Fluorine-Containing sp3-Enriched Building Blocks for the Multigram Synthesis of Fluorinated Pyrazoles and Pyrimidines with (Hetero)aliphatic Substituents

Efficient approaches to the gram-scale synthesis of fluorinated pyrazoles and pyrimidines bearing saturated (hetero)cyclic substituents are described. The methods rely on the heterocyclizations of sp(3)-enriched beta-bromo-alpha,alpha-difluoroketones and fluorinated enaminones (in turn prepared from saturated heterocyclic alpha-fluoroketones), respectively; these compounds themselves are useful synthetic intermediates that have been prepared on multigram scale for the first time. LogP and aqueous solubility measurements, as well as lead-likeness assessment using the Nelson's LLAMA tool show that the 19 synthesized sp(3)-enriched fluorinated building blocks meet the lead-oriented synthesis criteria.

Automated summary

Efficient approaches for the synthesis of fluorinated pyrazoles and pyrimidines with saturated (hetero)cyclic substituents were described. The methods rely on heterocyclizations using sp(3)-enriched beta-bromo-alpha,alpha-difluoroketones and fluorinated enaminones derived from saturated heterocyclic alpha-fluoroketones. These compounds serve as useful synthetic intermediates and meet the lead-oriented synthesis criteria.