Synthesis of 3-fluoro-oxindoles and phenyl fluoroacetic acid derivatives

Fluorinated heterocycles are potentially interesting compounds for the pharmaceutical and agrochemical industry. Fluorinated indole and oxindole derivatives are generally synthesised by late stage fluorination methodologies (Selectfluor™, NFSI). Here, a new method for the synthesis of 3-fluorooxindoles starting from 1-fluoro-2-nitrobenzenes and diethyl fluoromalonate is presented. The SNAr reaction is very efficient: 2-aryl-2-fluoromalonates are obtained in quantitative yields and are used without any purification in the hydrolysis step. Following esterification and reduction 3-fluorooxindoles are obtained in moderate yield. The reduction is the most challenging step in the reaction sequence, as the most commonly used metal based techniques (catalytic hydrogenation, dissolving metals) eliminate the benzylic fluorine. This is the first reported example of aromatic nucleophilic substitution using fluoromalonates and is a simple and potentially scalable route to 2-aryl-2-fluoroacetic acids and derivatives. As the anion derived from diethyl fluoromalonate is a weak nucleophile, only fluorobenzenes with strong deactivating groups are suitable substrates for this reaction.