99. Synthesis of α‐Fluoro‐α,β‐unsaturated esters monitored by 1D and 2D benchtop NMR Spectroscopy

Dennis Weidener, Kawarpal Singh and Bernhard Blümich, Magnetic Resonance in Chemistry, (2019) DOI: 10.1002/mrc.4843

This present study explores the use of a robust and compact NMR spectrometer to monitor the stereo‐selective formation of α‐fluoro‐α,β‐unsaturated esters from α‐fluoro‐β‐keto esters via deprotonation and deacylation in real‐time. These compounds are precursors of various pharmaceutically active substances. The real‐time study revealed the deprotonation and deacylation steps of the reaction. The reaction was studied at temperatures ranging from 293 to 333 K by interleaved 1D 1H, 19F and 2D 1H‐1H COSY experiments. The kinetic rate constants were evaluated using a pseudo‐first order kinetic model. The activation energies for the deprotonation and deacylation steps were determined to (‐28 ± 2) and (63.5 ± 8) kJ/mol, respectively. This showed that the deprotonation step is fast compared to the deacylation step and that the deacylation step determines the rate of the overall reaction. The reaction was repeated three times at 293 K to monitor the repeatability and stability of the system. The compact NMR spectrometer provided detailed information on the mechanism and kinetics of the reaction which is essential for optimizing the synthetic routes for stepwise syntheses of pharmaceutically active substances.