Multicomponent domino synthesis of 6-azabicyclo[3.2.1]octanes and their cascade ring expansion toward 2-azabicyclo[4.3.1]decanes

Abstract

Herein, we report an efficient synthesis of 6-azabicyclo[3.2.1]octane and 2-azabicyclo[4.3.1]decane derivatives via base-promoted multicomponent domino reactions (MDRs). These reactions employ a new isoindole-based active methylene compound along with readily available aldehydes and malononitrile, enabling access to structurally diverse azabicyclic frameworks. Notably, a two-carbon cascade ring expansion (CRE) of the 6-azabicyclo[3.2.1]octane core to the corresponding 2-azabicyclo[4.3.1]decane was observed in situ and confirmed through control experiments. Structural elucidation was carried out using NMR spectroscopy, high-resolution mass spectrometry (HRMS), and single-crystal X-ray diffraction (S-XRD). This method offers operational simplicity, good atom economy, and mostly delivers a single diastereomer, providing a valuable platform for the rapid synthesis of complex, biologically relevant heterocycles.