# Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling in Continuous Flow
## 4 Heterogeneous Suzuki-Miyaura Cross-Coupling Reaction in Continuous Flow
Two exits (**d** and **g**) were present to recover the mixture after completion of the reaction (Scheme 14). In comparison with microreactor and mesoreactor, this process permitted to furnish biaryl derivatives on a gram scale in continuous flow. Reactions of various aryl iodides with phenylboronic acids gave excellent yields. Aryl iodides having different substituents were explored without significant change in their reactivity. The activation of the aryl chloride was more difficult than expected, but gave good yields using this methodology (Scheme 15) [101]. The catalytic stability in MeOH-H\({}_{2}\)O under flow conditions was studied by [PERSON] and a mechanism was proposed (Scheme 16) [101]. No significant loss of activity was observed after recycling five times. In their hands, the SEM analysis of SS-Pd showed the presence of Pd(0) nano-microparticulates on the solid support which implies its reusability and minimum leaching of Pd from the solid surface. Figure 14: Continuous flow Suzuki–Miyaura cross-coupling on a gram scale of the substrate. [PERSON] developed a novel strategy using Pd nanoparticles supported in a functionalized mesoporous Metal-Organic Frameworks (MOFs) [102]. To the best of our knowledge, it was the first report on the use of metallic nanoparticles supported on MOFs in flow chemistry for catalytic applications. A mixture of aryl halide, boronic acid/ester and K\({}_{2}\)CO\({}_{3}\) in water and ethanol was passed through a column of homemade 8 wt % Pd@MIL-101-NH\({}_{2}\) at room temperature for a residence time of 35-40 min (Scheme 17). Variations of the aryl halides and boronic acid derivatives permitted the production of a mini-library (Figure 5). The authors always used the same cartridge for the preparation of the mini-library of baryl derivatives. It is noticeable that after the reaction, the recovery catalyst was found to be partially crystalline with a remaining Pf content of 6.81 wt % (initially 7.29 wt %) [102]. Figure 16: A schematic diagram of the Suzuki–Miyaura cross-coupling reaction of phenyl boronic acid with aryl halides using SS-Pd as heterogeneous catalyst. A very nice strategy based on dendrimer-encapsulated Pd nanoparticles as catalyst in flow reactor was developed by [PERSON] [103; 104]. In contrast with the conventional heterogeneous Suzuki-Miyaura cross-coupling reaction using cartridge filled with solid catalysts, [PERSON]'s method anchored Pd nanoparticles onto the inner walls of the flow reactor. Aryl halides (10 mM) were mixed with boronic acid derivatives (15 mM) in ethanol at 80 \({}^{\circ}\)C using n-Bu\({}_{4}\)NOH (20 mM) as base at 80 \({}^{\circ}\)C. The solution was passed through the catalytic microreactor with a residence time of 13 min (Scheme 18). The electronic substituents effects have been studied and different biaryl compounds have been obtained (Figure 6). This strategy demonstrated the influence of dendrimers in the stabilization of the Pd NPs with low metal leaching [103; 104]. Figure 5: Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence using immobilized Pd on MOFs. Another group developed dendrimers for continuous flow Suzuki-Miyaura cross-coupling reaction [105]. Variation was noticeable since the authors described magnetic Fe\({}_{3}\)O\({}_{4}\) fixation of dendron-functionalized iron oxide nanoparticles containing Pd nanoparticles. In this process, the non-covalent magnetic fixation of solid material inside the glass reactor microstructures was applied using external magnetic forces and the reversible immobilization of catalyst materials onto the wall of microchannels was possible. Application of this methodology was realized to produce only one compound using 4-methoxy-1-bromobenzene and boronic acid. Another strategy used palladium nanoparticles immobilized in a polymer membrane for the Suzuki-Miyaura cross-coupling reaction but this particular area has not been developed in this review.