Nonheme Manganese-Catalyzed Oxidative <i>N</i>-Dealkylation of Tertiary Amides: Manganese(IV)-Oxo Aminopyridine Cation Radical Species and Hydride Transfer Mechanism

The development of efficient and practical <i>N</i>-dealkylation reactions stands as a longstanding objective in synthetic chemistry. Inspired by the oxidative <i>N</i>-dealkylation reactions mediated by heme and nonheme metalloenzymes, we disclose a biomimetic oxidative <i>N</i>-dealkylation catalysis that utilizes a nonheme manganese complex bearing anthryl-appended aminopyridine ligand and hydrogen peroxide (H₂O₂) as the terminal oxidant. A variety of Weinreb amides and cyclic aliphatic amines are efficiently transformed into valuable methyl hydroxamates and ω-amino acids through oxidative C-N bond cleavage. Mechanistic studies, including density functional theory (DFT) calculations, reveal that a manganese(IV)-oxo aminopyridine cation radical species, which is formed via the bromoacetic acid-assisted heterolytic O-O bond cleavage of a presumed manganese(III)-hydroperoxo aminopyridine species and the subsequent intramolecular electron transfer (ET) from the anthryl group of the aminopyridine ligand to the manganese center, is the active intermediate that initiates the oxidative <i>N</i>-dealkylation reactions; this process is reminiscent to the heterolytic O-O bond cleavage of iron(III)-hydroperoxo porphyrin intermediates (Cpd 0) to form iron(IV)-oxo porphyrin π-cation radicals (Cpd I) that are responsible for diverse selective oxidation reactions. Moreover, it is revealed that the oxidative activation of the C-H bond adjacent to the nitrogen atom proceeds via a hydride transfer (HT) mechanism, which involves a concerted asynchronous proton-coupled electron transfer (PCET), followed by an ET process. Thus, this study reports the first instance of catalytic oxidative <i>N</i>-dealkylation of a variety of tertiary amides, such as Weinreb amides and cyclic aliphatic amines, mediated by a Cpd I-like nonheme manganese(IV)-oxo aminopyridine cation radical species via an initial HT pathway.