. Front., 2019, 6, 2678
    DOI: 10.1039/C9QO00602H

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