# Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling in Continuous Flow
## 4 Heterogeneous Suzuki-Miyaura Cross-Coupling Reaction in Continuous Flow
As examples, some works have been written recently in this field and are just quoted in this review for interested researchers wishing to gain deeper knowledge of the field [106; 107; 108]. [PERSON] reported an efficient cross-coupling reaction using commercial heterogeneous silica-supported palladium catalyst and a mesoreactor [109]. The authors used a simple and efficient experimental set-up using a 6.6 mm (internal diameter) Omnifit column containing 1 g of heterogeneous catalyst and commercial boronic acids and aryl halides (Scheme 19). A solution of aryl halide in THF and a solution of boronic acid and base in water were pumped at 0.2 mL min\({}^{-1}\) with two independent pumps. The flow streams met at a T-shaped mixer and then passed through a column containing SiliaCat DPP-Pd as diphenylphosphine palladium (II) heterogeneous catalyst at 60 \({}^{\circ}\)C with a residence time of 5 min. A biphasic solvent system such as THF-H\({}_{2}\)O was used to ensure complete dissolution of any solid and avoiding any subsequent clogging. Figure 6: Substrate scope of continuous flow [PERSON]–Miyaura cross-coupling sequence using Pd dendrimers encapsulated microreactor. Application of this strategy permitted the synthesis of the biaryl derivatives starting from halides/pseudohalides and (4-methoxylyn) boronic acid in excellent yields (Scheme 20) [109]. Whatever the leaving group on the benzene ring, the target biphenyl derivatives were obtained in high yields. Of course, the use of aromatic ring bearing electron-donor groups such as 2,4-dimethoxy analogs gave lower yields (50%). It was notable that bromo- and chloropyridines provided good yields and the ester functionality was tolerated despite the use of KOH as strong base. Using this process, the authors claimed that the crude products are clean and free of phosphine ligand avoiding the need of chromatographic purification. Moreover, low leaching of palladium from the support and the stability of the catalyst after more than 30 cycles was observed. In order to further explore the scope of the reaction, [PERSON] reported the use of bromobenzene and phenyltriflate as starting materials with different boronic acid derivatives (Scheme 21) [109]. Excellent yields were obtained with commercial boronic acids and boronic ester, borane and borate freshly prepared from the corresponding bromo derivatives by metalation [110]. Recently, [PERSON] presented a comparative investigation of four commercial immobilized phosphine-based Pd catalyst [111]. One of them was SiliaCat DPP-Pd as diphenylphosphine palladium (II) heterogeneous catalyst developed by [PERSON] [112; 113; 114]. In this work, the best process used two stock solutions. The first solution contained aryl halide (0.83 M) in THF and the second one phenylboronic acid (0.45 M) and K2 CO3 (0.55 M) in a mixture of H2O-EtOH (1:1). These two solutions were pumped in different feeds, 0.055 mL min\({}^{-1}\) and 0.155 mL min\({}^{-1}\), respectively, and mixed in a T-mixer and then introduced to the catalyst cartridge of the X-cube flow reactor at 80 \({}^{\circ}\)C (Scheme 22). Under these conditions, full conversion was obtained in less than 20 min and almost quantitative yield of the biaryl target compound was reported. Figure 20: Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence with different aryl bromides and 4-methoxylynbenzoic acid. [PERSON] and [PERSON] reported an interesting work using heterogeneous catalyst from Covalent Organic Frameworks (COFs) [115], COFs are different than MOFs since COFs do not contain metallic ions or heavy elements as part of their structures. In this study, the authors developed Pd(OAc)\({}_{2}\)@COF-300 for the Suzuki-Miyaura cross-coupling reaction in continuous flow (Scheme 23). The mixture of bromobenzene, phenylboronic acid in a solution of MeONa (2 M) in MeOH was injected on to a glass column (Omnifit column with a volume of 6.3 mL), which was filled with glass beads (2 mm) and Pd(OAc)\({}_{2}\)@COF-300 (100 mg).