# Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling in Continuous Flow
## 4 Heterogeneous Suzuki-Miyaura Cross-Coupling Reaction in Continuous Flow  
A suitable solid support having Pd(II) species precursors to Pd(0) catalysts are now commercially available but different groups prefer to design their home-made catalysts. In the first part the use of Pd(0) reagent is reported and in the second part Pd(II) is described. [PERSON] and [PERSON] reported a palladium on carbon-catalyzed Suzuki-Miyaura coupling reaction using an efficient and continuous flow system (Scheme 10) [97]. To investigate the scope of the reaction, a range of arylboronic acids and halogenobenzene derivatives were tested in mild conditions for 20 s during a single-pass (Figure 3). The authors have reported the detection of little leaching (<1 ppm). Figure 3: Substrate scope of continuous flow Suzuki–Miyaura cross-coupling sequence in a flow system using H-Cube®. Using the same apparatus H-Cube(r), another group reported the Suzuki-Miyaura cross coupling in the presence of graphene supported palladium nanoparticles [98]. A solution of 4-bromobenzaldehyde and phenylboronic acid dissolved in H\({}_{2}\)O-EtOH-THF (1:1:1) was injected with a flow rate of 0.2 mL min\({}^{-1}\) resulting in a contact time of less than 1 min at 135 \({}^{\circ}\)C. The target biaryl compound was obtained in good yield with a conversion of 96% (Scheme 11). In 2006, Canty was the first to develop a macroporous monolith support as a suitable substrate for anchoring a palladium complex for Suzuki-Miyaura cross-coupling continuous flow capillary microreactors [99]. Ten years after, [PERSON] reported an efficient three-step flow sequence using Pd catalyst [100]. The aryllithium obtained from arylbromide reacted with B(OMe)\({}_{3}\); after the borylation reaction, the Suzuki-Miyaura cross coupling reaction in the presence of immobilized Pd(0) on the polymer afforded the target biaryl derivatives (Scheme 12). In this report, a solution of bromobenzene in THF (0.10 M) and a solution n-BuLi (0.6 M in hexane) were injected simultaneously with a flow rate of 6.0 mL min\({}^{-1}\) and 1 mL min\({}^{-1}\), respectively, in a micromixer (ID = 500 \(\upmu\)m) and then in a reactor (ID = 1000 \(\upmu\)m) for a residence time of 1.7 s. A solution of diluted B(OMe)\({}_{3}\) (0.12 M) in THF was injected with a flow rate of 6.0 mL min\({}^{-1}\) and the main stream was introduced to a micromixer (ID = 500 \(\upmu\)m) and the second reactor (ID = 1000 \(\upmu\)m) for a residence time of 2.0 s (Scheme 13). After producing the boronic acid solution, iodoaryl derivative (0.33 M) in methanol was added and the mixture was passed through the palladium catalyst at 100 \({}^{\circ}\)C with a residence time of 4.7 min or at 120 \({}^{\circ}\)C with a residence time of 9.4 min. Application of the above methodology was successfully applied to the cross-coupling of various functional aryl and heteroaryl iodides (Figure 4) [100]. It was noticeable that cyano derivatives in this process tolerated the experimental conditions. Adapalene, a drug used for the treatment of acne, was produced in 86% yield by applying this methodology. A large-scale Suzuki-Miyaura cross-coupling reaction using solid supported palladium Pd\({}^{0}\) nano/microparticles and ultrasound irradiation was reported in continuous flow by [PERSON] [101]. The continuous flow technique used by the authors required a syringe, a reservoir, a pump and a reaction vessel. After the introduction of the aryl bromide, phenylboronic acid and potassium carbonate in MeOH-H\({}_{2}\)O in the reservoir via the syringe **a**, the reagents were pumped (127 mL min\({}^{-1}\)) to the reaction vessel **e** where the solid supported palladium (0) nano/microparticles (SS-Pd) as  
Figure 4: Substrate scope of continuous flow lithiation/borylation/Suzuki–Miyaura cross-coupling sequence in a flow system using immobilized Pd on polymer monolith. heterogeneous catalyst had been charged. Ultrasonication of the mixture (20 kHz) was realized and the reaction product was poured through **b** into the reservoir.