# Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling in Continuous Flow
## 3 Homogeneous Suzuki-Miyaura Cross-Coupling Reaction in Continuous Flow
After optimization of the first continuous flow process (Scheme 4), the borylation was made at room temperature with a reduced time (6 s vs. 60 s) and acoustic irradiation was not needed for this step in reactor 2 (Scheme 5) [84]. Application of the method was realized to show the scope of the reaction [84]. Starting from thiophene, 2-alkylthiophene and 2-alkylfuran, borylation in two steps was efficient: the coupling with different substituted aryls and heteroaromatic halides afforded the target compounds in good yields (Scheme 6). This novel process allows the use of low-cost heteroarenes instead of more expensive and unstable 2-heteroaromatic boronic acids and 2-heteroaromatic bromides. In order to illustrate the synthetic potential of this methodology, Diflunisal [91; 92] was obtained in a multi-step sequence [84]. Starting from 4-bromoanisole, the lithiation/borylation followed by Suzuki-Miyaura cross-coupling with 1-bromo-2, 4-difluorobenzene permitted the synthesis of the key intermediate in the production of Diflunisal (Scheme 7). Figure 1: Substrate scope of continuous flow lithiation/borylation/Suzuki–Miyaura cross-coupling sequence starting from aryl bromides. In order to develop an automated, droplet-flow microfluidic system applied to Suzuki-Miyaura cross-coupling reaction, [PERSON] and [PERSON] reported a systematic methodology including key mechanistic insights [93]. A three-step flow diazotization, iododediazotization and Suzuki-Miyaura cross coupling reaction has been reported by [PERSON] starting from aniline derivatives [94]. Starting from the arylamine, the diazotation followed by the introduction of iodide atom furnished the iodobenzene derivatives. Then conventional Suzuki-Miyaura cross coupling afforded the biphenyl derivatives (Scheme 8). Three reactors were made with PFA capillary tubing with an inner diameter of 1.52 mm and different volumes. The residence time in reactors was adjusting the length of the reactor tubing. A solution of aniline derivative in CH\({}_{3}\)CN and a solution of tBuONO in CH\({}_{3}\)CN were injected simultaneously, followed by mixing with a T-mixer and injection of a solution of methanesulfonic acid in CH\({}_{3}\)CN. The three solutions were used with a flow rate of 22 \(\upmu\)L min\({}^{-1}\). The mixed stream was introduced to the first reactor at room temperature with a residence time of 2.7 min. Then, a solution of nBuNI in CH\({}_{3}\)CN was injected into the stream with the same flow. The combined mixture was introduced to the second reactor for which is immersed in an ultrasonic bath. The residence time was 20 min at room temperature and then the segmented effluent was temporarily collected in an intermediate reservoir. Due to the used reservoir a continuous flow unit (CFU) was accommodated. A solution of [PdCl\({}_{2}\)(PPh\({}_{3}\))\({}_{2}\)], CuI, iP\({}_{2}\)NH in CH\({}_{3}\)CN and a solution of boronic acid in MeOH were injected simultaneously to the main stream and introduced to the third reactor at 60 \({}^{\circ}\)C for 45 min (Scheme 9) [94]. Application of the above protocol with little variations to the production of biphenyl compounds was reported (Figure 2). In function of the different steric and electric demands in the aromatic core, the coupling gave satisfactory yields [94]. Figure 2: Substrate scope of continuous flow diazotization/iododediazotization/Suzuki–Miyaura cross-coupling sequence starting from aniline derivative. Application to continuous flow process on a large scale was reported recently and could open new way for industrial use [95; 96].