The development of a two-step synthesis of multi-substituted N-methoxyamines from N-methoxyamides is reported. Utilization of the N-methoxy group as a reactivity control element was the key to success in this two-step synthesis. The first reaction involves a N-methoxyamide/aldehyde coupling reaction. Whereas ordinary amides cannot condense with aldehydes intermolecularly due to the poor nucleophilicity of the amide nitrogen, the N-methoxy group enhances the nucleophilicity of the nitrogen, enabling the direct coupling reaction. The second reaction in the two-step process was nucleophilic addition to the N-methoxyamides. Incorporation of the N-methoxy group into the amides increased the electrophilicity of the amide carbonyls and promoted the chelation effect. This nucleophilic addition enabled quick diversification of the products derived from the first step. The developed strategy was applicable to a variety of substrates, resulting in the elaboration of multi-substituted piperidines and acyclic amines, as well as a substructure of a complex natural alkaloid. Remote control: A two-step synthesis of multi-substituted N-methoxyamines including amide/aldehyde coupling and nucleophilic addition to amide carbonyls is reported (see scheme; TMS=trimethylsilyl). Incorporation of the N-methoxy group to the amides dramatically changes their reactivities, and enables quick access to diverse multi-substituted piperidines and acyclic substituted amines.
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