With this workflow, we show that ytterbium (III) triflate effectively catalyzes the Biginelli cyclocondensation of 4,4,4-trifluorinated β-ketoesters, aryl aldehydes, and thiourea in to tetrahydropyrimidinones, and that this proceeds through initial condensation of thiourea and the trifluorinated ketoester. This stands in contrast to earlier reports of the Biginelli cyclocondensation preferring the imine mechanism pathway, and this might be rationalized by the inductive activation by the neighboring fluorine atoms on the ketoester such that this outcompetes the aryl aldehyde as a preferred electrophile for initial condensation with thiourea. Also enabled by this workflow, the relative rates of this reaction observed by timecourse 19 F qNMR show a distinct negative Hammett linear free energy correlation, corresponding to a decrease in positive charge at the benzylic carbon in the transition state of the rate determining step. Both of these observations were consistent with DFT calculations of reaction pathways. Finally, this workflow has led to the rapid synthesis of a library of nineteen tetrahydropyrimidinones and a novel trifluorinated analog of monastrol, which was subsequently evaluated for antiproliferative activity against non-fluorinated monastrol.