Convergent approach for direct cross-coupling enabled by flash irreversible generation of cationic and anionic species.

In biosynthesis multiple kinds of reactive intermediates are generated, transported, and reacted across different parts of organisms, enabling highly sophisticated synthetic reactions. Herein we report a convergent synthetic approach, which utilizes dual intermediates of cationic and carbanionic species in a single step, hinted at by the ideal reaction conditions. By reactions of unsaturated precursors, such as enamines, with a superacid in a flow microreactor, cationic species, such as iminium ions, are generated rapidly and irreversibly, and before decomposition, they are transported to react with rapidly and independently generated carbanions, enabling direct C-C bond formation. Taking advantage of the reactivity of these double reactive intermediates, the reaction take place within a few seconds, enabling synthetic reactions which are not applicable in conventional reactions.

Expanding the Scope of C-Glycoside Synthesis from Unstable Organolithium Reagents Using Flow Microreactors.

C-glycosides are versatile scaffolds for drugs and bioactive compounds. The common organolithium-based synthesis of C-glycosides is limited by low reaction temperatures and a restricted substrate scope. To address these issues, a flow microreactor (FMR) was utilized for rapid mixing and precise temperature control, enabling C-glycoside synthesis at temperatures up to 40 °C and expanding the substrate scope. Continuous C-glycoside synthesis was achieved with a throughput of 21.9 g h-1, demonstrating the industrial potential of FMRs.

Spatiotemporal Control of Protein Refolding through Flash-Change Reaction Conditions.

Recombinant protein production is an essential aspect of biopharmaceutical manufacturing, with Escherichia coli serving as a primary host organism. Protein refolding is vital for protein production; however, conventional refolding methods face challenges such as scale-up limitations and difficulties in controlling protein conformational changes on a millisecond scale. In this study, we demonstrate the novel application of flow microreactors (FMR) in controlling protein conformational changes on a millisecond scale, enabling efficient refolding processes and opening up new avenues in the science of FMR technology. FMR technology has been primarily employed for small-molecule synthesis, but our novel approach successfully expands its application to protein refolding, offering precise control of the buffer pH and solvent content. Using interleukin-6 as a model, the system yielded an impressive 96% pure refolded protein and allowed for gram-scale production. This FMR system allows flash changes in the reaction conditions, effectively circumventing protein aggregation during refolding. To the best of our knowledge, this is the first study to use FMR for protein refolding, which offers a more efficient and scalable method for protein production. The study results highlight the utility of the FMR as a high-throughput screening tool for streamlined scale-up and emphasize the importance of understanding and controlling intermediates in the refolding process. The FMR technique offers a promising approach for enhancing protein refolding efficiency and has demonstrated its potential in streamlining the process from laboratory-scale research to industrial-scale production, making it a game-changing technology in the field.

Flowmicro in-Line Analysis-Driven Design of Reactions Mediated by Unstable Intermediates: Flash Monitoring Approach.

Invited for the cover of this issue is the group of Aiichiro Nagaki, Yosuke Ashikari and co-workers at Hokkaido University. The image depicts flash monitoring of reactive intermediate in a flow microreactor. Read the full text of the article at 10.1002/chem.202303774.

Synthesis of Deuterated Compounds by Flow Chemistry.

Development of the efficient and practical method for the synthesis of deuterated compounds which occupies the broadest area among stable isotopes is one of the most essential issues toward the industrial advance and building a sustainable society. This review describes recent advances in deuteration reactions, where the continuous flow chemistry plays pivotal roles for the successful installation of deuterium atom into diverse organic frameworks, opening new fields of isotope-based synthetic chemistry.

Flowmicro In-Line Analysis-Driven Design of Reactions Mediated by Unstable Intermediates: Flash Monitoring Approach.

The direct observation of reactive intermediates is an important issue for organic synthesis. However, intermediates with an extreme instability are hard to be monitored by common spectroscopic methods such as FTIR. We have developed synthetic method utilizing flow microreactors, which enables a generation and reactions of unstable intermediates. Herein we report that, based on our flowmicro techniques, we developed an in-line analysis method for reactive intermediates in increments of milliseconds. We demonstrated the direct observation of the living and dead species of the anionic polymerization of alkyl methacrylates. The direct information of the living species enabled the anionic polymerization and copolymerization of oligo(ethylene glycol) methyl ether methacrylates, which is the important but difficult reaction in the conventional method.

External Flash Generation of Carbenoids Enables Monodeuteration of Dihalomethanes.

In this study, incorporation of one deuterium atom was achieved by H-D exchange of one of the two identical methylene protons in various dihalomethanes (halogen=Cl, Br, and I) through a rapid-mixing microflow reaction of lithium diisopropylamide as a strong base and deuterated methanol as a deuteration reagent. Generation of highly unstable carbenoid intermediate and suppression of its decomposition were successfully controlled under high flow-rate conditions. Monofunctionalization of diiodomethane afforded various building blocks composed of boryl, stannyl, and silyl groups. The monodeuterated diiodomethane, which served as a deuterated C1 source, was subsequently subjected to diverted functionalization methods to afford various products including biologically important molecules bearing isotope labelling at specific positions and homologation products with monodeuteration.

Flow-Chemistry-Enabled Synthesis of 5-Diethylboryl-2,3'-bipyridine and Its Self-Assembly Dynamics.

5-Diethylboryl-2,3'-bipyridine (1), which is inaccessible by conventional batch methods, was synthesized by using a flow microreactor. Compound 1 was obtained as an equilibrium mixture of a cyclic trimer and a cyclic tetramer in solution, the latter of which was crystallized in benzene by vapor diffusion of hexane at 7 °C. The dynamic nature of this system was confirmed by solvent- and concentration-dependent experiments. Notably, the dynamics was verified by using flow NMR spectroscopy, which revealed that the time required to reach equilibrium was influenced by the solvent ratio (<18 s, 24-28 s, and 34-42 s in 2 : 1, 1 : 1, and 1 : 2 mixtures of [D6 ]acetone and C6 D6 , respectively). Compound 1 and 3-[4'-(diethylboryl)phenyl]pyridine (2) exhibited different self-assembly behavior in solution and crystals. Density functional theory calculations suggested that this difference was largely due to enhanced planarity between two consecutive aromatic rings.

Rapid access to organic triflates based on flash generation of unstable sulfonium triflates in flow.

Flash (extremely fast) electrochemical generation of unstable arylbis(arylthio)sulfonium triflates [ArS(ArSSAr)]+ [OTf]- that are unsuitable for accumulation in batch processes was achieved within 10 s in a divided-type flow electrochemcial reactor, enabling one-flow access to vinyl triflates, short-lived oxocarbenium triflates and glycosyl triflates.

Rapid gas-liquid reaction in flow. Continuous synthesis and production of cyclohexene oxide.

The enhanced reaction rate in the epoxidation of cyclohexene with air as an oxidant was discovered without any added catalyst utilizing a continuous flow reactor constructed with readily available stainless steel parts and devices. This continuous-flow process demonstrates a significant improvement in reaction time for highly selective epoxide production over the batch process due to the efficient mass transfer between the liquid phase and air. The flow process discovered was operated continuously with good operational stability, evaluated by a constant high yield of cyclohexene oxide, to obtain the desired product with high productivity.

Flash Electrochemical Approach to Carbocations.

A novel flow electrochemical reactor that accomplishes electrolysis within a few seconds in a single passage was developed. By using the flow reactor system, the flash electrochemical generation of short-lived carbocations, including oxocarbenium ions, N-acyliminium ions, glycosyl cations, and Ferrier cations was achieved within a few seconds, enabling the subsequent reaction with nucleophiles before their decomposition. Moreover, continuous operation based on the present system enabled the rapid synthesis of pharmaceutical precursors on demand.

Switchable Chemoselectivity of Reactive Intermediates Formation and Their Direct Use in A Flow Microreactor.

A chemoselectivity switchable microflow reaction was developed to generate reactive and unstable intermediates. The switchable chemoselectivity of this reaction enables a selection for one of two different intermediates, an aryllithium or a benzyl lithium, at will from the same starting material. Starting from bromo-substituted styrenes, the aryllithium intermediates were converted to the substituted styrenes, whereas the benzyl lithium intermediates were engaged in an anionic polymerization. These chemoselectivity-switchable reactions can be integrated to produce polymers that cannot be formed during typical polymerization reactions.

Insight into the Ferrier Rearrangement by Combining Flash Chemistry and Superacids.

The transformation of glycals into 2,3-unsaturated glycosyl derivatives, reported by Ferrier in 1962, is supposed to involve an α,ß unsaturated glycosyl cation, an elusive ionic species that has still to be observed experimentally. Herein, while combination of TfOH and flow conditions failed to observe this ionic species, its extended lifetime in superacid solutions allowed its characterization by NMR-based structural analysis supported by DFT calculations. This allyloxycarbenium ion was further exploited in the Ferrier rearrangement to afford unsaturated nitrogen-containing C-aryl glycosides and C-alkyl glycosides under superacid and flow conditions, respectively.

A Synthetic Approach to Dimetalated Arenes Using Flow Microreactors and the Switchable Application to Chemoselective Cross-Coupling Reactions.

In spite of their potential utility, the chemistry of dimetalated arenes is still in its infancy because they are extremely difficult to synthesize. We report a novel method of synthesizing arenes bearing a boryl group and a metallic substituent, such as boryl, silyl, stannyl, or zincyl groups, in an integrated flow microreactor based on the generation and reactions of aryllithiums bearing a trialkyl borate moiety. The bimetallic arenes showed a remarkable chemoselectivity in palladium-catalyzed cross-coupling reactions. The selectivity was switched by the selection of the metal species that constitutes the dimetalated arenes as well as appropriate catalysts.

Fluoro-Substituted Methyllithium Chemistry: External Quenching Method Using Flow Microreactors.

The external quenching method based on flow microreactors allows the generation and use of short-lived fluoro-substituted methyllithium reagents, such as fluoromethyllithium, fluoroiodomethyllithium, and fluoroiodostannylmethyllithium. Highly chemoselective reactions have been developed, opening new opportunities in the synthesis of fluorinated molecules using fluorinated organometallics.

A Novel Approach to Functionalization of Aryl Azides through the Generation and Reaction of Organolithium Species Bearing Masked Azides in Flow Microreactors.

A novel straightforward method for aryl azides having functional groups based on generation and reactions of aryllithiums bearing a triazene group from polybromoarenes using flow microreactor systems was achieved. The present approach will serve as a powerful method in organolithium chemistry and open a new possibility in the synthesis of polyfunctional organic azides.

Generation and Reaction of Functional Alkyllithiums by Using Microreactors and Their Application to Heterotelechelic Polymer Synthesis.

Flow microreactors enabled the successful generation of various functional alkyllithiums containing electrophilic functional groups, as well as the use of these alkyllithiums in subsequent reactions. The high reactivity of these series of reactions could be achieved by the extremely accurate and selective control of residence time. Moreover, integrated flow microreactor systems could be used to successfully synthesize heterotelechelic polymers with two functionalities, one at each end, via a process involving controlled anionic polymerization initiated by functional alkyllithium compounds, followed by trapping reactions with difunctional electrophiles.

Oxo-Thiolation of Cationically Polymerizable Alkenes Using Flow Microreactors.

The present study describes the cationic oxo-thiolation of polymerizable alkenes by using highly reactive cationic species generated by anodic oxidation. These highly reactive cations were able to activate alkenes before their polymerization. Fast mixing in flow microreactors effectively controlled chemoselectivity, enabling higher reaction temperatures.

Anionic Polymerization Using Flow Microreactors.

Flow microreactors are expected to make a revolutionary change in chemical synthesis involving various fields of polymer synthesis. In fact, extensive flow microreactor studies have opened up new possibilities in polymer chemistry including cationic polymerization, anionic polymerization, radical polymerization, coordination polymerization, polycondensation and ring-opening polymerization. This review provides an overview of flow microreactors in anionic polymerization and their various applications.

Synthesis of Functionalized Ketones from Acid Chlorides and Organolithiums by Extremely Fast Micromixing.

Synthesis of ketones containing various functional groups from acid chlorides bearing electrophilic functional groups and functionalized organolithiums was achieved using a flow microreactor system. Extremely fast mixing is important for high chemoselectivity.