Benchtop 19F nuclear magnetic resonance (NMR) spectroscopy provides mechanistic insight into the Biginelli condensation towards the chemical synthesis of novel trifluorinated dihydro- and tetrahydropyrimidinones as antiproliferative agents

07 December 2022, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Benchtop nuclear magnetic resonance (NMR) spectroscopy has enabled the monitoring and optimization of chemical transformations while simultaneously providing kinetic, mechanistic, and structural insight into reaction pathways with quantitative precision. Moreover, benchtop NMR proton lock capabilities further allow for rapid and convenient monitoring of various organic reactions in real-time, as the use of deuterated solvents is not required. The complementary role of 19F NMR-based kinetic monitoring in the fluorination of bioactive compounds serves many benefits in the drug discovery process, since fluorinated motifs additionally improve drug pharmacology. In this study, 19F NMR spectroscopy was utilized to monitor the synthesis of novel trifluorinated analogs of monastrol, a small molecule dihydropyrimidine kinesin-Eg5 inhibitor, and to probe the mechanism of the Biginelli cyclocondensation, a multicomponent reaction used to synthesize dihydropyrimidine and tetrahydropyrimidines through a Bronsted- or Lewis-acid catalyzed cyclocondensation between ethyl acetoacetate, thiourea, and an aryl aldehyde. In the present study, a trifluorinated ketoester serves a dual purpose as being the source of the trifluoromethyl group in our fluorinated dihydropyrimidines and as a spectroscopic handle for real time reaction monitoring and tracking of reactive intermediates by 19F NMR. Further, upon extending this workflow to a diverse array 3- and 4-substituted aryl aldehydes, we were 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. In addition, we used density functional theory (DFT) calculations to corroborate our experimental results through the thermodynamic values of key intermediates in each mechanism. Finally, these studies cumulate in the synthesis of a novel trifluorinated analog of monastrol and its subsequent biological evaluation in vitro. More broadly, we show an application of benchtop 19F NMR spectroscopy as an analytical tool in the real-time investigation of a mechanistically and chemically complex multicomponent reaction mixture.

Keywords

Multicomponent reactions
19F nuclear magnetic resonance spectroscopy
monastrol
dihydropyrimidine
Hammett linear free energy relationship

Supplementary materials

Title
Description
Actions
Title
Supporting Information for Benchtop 19F nuclear magnetic resonance (NMR) spectroscopy provides mechanistic insight into the Biginelli condensation towards the chemical synthesis of novel trifluorinated dihydro- and tetrahydropyrimidines as antiproliferative agents
Description
Contains experimental protocols, characterization information, supporting figures, and computer modeling paramaters, and copies of spectroscopic data
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.