Microwave assisted batch and continuous flow Suzuki-Miyaura reactions in GVL using a Pd/PiNe biowaste-derived heterogeneous catalyst

Aiming at the development of alternative and low-impact synthetic pathways, we herein report the exploitation and the simultaneous employment of different tools to improve the overall sustainability of the Suzuki-Miyaura (SM) cross-coupling process with a circular economy approach. For the first time, in this study, we have combined the use of our biowaste-derived heterogeneous catalyst Pd/PiNe with the biomass-derived reaction medium γ-valerolactone (GVL) proving that an optimised protocol can be obtained for the SM process with a significant substrate scope. The microwave irradiation technology highly enhanced the energy efficiency, allowing the synthesis of different biphenyls and reducing the reaction time. In addition, the good efficiency and selectivity of the SM reaction led to further optimisation of the work-up procedure, minimising the waste generation and the E-factor values associated with the process (3.2-9.4). The optimised conditions tolerated the free carboxylic acid group well, realizing the step-economical preparation of the non-steroidal anti-inflammatory analgesic Fenbufen in quantitative yield. Finally, the scale-up of the MW-assisted process was performed in synergy with the optimisation of the continuous flow protocol and the waste minimised synthesis of Fenbufen was achieved.