# Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling in Continuous Flow
## 3 Homogeneous Suzuki-Miyaura Cross-Coupling Reaction in Continuous Flow  
[PERSON] reported an efficient synthesis of biaxyls from aryl halide substrates using a successive lithiation/borylation/Suzuki-Miyaura cross-coupling sequence in three successive mesoreactors [84]. Starting from aryl bromide, the bromine-lithium exchange afforded the corresponding aryllithium which reacted with borate to form the boronate agent. Conventional Suzuki-Miyaura cross-coupling reaction using homogeneous second-generation palladium let precatalyst **a** furnished the target biaxyl derivatives (Scheme 3). One of the main drawbacks of this nice concept was the formation of solids such as lithium trisisopropyllyborate during the process; optimization of the nature of the solvent (THF and H\({}_{2}\)O), the concentration of reagents and the use of acoustic irradiation have been reported to avoid the formation of such solids. **Scheme 3. ** Lithiation/borylation/Suzuki-Miyaura cross-coupling sequence for the synthesis of biaxyl derivatives. In this report, the development of different reactors made with a perfluoroalkoxyalkane (PFA) tube having the inner diameter of 1 mm has been described [84]. A solution of arylbromide in THF and a solution of _n_-butyllithium in hexane (1.6 M or 2.5 M) were injected simultaneously, then mixed at a T-shaped mixer and delivered to the first reactor (_reactor 1_) at room temperature with a flow rate of 50-78 \(\upmu\)L min\({}^{-1}\) and a varying residence time (2-120 s). A solution of diluted B(OiPr)\({}_{3}\) in THF was injected with a flow rate of 1 \(\upmu\)L min\({}^{-1}\) and mixed with the exiting stream of aryllithium derivative at a T-shape mixer. The mixed stream was introduced to the second reactor (_reactor 2_) at 60 \({}^{\circ}\)C under acoustic irradiation with a residence time of 1 min. Then, a solution of aqueous KOH (0.87 M) and a solution of aryl halide (1.00 M) and XPhos precatalyst (**a**, 1 mol %) in THF were successively injected into the exiting stream with a flow rate of 100 \(\upmu\)L min\({}^{-1}\) and 21-40 \(\upmu\)L min\({}^{-1}\), respectively. The combined mixture was introduced to the third reactor (reactor 3) at 60 \({}^{\circ}\)C under acoustic irradiation with a residence time of 10 min (Scheme 4). Ultrasound chemistry was used for reactors 2 and 3 to avoid reactor clogging and ensure a good mixing of reagents during the formation of the borate and the Suzuki-Miyaura cross-coupling reaction. Application of the above methodology was realized with a range of various aryl halides (Figure 1), the limiting step of the process being the lithiation of aryl halides. In their hands, [PERSON] described that the aryl bromide could be lithiated at room temperature. Whatever the nature of the starting aryl bromide having different electronic and steric demands in _para_, _meta_ and _ortho_ positions, the aryllithium and then the corresponding lithium arylborate were obtained in good yields. For the third step, the Suzuki-Miyaura cross-coupling reaction with aryl bromide or chloride with both electron-withdrawing and electron-donating substituents, afforded the target compounds in good yields. It was noteworthy that non-canonic heteroatomic halides such as quinoline, isoquinoline, pyrimidine and benzothiophene were good reagents for the continuous flow reaction. It is noteworthy that five-membered 2-heteroaromatic boronic acids are unstable at room temperature and consequently give low yields in the Suzuki-Miyaura cross-coupling reaction [85; 86; 87; 88; 89; 90]. Consequently, [PERSON] turned attention to the lithiation/borylation/Suzuki-Miyaura cross-coupling of heteroarenes such as thiophene and furan derivatives; starting from furanic derivatives, selective deprotonation of the hydrogen atom in position 2 at room temperature afforded the corresponding lithium analog which reacted with borate to form the boronate agent. Then, conventional homogeneous Suzuki-Miyaura cross-coupling reaction furnished the target biaryl derivatives.