Synthesis of tetrahydropyrimidinone (Biginelli reaction)

Objective

To perform one-pot synthesis of a tetrahydropyrimidinone by a three-component reaction (Biginelli reaction).

Background

The Biginelli reaction, first described in 1893, is a three-component reaction between an aldehyde, a β-ketoester, and urea to yield in a one-pot procedure dihydropyrimidones. This reaction is a quick and easy method to synthesize heterocycles, compounds with a great potential for pharmaceutical application.

synthesis of tetrahydropyrimidinone by Biginelli reaction
Synthesis of tetrahydropyrimidinone by Biginelli reaction

Experimental procedure

In a mortar, grind together equivalent amounts of benzaldehyde (0.5 mol), ethyl acetoacetate (0.5 mol), and urea (0.5 mol) with a small amount of p-toluenesulfonic acid (as an acid catalyst), for about 3-5 min to give a light-yellow solid mass that will be mostly the target tetrahydropyrimidinone. Wash the crude product with cold water to remove the color, and purify by recrystallization from acetone/EtOH (m.p. = 208–210 ºC, estimated yield 94 %).

Physico-chemical properties

This table collects data for the molecular weight (Mw), melting point (M.p.) boiling point (B.p.) and density of the reactives and compounds used in this laboratory experiment.

Name Mw (g/mol) M.p. (ºC) B.p. (ºC) Density (g/ml)
Ethyl acetoacetate130.14-431811.029
Benzaldehyde106.12-26178-1791.044
Urea 60.06132-135 -1.335
p-Toluenesulfonic acid172.2106-107 -1.240
Acetone58.08-94560.791
EtOH46.07-114.178.50.790

GHS pictograms

Hazard pictograms form part of the international Globally Harmonized System of Classification and Labelling of Chemicals (GHS) and are collected in the followinf Table for the chemical compounds used in this experiment.

Name GHS
Ethyl acetoacetate ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram
Benzaldehyde ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram
Urea ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram
p-Toluenesulfonic acid ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram ghs05  Danger Warning Corrosive cat. 1 pictogram
Acetone ghs02  Danger Warning Flammable pictogram ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram
EtOH ghs02  Danger Warning Flammable pictogram

International Chemical Identifier

The IUPAC InChI key identifiers for the main compounds used in this experiment are provided to facilitate the nomenclature and formulation of chemical compounds and the search for information on the Internet for these compounds.

Ethyl acetoacetateXYIBRDXRRQCHLP-UHFFFAOYSA-N
BenzaldehydeHUMNYLRZRPPJDN-UHFFFAOYSA-N
Urea XSQUKJJJFZCRTK-UHFFFAOYSA-N
p-Toluenesulfonic acidJOXIMZWYDAKGHI-UHFFFAOYSA-N
AcetoneCSCPPACGZOOCGX-UHFFFAOYSA-N
EtOHLFQSCWFLJHTTHZ-UHFFFAOYSA-N

References

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