Novel synthetic studies of heterocycles containing nitrogen by reductive ring expansion of oximes and their application to synthesis of candidate compounds for clinical studies.

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The reductive rearrangement of various cyclic and acyclic oximes with aluminum reductants (DIBALH, AlHCl2 etc.) was performed to afford various secondary amines. This reaction regioselectively afforded a variety of five- to eight-membered bicyclic heterocycles or tricyclic heterocycles containing nitrogen neighboring an aromatic ring.The reaction proceeds through a three-centered transition state via a stepwise mechanism, because the potential energy curve along the intrinsic reaction coordinate had two maxima and the partial phenonium cation intermediate. The preference of the migration of a substituent was clarified that the more electron-rich group migrated preferentially to give the corresponding compounds. Their application to synthetic studies of several candidate compounds (AVP antagonist, 17 beta-HSD inhibitor, URAT-1 inhibitor) for clinical studies was demonstrated. Therefore, this reaction could be of practical use for the synthesis of fine chemistry and medicinal chemistry.