Synthesis of 2-Arylpyrroles via an Optimized Palladium Coupling

Abstract Using response surface methods, we have re-optimized a palladium-catalyzed method for coupling ClZn(pyrrolide) with aryl bromides to selectively generate 2-arylpyrroles. We optimized based on four variables: temperature, ClZn(pyrrolide)/ArBr ratio, catalyst loading, and time. To find a protocol applicable to most substrates of interest, we optimized three different substrates: a bulky arene (mesityl bromide), an electron-rich arene [4-(NMe2)C6H4Br], and an electron-deficient arene [3,5-(CF3)2C6H3Br]. The re-optimized procedures give as good or better yields than the previously published protocols, always in a fraction of the time. In addition, the reactions are generally cleaner with the new conditions, especially with electron-rich substrates, making the products easier to isolate. We applied the conditions to a variety of different substrates in each category, which provided good to excellent isolated yields.