Synthesis and Applications of Fluorinated Multi-Carbonyl Systems via Batch and Flow Processes

Abstract

Organofluorine chemistry has played a significant role in the majority of the spectacular scientific and technological developments of the past century. Two key challenges in organofluorine chemistry remain selective methods for the formation of carbon-fluorine bonds and the synthesis of complex fluorinated molecules under mild conditions.

The incorporation of fluorine atoms into a pharmaceutical candidate is a well established approach to, for example, affect lipophilicity, pKa and metabolic stability of new chemical entities as part of drug discovery programs. Consequently, effective and inexpensive methodologies for the synthesis of selectively fluorinated multifunctional building blocks for incorporation into drug synthesis campaigns are very desirable.

In the context of developing the use of 2-fluoro-1,3-dicarbonyl substrates for the synthesis of more structurally complex fluorinated intermediates, we investigated routes to various fluorinated systems. As part of a general strategy aimed at assessing the effect of the carbon-fluorine bond attached to the reactive enolic site of the 2-fluoro-1,3-dicarbonyl system, we used this reactivity profile for the synthesis of pharmaceutically relevant fluorinated intermediates.

Several APIs present a fluoro-pyrimidinone structure, therefore a synthetic pathway giving access to functionalized fluorinated pyrimidinones has been established. Secondly, after testing various radical initiators, we applied a free radical chemistry strategy to reactions of 2-fluoro-1,3-dicarbonyl systems using Ceric Ammonium Nitrate (CAN) and various olefins, affording fluorinated nitro-oxy products by a catalytic oxidative addition. Finally, as the value of multicomponent reactions (MCRs) in drug development gives rapid access to large libraries of molecules possessing a high degree of functionality and structural diversity, we developed a synthetic strategy using β-fluoroketoesters and β-fluoromalonate substrates as MCR components in Mannich reactions involving various aldehydes and amines, using both batch and flow processes.

Additionally, we investigated the potential use of fluorinated 1,3-dicarbonyl systems to act as nucleophiles in nucleophilic substitutions involving poly-fluorinated aromatic systems and also studied the direct fluorination of functionalized tri-carbonyl systems.