Development of a mild and robust method for large-scale palladium-catalysed cyanation of aryl bromides: Importance of the order of addition

A mild and robust method for the large-scale palladium-catalysed cyanation of aryl bromides has been developed. The reaction is sensitive to cyanide poisoning of the catalyst, and it was found that the order of adding the reagents had a strong impact on the performance of the reaction. Addition of the cyanide source to a preheated mixture of the other reagents was critical for achieving a robust and scalleable process. This improved protocol allowed the reaction to be run to full conversion within 3 h at 50 degrees C on a 6.7 kg scale. Furthermore, it led to the identification of several new efficient catalysts for the reaction.