In Continuo Pd-Catalysed Cross Coupling Reactions of Organolithium Reagents with Aryl Bromides Under Aerobic Conditions

Transition metal-catalysed C-C couplings are widely used to synthesize organic molecules. In this area, the direct use of readily available and relatively inexpensive organolithium reagents in Pd cross-coupling reactions represents an attractive option, but its large-scale application remains a formidable challenge. The high reactivity of organolithium reagents, along with the need (sometimes) of tailored, expensive catalysts and long reaction times, often prevent these procedures from being applied to industry. However, continuous flow technologies recently emerged as a powerful tool in discovery and process chemistry, and may offer a solution to overcome the above issues. Here, we wish to report fast, efficient, in continuo Pd-catalysed cross coupling reactions of organolithium reagents with aryl bromides, under aerobic conditions, that do not require an inert atmosphere, with a catalyst loading that has been lowered up to 0.5 % mol. The methodology has a wide scope and has been successfully applied to the synthesis in flow of a novel class of anti-cancer compounds. The direct use of readily available and relatively inexpensive organolithium reagents in cross-coupling reactions is grown in recent years. However, the large-scale application of these commodity reagents remains a formidable challenge. Here we report fast, efficient, and in continuo Pd-catalysed cross couplings of organolithium reagents with aryl bromides that proceed in 40 s, allowing the synthesis of a variety of functionalised aryl compounds without pre-catalyst activation and inert atmosphere.image