Synthesis of arenediazonium salts and Suzuki- Miyaura cross-coupling reaction in microreactors

Abstract

The process characteristics of two main steps in the preparation of 4-nitrobiphenyl (4-NBP) from 4-nitroaniline (PNA) were clearly revealed by applying two continuous-flow microreactors. The first step was the synthesis of 4-nitrobenzene diazonium tetrafluoroborate (4-NBDT) through the diazotization reaction. The reaction temperature, the residence time, and the molar ratio of different reactants were investigated to achieve optimal reaction conditions with the highest yield of 4-NBDT. Notably, the yield of 4-NBDT reached 97% at 25 °C only in 2.3 s with the optimal molar ratio of HBF4, NaNO2 and PNA (i.e., 2.72:1.05:1). The second step was the Suzuki-Miyaura cross-coupling reaction, in which HNO3 was used to transform the reaction system into a homogeneous state. The effects of mixing performance, the molar percentage of Pd(OAc)2 to 4-NBDT, the reaction temperature and the residence time on the Suzuki-Miyaura cross-coupling reaction were investigated systematically. With the molar percentage of Pd(OAc)2 to 4-NBDT of 1 mol%, the yield of 4-nitrobiphenyl (4-NBP) was optimized to 99% in just 13 min at 25 °C. This study demonstrated the excellent potential of utilizing the continuous-flow microreactor for the diazotization and the following Suzuki-Miyaura cross-coupling reaction.