TCFH–NMI Ketone Synthesis Inspired by Nucleophilicity Scales

<i>N</i>,<i>N</i>,<i>N</i>',<i>N</i>'-Tetramethylchloroformamidinium hexafluorophosphate (TCFH) and <i>N</i>-methylimidazole (NMI) enable the facile and practical reaction of carboxylic acids with amines, alcohols, and thiols to form amides, esters, and thioesters. To develop a mild synthesis of ketones with TCFH-NMI directly from carboxylic acids at room temperature, the Mayr nucleophilicity scale was used to compare the <i>N</i> values of competent nucleophiles to potential carbon-centered nucleophiles, identifying pyrroles and indoles as successful substrates when <i>N</i> ≥ 10.