Herein, we report an efficient synthesis of 6-azabicyclo3.2.1octane and 2-azabicyclo4.3.1decane 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-azabicyclo3.2.1octane core to the corresponding 2-azabicyclo4.3.1decane 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.
Natarajan et al. (Thu,) studied this question.