Synthesis, characterization, molecular structure, and computational studies on 4(1H)-pyran-4-one and its derivatives

Abstract 4(1H)-Pyridone-based compounds have shown promise as potent bioactive inhibitors against a broad range of diseases, particularly malaria. Our interest in 4(1H)-pyridones initiated the design and synthesis of a series of 4(1H)-pyridone derivatives, with the hope of finding new antimalarial leads. The synthesis of 4(1H)-pyran-4-one analogues (4(1H)-pyridone intermediates was successfully achieved using palladium catalyzed Suzuki-Miyaura coupling reactions. The synthesized 4(1H)-pyran-4-ones were unambiguously confirmed by TGA, 13C, 1H NMR, and IR spectroscopic analysis. Further comprehensive insights to rationalize the outcome of several reactions were deduced by means of single crystal X-ray diffraction, which was used to determine the single crystal structures of compounds 4 and 5. Compounds 5, 9 and 9a-e were successfully synthesized in moderate to excellent yields, apart from compound 9e which gave a very low yield. NMR and XRD analysis of the by-product of compound 9e showed that the boronic acid substituents reacted with each other in a side-reaction reminiscent to aryl boronic acid homo coupling or Ullmann coupling reactions. Complimentary DFT analysis of the pyranone and pyridone compounds provided insight into the substituent effect of the pyranone compounds with regards to the stability and lack of reactivity to form the corresponding pyridone compounds.