Methyl-selective α-oxygenation of tertiary amines is a highly attractive approach for synthesizing formamides while preserving the amine substrate skeletons. Therefore, the development of efficient catalysts that can advance regioselective α-oxygenation at the N-methyl positions using molecular oxygen (O2 ) as the terminal oxidant is an important subject. In this study, we successfully developed a highly regioselective and efficient aerobic methyl-selective α-oxygenation of tertiary amines by employing a Cu/nitroxyl radical catalyst system. The use of moderately hindered nitroxyl radicals, such as 1,5-dimethyl-9-azanoradamantane N-oxyl (DMN-AZADO) and 1-methyl-2-azaadamanane N-oxyl (1-Me-AZADO), was very important to promote the oxygenation effectively mainly because these N-oxyls have longer life-times than less hindered N-oxyls. Various types of tertiary N-methylamines were selectively converted to the corresponding formamides. A plausible reaction mechanism is also discussed on the basis of experimental evidence, together with DFT calculations. The high regioselectivity of this catalyst system stems from steric restriction of the amine-N-oxyl interactions.
Keywords: copper; formamides; methyl-selective α-oxygenation; nitroxyl radical; tertiary amines.
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