The Biginelli cyclocondensation is a multicomponent reaction to synthesize dihydropyrimidines by utilizing ethyl acetoacetate, thiourea, and an aryl aldehyde under acidic conditions. In this study, 19F NMR spectroscopy was utilized to monitor the synthesis of novel trifluorinated analogs of monastrol, a small molecule DHPM kinesin Eg5 inhibitor, and to probe the mechanistic pathways of the Biginelli cyclocondensation. Through 19F NMR time course experiments, we identified an unknown reactive intermediate, suggesting that the trifluorinated analogues of monastrol proceeded through a different operative mechanism. By analyzing kinetics experimental data, we were also able to derive Hammett linear free energy relationships (LFER) to determine stereoelectronic effects of para- and meta- substituted aryl aldehydes to corresponding reaction rates and mechanistic routes. Here, we present discoveries regarding the application of benchtop 19F NMR spectroscopy to provide high resolution reaction kinetics and mechanistic insight into the Biginelli reaction.

Benchtop nuclear magnetic resonance spectroscopy enables mechanistic insight of the Biginelli cyclocondensation in the synthesis of novel trifluorinated 2,4-dihydropyrimidine and tetrahydropyrimidine compounds as antiproliferative agents

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