Online and In Situ Monitoring of the Exchange, Transmetalation, and Cross-Coupling of a Negishi Reaction

We have developed a reaction monitoring method which provides quantitative information through exchange, transmetalation (TM), and cross-coupling for a Negishi reaction. Online HPLC and ReactIR were used as orthogonal techniques to corroborate time-course data through each step. Excellent agreement between the two techniques was observed through monitoring the magnesium/bromine exchange. Quantitative information regarding the TM was gathered via a novel, inline quenching technique facilitated by online HPLC. Quenching reaction aliquots with the electrophile 4-chlorobenzaldehyde allowed us to determine the extent of TM because of its selectivity for reacting with organomagnesiums. After TM, the Negishi reaction was performed and monitored using online LC. Titrating ZnCl2 into a solution of arylmagnesium allowed us to gain insights into zinc speciation in situ. Less than 1 equiv of ZnCl2 was needed to achieve complete TM, evidencing the presence of diorganozincs/arylzincates. Additionally, using substoichiometric quantities of ZnCl2 resulted in higher rates of catalysis for the Negishi reaction.