自20世纪90年代全球范围内全面研发开展以来，从药品和农用化学品到塑料化学品，流动化学（Folw-Chem）受到了广泛关注，并迅速成为各种化学合成中最有用和最不可或缺的技术之一。 F-C 具有独特的功能，最重要的是提供可用于增强传质换热效率和降低成本的优点，与传统间歇反应相比，其安全性和反应速率也大大提高。
来自日本的武田制药流动化学研究小组的Hirotsugu Usutani and David G. Cork教授，最近在《Organic Process Research & Development》期刊上发表了一篇题为“Effective Utilization of Flow Chemistry: Use of Unstable Intermediates, Inhibition of Side Reactions, and Scale-Up for Boronic Acid Synthesis”的文章，为我们详细介绍了利用丁基锂法，在微通道中高效合成有机硼酸的案例。
. Feasibility Study and Proof of Concept. As is wellknown, FC has already been applied to boronic acid synthesis,11,12 but the scope of its application is still limited.The key parameters for robust scale-up are the mixing efficiency, temperature, and residence time control, even though there are numerous other parameters to be considered for process development by flow. On the basis of our previously reported insights,5 it was planned to utilize FC for the manufacture of (4-(cyclohexyloxy)phenyl)boronic acid (3a). When 3a was synthesized in batch, a side reaction was found to be unavoidable if a halogen-lithium exchange reaction was utilized, with butylation13 being a major issue even when the reaction was carried out at -25 °C (Scheme 2). In order to partially suppress the side reaction in batch, cryogenic conditions were required, and thus, a flow reaction was investigated to develop milder conditions and further decrease the side products. First, as a feasibility study, the halogen-lithium exchange reaction and its quench by MeOH was investigated in a flow setup (Figure 1 and Table 1).The initial experiments for the feasibility study were conducted with 1.07 equiv of n-BuLi, a reaction temperature of 0 °C, and residence times of 0.24-31.42 s. When less than 1s was allowed for lithiation, not all of the raw materials were converted, showing the minimum time required to consume all of the raw materials. However, as the residence time was increased, more raw material was consumed until 1a was totally converted to the lithiated species when a residence time of more than 3.93 s was used for lithiation. Surprisingly, the protonated compound (4a), representing the desired product pathway, was obtained in the highest yield in Table 1, entry 3,and the yield decreased as the residence time for lithiation was prolonged. Furthermore, the side reaction (butylation, 5a)increased as the residence time increased.
As shown in Figure 2, the flow synthesis of boronic acid 3a was achieved in good yield through minimization of the major side reactions. Crystallization in batch was conducted after the flow reaction, and the boronic acid was isolated as white crystals in 75% yield.
2.2. Application of Flow for Diversity-Oriented Syntheses of Boronic Acids. The flow chemistry process for 3a was successfully developed at lab scale, and the procedure was applied to other boronic acid syntheses. The concept for a flow process to obtain boronic acids starting from aryl bromides as raw materials is shown in Figure 3,14 and a summary of the results obtained after an optimization study onthe residence time is shown in Table 2.
Application of a Flow Chemistry Process to Diversity-Oriented Synthesis of Boronic Acids
Org. Process Res. Dev., 2018, 22 (6), pp 741–746