Continuous flow Pd-catalyzed cross-coupling reactions with organolithium

The present work has the goal to use flow chemistry to develop a safer, faster and cheaper version of the palladium-catalyzed Murahashi cross-coupling reaction, that involves the use of organolithium reagents as nucleophilic coupling partners. These reactions have received a lot of interest by chemists and in 2010 the Nobel Prize in chemistry was awarded to R.F. Heck, E. Negishi and A. Suzuki ‘’for palladium-catalysed cross-couplings in organic synthesis’.[1,2,3] In 1979, Murahashi and co-workers reported for the first time the possibility to employ organolithium as nucleophile in a cross-coupling reaction,[4] that was also recently revitalized by Feringa[5]. Organolithium species are difficult to handle since they are very reactive, flammable and sensitive to air and moisture. A promising solution can be the use of a in continuo approach. The use of channels with small dimensions allows a better mixing and the high surface-area-to-volume ratio brings to a better heat transfer.[6] In the study, different methods, set-up configurations, type of reactors and parameters (solvents, additive, residence time, temperature, catalyst and catalyst loading) were tested using 4-bromoanisole as a substrate model in reaction with hexylllithium. At the end, with the best conditions in our hands (20 cm coil reactor made of FEP (0.389 mL), 1 M starting material in toluene, Pd(PtBu3)2 (2.5 mol%) as the catalyst, 1.1 equivalents of organolithium and a residence time of 0.66 minutes) the scope of the reaction was explored. Excellent results were obtained with different electron-rich, electron-poor, polycyclic and hetero-aryl bromides. Moreover, the scalability of the process was evaluated on the model reaction and a ten-time scale up with a high reproducibility of the process was demonstrated.