Continuous-Flow Cross-Coupling Reactions Using Organolithium Reagents

Continuous-Flow Cross-Coupling Reactions Using Organolithium Reagents

Author: European Journal of Organic Chemistry

The use of readily available and relatively inexpensive organolithium reagents in Pd-catalyzed cross-coupling reactions is an attractive option for the preparation of organic compounds. However, the large-scale application of organolithium compounds has remained challenging due to their high reactivity. Continuous flow technologies can allow the handling of hazardous chemicals in a safer way and, thus, may offer a solution to this problem.

Maurizio Benaglia, Università degli Studi di Milano, Milan, Italy, and colleagues have developed an efficient continuous-flow protocol for Pd-catalyzed cross-coupling reactions of organolithium reagents with aryl bromides under aerobic conditions. The team first studied a model reaction between n-hexyllithium and 4-bromoanisol in a coil reactor, using Pd[P(tBu)3]2 as a catalyst with a 2.5 mol% loading and obtaining the desired product in a yield of 67 %. The researchers found that the catalyst loading could be lowered to 0.5 mol% while retaining a yield of 50 %.

Using optimized conditions, different organolithium reagents were reacted with a range of substituted aryl bromides, including polycyclic aromatic compounds and heteroarenes, leading to high yields in just 40 s residence time. The reaction was successfully scaled up and could also be applied to the synthesis of a class of lysine and arginine methyltransferase inhibitors used for the treatment of cancer.


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