A Practical Method for Continuous Production of sp3‐Rich Compounds from (Hetero)Aryl Halides and Redox‐Active Esters

Abstract

A practically useful coupling reaction between aromatic halides and redox‐active esters was realized by nickel catalysis through the use of a packed zinc bed column in continuous flow. Multiple reuse of the column showed a negligible decrease in efficiency, affording high space/time yields. A wide range of substrates, including a number of heteroaryl halides and polyfunctional materials were coupled in generally good yields. Longer‐time and larger‐scale experiments further demonstrates the robustness of the system.

Investigation of Parameter Control for Electrocatalytic Semihydrogenation in a Proton-Exchange Membrane Reactor Utilizing Bayesian Optimization

“…The PEM reactor features many characteristics designed to overcome the disadvantages of conventional electrosynthetic processes, such as the necessity of supporting electrolytes. Moreover, because the PEM reactor is a flow reactor (Masui et al, 2019;Ashikari et al, 2020;Colella et al, 2020;Harenberg et al, 2020;Ichinari et al, 2020;Otake et al, 2020;Saito and Kobayashi, 2020;Watanabe et al, 2020;Ahn et al, 2021;Prieschl et al, 2021;Sivo et al, 2021), it offers numerous advantages, including precise control of the reaction time, the applicability of successive reactions, and scalability, which are rarely applicable in batch electrosynthesis (Elsherbini and Wirth, 2019;Noël et al, 2019;Hu et al, 2020). Therefore, various applications of PEM reactor systems utilizing electrosynthetic processes, such as the reduction of toluenes (Takano et al, 2016;Fukazawa et al, 2018) and alkenes (Ogumi et al, 1981), and asymmetric hydrogenation of α,β-unsaturated acids (Fukazawa et al, 2020), have been reported (Raoult et al, 1984;Jorissen, 1996;Kishi et al, 2020;Fukazawa et al, 2021).…”

Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Chlorides with Primary Alkyl Chlorides

“…substrates, this chemistry can be scaled up using standard techniques (3ac). 32 The distinctive feature of this reaction, when compared to other cross-electrophile couplings of aryl halides with alkyl halides, is the ability to engage two relatively unreactive substrates in a selective manner (Scheme 1). There are three keys to the success of this method.…”

Use of Lithium Diisopropylamide in Flow: Operability and Safety Challenges Encountered on a Multigram Scale

“…Historically, the focus within GSK has been on the design and industrialization of late-phase continuous manufacturing processes for the production of molecules in phase 3 or later, requiring detailed understanding and control strategies. − To make the most of continuous technology as a tool for solving processing problems, the GSK continuous manufacturing (flow) group is targeting key transformations, common in the manufacture of pharmaceutical intermediates and active ingredients (APIs), that benefit from the application of continuous approaches. Examples of these transformations include reactions with fast kinetics and/or significant exotherms, reactions employing organometallics (including packed beds to generate organometallics), and reactions that carry risk in batch, for example, reactions utilizing hazardous reagents (safety risk). − One of the other well-known advantages of continuous processing is rapid scale-up; we are now turning our attention to the application of flow technologies to New Chemical Entity (NCE) projects in preclinical and phase 1, where we can utilize this advantage to speed up the delivery of key assets. ,, Currently, we are working on several projects in support of medicinal chemistry for rapid scale-up for preclinical and phase 1 supply. This phase of activity focuses on a functional process to deliver material, i.e., a process that is fit for purpose, often using the medicinal chemistry route rather than a final commercial route; therefore, a reduced level of understanding is required compared to the late phase.…”