TGA-FTIR Guided Ligand Evaluation for Iron Photocatalyzed Decarboxylative Giese Reactions

A general Fe photocatalyzed Giese reaction was developed using a unique analytical technique for synthetic organic chemistry: Thermal Gravimetric Analysis-Fourier Transform Infrared Spectroscopy (TGA-FTIR). The optimized Giese conditions proceed with low loadings of a simple Fe salt with a commercial amine ligand and obviates the need for the traditional large excess of one coupling partner to facilitate radical capture. This protocol enables the successful coupling of primary, secondary, and tertiary carboxylic acids with sterically hindered, cyclic, and acyclic electron-deficient acceptors. Additionally, methylation of acceptors proceeds smoothly at room temperature from commercial acetic acid. Protected amines, heterocycles, and electron-rich alkenes are well-tolerated, enabling functionalization of Osimertinib, a kinase inhibitor for non-small-cell lung carcinoma. Preliminary investigation of the reaction mechanism was consistent with formation of an Fe-carboxylate species followed by a light-promoted decarboxylation. TGA-FTIR was used to evaluate ligand trends for Fe carboxylates. Using 30-minute decomposition times a correlation was revealed between Fe carboxylate CO2 extrusion time and the yield attained with aliphatic amine ligands coordinated to Fe. Less substituted amine ligands gave greater yields of product and could eliminate the need for stoichiometric quantities of base and provide control for decarboxylation chemistry over hydrogen atom transfer chemistry.