Biginelli Reaction - ChemContent

Vijay Ishwar
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It is a chemical reaction in organic chemistry in which three molecules, urea, aldehyde and β-keto ester are reacted together in presence of an acid catalyst to form a cyclic compound as final product called dihydropyrimidones.

Biginelli Reaction - Chemical Reaction Scheme

Mechanism: 

Multiple paths have been proposed over the years for this reaction. The mechanism that is accepted by most scientists include a three steps process in which a series of reactions occurs step by step.

Step-I: Nucleophilic addition of urea on aldehyde in presence of acid is followed by dehydration to form benzylidene urea (A).

Biginelli Reaction - Mechanism Step - I

Step-II: Deprotonation of β-keto ester form a carbanion which reacts with benzylidene urea formed in step I.

Biginelli Reaction - Mechanism Step - II

Step-III: Cyclization occurs by nucleophilic substitution resulting into dehydration and a 6 membered ring called dihydropyrimidone is formed.

Biginelli Reaction - Mechanism Step - III

Salient Features:

1. Cyclization happens with attack of amine group on ketonic group because ketone has more electrophilic carbonyl than ester. +M effect of methoxy group lower down the electrophilicity of carbonyl carbon.

Biginelli Reaction - Features

Examples:

Ex-1

Biginelli Reaction - Example

Ex-2

Biginelli Reaction - Example

References:

1. H. G. O. Alvim D. L. J. Pinheiro, V. H. Carvalho-Silva, M. Fioramonte, F. C. Gozzo, W. A. da Silva, G. W. Amarante, B. A. D. Neto, J. Org. Chem.201883, 12143-12153.

2. Y. Ma, C. Qian, L. Wang, M. Yang, J. Org. Chem.200065, 3864-3868.

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