A Pyridine Cyclization Cascade with and without Dichloromethane

A new undergraduate organic laboratory experiment has been developed based on the Reisman group’s pyridine dearomatization route to matrine-type alkaloids. The remarkably diastereoselective dearomative annulation cascade directly generates a complex tetracycle with three stereocenters in a single step from pyridine and glutaryl chloride. While the original and most effective solvent for this reaction is dichloromethane, we found that a 1:1 acetonitrile/toluene solvent mixture is a viable, less-hazardous alternative. We adjusted the scale, reaction, and workup conditions to craft a greener procedure that works reliably in the hands of second-year undergraduates. Students successfully collected their product by liquid–liquid extraction, then characterized it by nuclear magnetic resonance (NMR) (1H, 13C, COSY, HSQC, HMBC), infrared (IR) spectroscopy, and mass spectrometry (MS). Students also explored the reaction mechanism and considered the green chemistry aspects of their procedure, whether they used dichloromethane or acetonitrile/toluene.