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 has 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 dihydropyrimidinone kinesin-Eg5 inhibitor,
and to probe the mechanism of the Biginelli cyclocondensation, a multicomponent
reaction used to synthesize dihydropyrimidinone and tetrahydropyrimidinones
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 dihydropyrimidinones
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 of 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 culminate 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.
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