Product yields were determined through GC analyses (Shimadzu GC-2014) calibrated using internal standards with commercial samples. Syringe pumps (Harvard Model PHD 2000 or PHD ULTRA) equipped with gastight syringes (purchased from SGE) were used to introduce the reaction solutions. PTFE tubes with inner diameters of 10 μm were purchased from ISIS. Stainless steel (SUS316) flow reactors with inner diameters of 1000 and 2,170 μm were purchased from GL Sciences. T-shaped stainless steel (SUS304) micromixers with inner diameters of 500 and 250 μm were manufactured by Sanko Seiki. Moreover, by utilizing flash chemistry thoroughly, we demonstrated room-temperature coupling of aryl halides.Ĭhemicals were purchased from Kanto Chemical, FUJIFILM Wako Pure Chemical, Tokyo Chemical Industry, and Sigma–Aldrich, and were used without further purification unless otherwise stated. We applied this strategy to metal-selective cross-coupling reactions and demonstrated the synthesis of biaryls bearing metal substituents. Herein, we report the flow microsynthesis of functionalized biaryls by integrating lithiation, zincation, and coupling reactions mediated by functionalized aryl zinc. The modest electronegativity of zinc (1.7) causes adequate reactivity, resulting in functional group tolerance. Reaction integration ( Nagaki, 2021) allows the generated aryl zincs to be subsequently engaged in Negishi coupling in one flow.

Based on this idea, we envisaged that aryl lithiums bearing electrophilic functionalities are generated by functional-group-tolerant halogen–lithium exchange reactions and, before they decompose, are converted to aryl zincs. Taking the advantage of the flow microreactors, highly-selective chemical reactions have been achieved ( Ashikari et al., 2019 Sugisawa et al., 2020 Ashikari et al., 2021). The use of flow reactors, especially micro-meter-sized flow reactors, has several benefits, such as an efficient heat transfer, a rapid mixing, a precise control of the reaction time and a direct use of transient unstable species, in the organic synthesis field ( Heinz et al., 2021 Mazzarella et al., 2021 Ashikari, et al., 2022 Miyamura and Kobayashi, 2022 Nogami et al., 2022). To achieve rapid and functional group-tolerant cross-coupling, we applied the strategy of flash chemistry ( Yoshida, 2008 Colella et al., 2020 Nagaki et al., 2021 Takumi, et al., 2022) and reaction integration ( Figure 1) using flow reactors. This resulted in lower product diversity and overshadowed the utility of this process. However, because of the high reactivity of aryl lithium, the functional groups were limited and no electrophilic functionalities were utilized for both aryl lithium and its coupling partner (aryl halide). We demonstrated continuous-flow Murahashi-coupling ( Nagaki et al., 2010 Nagaki et al., 2012b) that enables the syntheses of biaryls and biheteroaryls in high yields within 90 s under mild conditions (temperature for coupling: 50 ☌). 1.3 for Mg and 2.0 for B), Murahashi coupling was assumed to be a rapid synthetic method. Because of the low electronegativity of lithium (Pauling scale: 0.98, c.f. We focused on the coupling process referred to as the Murahashi coupling ( Murahashi et al., 1979 Giannerini et al., 2013) using aryl lithium as the aryl metal. Thus, a rapid process that allows chemists in R&D to prepare libraries of candidate molecules quickly and manufacturers to promptly supply their customers with sufficient products for cross-coupling reactions is urgently required. Current social development has accelerated the demand for novel and high-performance organic molecules. A wide range of molecules have been obtained through cross-coupling in the pharmaceutical, agrochemical, and material-chemistry fields ( Nicolaou et al., 2005 Corbet and Mignani, 2006 Magano and Dunetz, 2011, respectively). As awarded the Nobel Prize in Chemistry in 2010, palladium-catalyzed cross-couplings, particularly coupling of aryl metals with aryl halides, are ubiquitous in our society.

Functional groups table