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. 2019 Jan 21;24(2):364.
doi: 10.3390/molecules24020364.

Highly Efficient Synthesis of Substituted 3,4-Dihydropyrimidin-2-(1 H)-ones (DHPMs) Catalyzed by Hf(OTf)₄: Mechanistic Insights into Reaction Pathways under Metal Lewis Acid Catalysis and Solvent-Free Conditions

Rui Kong  1 , Shuai-Bo Han  2 , Jing-Ying Wei  3 , Xiao-Chong Peng  4 , Zhen-Biao Xie  5 , Shan-Shan Gong  6 , Qi Sun  7
Affiliations

Highly Efficient Synthesis of Substituted 3,4-Dihydropyrimidin-2-(1 H)-ones (DHPMs) Catalyzed by Hf(OTf)₄: Mechanistic Insights into Reaction Pathways under Metal Lewis Acid Catalysis and Solvent-Free Conditions

Rui Kong et al. Molecules. .

Abstract

In our studies on the catalytic activity of Group IVB transition metal Lewis acids, Hf(OTf)₄ was identified as a highly potent catalyst for "one-pot, three-component" Biginelli reaction. More importantly, it was found that solvent-free conditions, in contrast to solvent-based conditions, could dramatically promote the Hf(OTf)₄-catalyzed formation of 3,4-dihydro-pyrimidin-2-(1H)-ones. To provide a mechanistic explanation, we closely examined the catalytic effects of Hf(OTf)₄ on all three potential reaction pathways in both "sequential bimolecular condensations" and "one-pot, three-component" manners. The experimental results showed that the synergistic effects of solvent-free conditions and Hf(OTf)₄ catalysis not only drastically accelerate Biginelli reaction by enhancing the imine route and activating the enamine route but also avoid the formation of Knoevenagel adduct, which may lead to an undesired byproduct. In addition, ¹H-MMR tracing of the H-D exchange reaction of methyl acetoacetate in MeOH-d₄ indicated that Hf(IV) cation may significantly accelerate ketone-enol tautomerization and activate the β-ketone moiety, thereby contributing to the overall reaction rate.

Keywords: 3,4-dihydropyrimidin-2-(1H)-ones; Biginelli reaction; hafnium triflate; mechanism; solvent-free.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
The three “sequential bimolecular condensation reactions” (a–c) under solvent-free conditions in the presence or absence of Hf(OTf)4. 1 Determined by 1H-NMR in DMSO-d6.
Figure 1
Figure 1
The photos (a) and proposed mechanism (b) for the Hf(OTf)4-catalyzed Biginelli reaction under solvent-free conditions.
Figure 2
Figure 2
Mechanism variation for N,N′-dimethylurea-based Biginelli reaction.
Figure 3
Figure 3
The H-D exchange reactions of methyl acetoacetate in MeOH-d4 in the absence (a) or presence (b) of Hf(OTf)4.
See this image and copyright information in PMC

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