Quinone-Catalyzed Amine α-C–H and α-C–C Functionalization
Amines are extremely useful compounds with diverse applications in multiple disciplines. For this reason, a myriad of synthetic methods has been developed for the preparation of amine compounds. Despite this, the majority of well-established methodology for amine synthesis relies on the introduction of amino groups. Emerging amine α-functionalization methodology enables the modification of existing amine-containing molecules at the α-amino position therefore providing new approaches to amine synthesis. Driven by our research interest in amine synthesis, we set out to explore novel synthetic methods for organocatalytic α-C–H functionalization of amine-containing molecules. Inspired by enzymatic catalysis, we studied sequential quinone-catalyzed oxidation/nucleophilic addition reactions of primary aromatic amines to quickly access corresponding α-substituted amines. The developed reaction conditions can be effectively applied to gram-scale synthesis. The excellent reactivity of quinone in oxidative amine C–H functionalization motived to us to investigate quinone-catalyzed oxidative C–C functionalization of amine-containing molecules. In this regard, we developed a novel method for homologation of aromatic α-amino acids through sequential quinone-catalyzed oxidative decarboxylation/Mukaiyama−Mannich addition under mild reaction conditions. Following this discovery, quinone-catalyzed deformylative functionalization of aromatic β-amino alcohols was realized to further demonstrate the synthetic utility of quinone-catalyzed oxidative C–C functionalization. Lastly, we addressed the scope limitation of quinone-catalyzed oxidative α-functionalization of amine-containing molecules. Through systematic optimization process, suitable conditions to incorporate aliphatic substrates were discovered. Hitherto we have developed a general methodology for quinone-catalyzed α-functionalization of amine-containing molecules. Taken together, these methods are expected to be useful for efficient amine synthesis and late-stage functionalization of natural products and drug molecules.
Organic chemistry, amine synthesis, amine α-functionalization, organocatalysis, quinone catalysis
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