Selective formation of gamma-lactams via C-H amidation enabled by tailored iridium catalysts

Abstract

Intramolecular insertion of metal nitrenes into carbon-hydrogen bonds to form gamma-lactam rings has traditionally been hindered bycompeting isocyanate formation. We report the application of theory and mechanism studies to optimize a class of pentamethylcyclopentadienyl iridium(III) catalysts for suppression of this competing pathway. Modulation of the stereoelectronic properties of the auxiliary bidentate ligands to be more electron-donating was suggested by density functional theory calculations to lower the C-H insertion barrier favoring the desired reaction. These catalysts transform a wide range of 1,4,2-dioxazol-5-ones, carbonylnitrene precursors easily accessible from carboxylic acids, into the corresponding gamma-lactams via sp(3) and sp(2) C-H amidation with exceptional selectivity. The power of this method was further demonstrated by the successful late-stage functionalization of amino acid derivatives and other bioactive molecules.