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

Abstract

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 sp3‐enriched β‐bromo‐α,α‐difluoroketones and fluorinated enaminones (in turn prepared from saturated heterocyclic α‐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 sp3‐enriched fluorinated building blocks meet the lead‐oriented synthesis criteria.