Theoretical investigation on enantioselective Biginelli reaction catalyzed by natural tartaric acid

Abstract

In this study, enantioselective Biginelli reaction of aldehyde, b-ketoester, and urea catalyzed by natural (2R, 3R)-tartaric acid has been investigated using density functional theory calculations. The results indicate that the most favorable pathway involves a protonated imine from aldehyde and urea in the first step. Tartaric acid forms H-bonds network with substrates enhancing the electrophilicity of protonated imine and the nucleophilicity of b-ketoester. (R)-3,4-Dihydropyrimidin-2-(1H)-ones is preferable for the reaction. The solvent effect is discussed in the prediction of enantiomeric excess (ee) values in ethanol and water.

Organocatalytic Asymmetric Biginelli-like Reaction Involving Isatin

“…The mechanism of the Biginelli reaction has been previously investigated by means of computational tools, 29 also in the presence of tartaric acid as catalyst. 30 Results indicated the iminium path as the most favorable, in accordance with a previously proposed mechanism. 31 Therefore, we decided to investigate the initial addition of the enol form of ethyl acetoacetate on the imine formed between isatin 1a and urea 2, in the presence of (R)-4a, since, in this step, the final configuration of 5a is determined.…”

“…These results allowed us to disclose the C3- S favoring enantioselectivity of the described organocatalyzed reaction and prompted us to perform theoretical calculations on the stereogenic center forming step. The mechanism of the Biginelli reaction has been previously investigated by means of computational tools, also in the presence of tartaric acid as catalyst . Results indicated the iminium path as the most favorable, in accordance with a previously proposed mechanism .…”

Understanding the Lack of Reactivity of 2,4-Dihydroxybenzaldehyde Towards the Biginelli Adduct Using Density Functional Theory Molecular Modeling

“…In this sense, three possible pathways proposed for the reaction of aromatic aldehyde, urea, and methyl acetoacetate: Iminium route, enamine-intermediate, and Knoevanagel pathway ( Figure 2) [13]. Some works have reported theoretical calculations that supplied sharp pieces of evidence that the iminium route is likely to occur when urea used as reagent [17,18,29,30]. However, no theoretical calculations had reported when thiourea was used.…”

“…The methodology was used from the procedures reported by Stadler and Kappe [32] and Manhas et al [33], with an environmentally friendly approach using microwave conditions, a solvent-free system, and low-cost acid catalyst [30]. The results are shown in Table 1.…”

Organocatalysis: Key Trends in Green Synthetic Chemistry, Challenges, Scope towards Heterogenization, and Importance from Research and Industrial Point of View

“…Various organocatalysts such as tartaric acid, oxalic acid, citric acid, and lactic acid were found effective in producing Biginelli products [164][165][166][167][168][169][170][171][172]. Because of the "privileged" green nature of this field, it has become an obligation for scientific community and academic institutions to be mindful and teach this branch of catalysis to students and also keep it as a driving force in the generation and dissemination of knowledge in pursuit of efficient synthetic methodologies and processes using organocatalysts.…”