Safe Handling of Air-Sensitive Organometallic Reagents Using Schlenk Line Techniques: Negishi Cross-Couplings for Trainee Graduate Students

A laboratory experiment has been devised to train new graduate trainees in the safe and controlled handling of air-sensitive organometallic reagents using Schlenk lines, high vacuum pumps, liquid nitrogen traps, and cannula transfers. The reaction involves the formation of air-, moisture-, and thermally sensitive 2-pyridyllithium, generated in situ by the reaction of 2-bromopyridine with n-butyllithium in dry THF at −78 °C. Subsequent transmetalation with dried ZnCl2 and reaction with 4-bromo-6-methyl-2-pyrone in the presence of catalytic Pd(PPh3)4 afforded the heterobiaryl product, 4-(2′-pyridyl)-6-methyl-2-pyrone. The many sensitivities of this experiment serve to provide an excellent practical demonstration for new graduate trainees of what can go wrong when experimental procedures are not accurately followed.