Serendipity as a Driving Force in the Synthesis of Isatins Substituted with Electron-Donating Groups

Abstract An efficient synthetic procedure for the synthesis of isatins was found after careful analysis of the serendipitous results of the unexpected products obtained by aromatic nucleophilic substitution when it was attempted to introduce 6-fluoroisatins to the classic Pfitzinger reaction. Attentive analysis of these results led to elaborating a methodology for synthesizing electron-enriched isatins, including those with hydroxy-, alkoxy-, alkylthio-, and dialkylamino-substituted aromatic rings. Limitations of the method were established. The reaction conditions were optimized according to the understanding of water’s role. Finally, the classic Pfitzinger reaction procedure was modified to yield the expected 2-substituted 7-fluoroquinoline-4-carboxylic acids.