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In biosynthesis multiple kinds of reactive intermediates are generated, transported, and reacted across different parts of organisms, enabling highly sophisticated synthetic reactions. Inspired by such ideal reaction conditions, herein we report a convergent synthetic approach using double intermediates, carbocations and carbanions, at once. By reactions of unsaturated precursors, such as enamines, with a superacid in a flow microreactor, carbocations were generated rapidly and irreversibly, and before decomposition, they were 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 took place within a few seconds, enabling synthetic reactions which are not applicable in conventional reactions.

We describe a novel strategy to increase the unit-time-productivity of flow synthesis by using hierarchical bimodal porous silica gel (HBPSG) supported palladium column reactors. Because HBPSG has a significantly large surface area, the column reactors have low pressure drop, enabling high-volume production. We demonstrated flow synthesis of the precursor of adapalene, a pharmaceutical compound, at 5 g/h which is over 10-fold greater productivity than previous approaches.

Protein PEGylation is a traditional bioconjugation technology that enhances the therapeutic efficacy and in vivo half-life of proteins by the formation of covalent bonds with highly activated ester group linked polyethylene glycol (PEG). However, the high reactivity of these reagents induces a random reaction with lysine residues on the protein surface, resulting in a heterogeneous mixture of PEGylated proteins. Moreover, the traditional batch-mode reaction has risks relating to scalability and aggregation. To overcome these risks of traditional batch-mode PEGylation, a manufacturing strategy utilizing structural analysis and a continuous-flow-mode reaction was examined. A solvent exposure analysis revealed the most reactive lysine of a protein, and the continuous-flow mode modified this lysine to achieve the mono-PEGylation of two different proteins within 2 seconds. This ultrarapid modification reaction can be applied to the gram-scale manufacturing of PEGylated bioconjugates without generating aggregates. A similar trend of the exposure level of protein lysine and mono-selectivity performed by continuous-flow PEGylation was observed, which indicated that this manufacturing strategy has the potential to be applied to the production of a wide variety of bioconjugates.

Protein PEGylation is a traditional bioconjugation technology that enhances the therapeutic efficacy and in vivo half-life of proteins by the formation of covalent bonds with polyethylene glycol (PEG). The most established methodology for PEGylation utilizes activated ester-incorporating PEG reagents; however, the high reactivity of these reagents induces a random reaction with lysine residues on the protein surface, resulting in a heterogeneous mixture of PEGylated proteins. Moreover, the traditional batch-mode reaction has risks relating to scalability and aggregation. To overcome these risks of traditional batch-mode PEGylation, a manufacturing strategy utilizing structural analysis and a continuous-flow-mode reaction was examined. A solvent exposure analysis revealed the most reactive lysine of a protein, and the continuous flow mode modified this lysine to achieve the mono-PEGylation of two different proteins within two seconds. This ultra-rapid modification reaction can be applied to the gram-scale manufacturing of PEGylated bioconjugates without generating aggregates. A similar trend of the exposure level of protein lysine and mono-selectivity performed by continuous-flow PEGylation was observed, which indicated that this manufacturing strategy has the potential to be applied to the production of a wide variety of bioconjugates.

Flash (extremely fast) electrolysis in flow realized rapid generation of highly unstable arylbis(arylthio)sulfonium triflates, enabling one-flow access to vinyl triflates, short-lived oxocarbenium triflates and glycosyl triflates.

Owing to their recyclability, heterogeneous transition metal catalysts represent a means of conserving depletable resources for the synthesis of pharmaceutical, agricultural, and functional chemicals. We recently developed a novel heterogeneous palladium catalyst and demonstrated its synthetic availability for Suzuki–Miyaura cross-coupling. Herein, we report the further application of the present catalyst to cross-coupling reactions in batch and flow, as well as a hydrogenative reduction reaction in flow. We demonstrate the flow synthesis for useful material, a liquid crystal, and a 1 h sequential operation of the coupling reaction and hydrogenation reaction.

5-Diethylboryl-2,3'-bipyridine (1), which is inaccessible using conventional batch methods, was synthesized 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 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 acetone-d6 and C6D6, 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.

Organolithium reagents are often too unstable to use due to being highly reactive. This limits their application in organic synthesis. This review highlights our approach to various synthetic react...

Aryl–aryl cross-coupling reactions are important reactions for the production of various biaryl compounds. This short review covers the various aryl–aryl cross-coupling reactions carried out in flow, focusing on the metal species of the aryl nucleophiles used in the cross-coupling reactions.1 Introduction2 Suzuki–Miyaura Coupling (B)3 Migita–Kosugi–Stille Coupling (Sn)4 Negishi Coupling (Zn)5 Kumada–Tamao–Corriu Coupling (Mg)6 Murahashi Coupling (Li)7 Conclusion

Selective trapping of (4,5-dibromo-2-thienyl)lithium, known to undergo halogen dance, was achieved in a flow microreactor. This transient thienyllithium, generated by mixing 2,3-dibromothiophene and lithium diisopropylamide at –78 °C for 1.6 seconds, reacted with benzaldehyde. The reaction system is also applicable to other carbonyl compounds to afford the corresponding adducts in good yields. Moreover, the established conditions permit the conversion of 2,5-dibromothiophene into a mixture of the two constitutional isomers. The contrasting results are discussed on the basis of the reaction pathway.

International audience; The transformation of glycals into 2,3-unsaturated glycosyl derivatives, reported by Ferrier in 1962, is supposed to involve an α,β 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 NMRbased 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.

We herein report that flow microreactors can promote an efficiency of radical chain reactions. The chain reactions with a fast propagation step can be accelerated by virtue of an efficient heat-transfer character of the microreactors, whereas the yield of those reactions with a slow propagation step was increased by flow microreactors. Moreover, the yield was further increased by a sequential addition of the initiators, which was allowed by a flow-sequential-addition system.

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.

International audience; The influence of the mixer shape on the stereoselectivity was measured for lithium–bromine exchange on a gem-dibromoalkene followed by proton trapping. Sixteen passive mixers with eight different angles (135, 120, and 105° (Y mixers); 90° (T mixer); 75, 60, 45, and 30° (W mixers)) and two internal diameters (500 and 250 μm) associated with a tubular microflow reactor having an internal diameter of 500 μm were used. The 45° W-shaped mixer with a smaller internal diameter gave the best selectivity for the monobrominated E product over a range of flow rates without the usual cryogenic conditions (20 °C). With methyl benzoylformate as the electrophile, the corresponding polyfunctionalized product was obtained in a space-time yield of 81 kg L–1 h–1.

Flow microreactors have allowed an efficient extended Pummerer reaction of ketene dithioacetal monoxides with anilines by precise control of unstable sulfonium intermediates and spatial separation ...

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.

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.

Two different types of palladium catalysts supported on dual-pore monolithic silica beads [5% Pd/SM and 0.25% Pd/SM(sc)] for chemoselective hydrogenation were developed. Alkyne, alkene, azide, and nitro functionalities and the aromatic N-Cbz protecting group were chemoselectively hydrogenated using 5% Pd/SM. On the other hand, 0.25% Pd/SM(sc) showed unique and higher hydrogenation catalyst activity toward a wide variety of reducible functionalities. Furthermore, the catalyst activities of both 5% Pd/SM and 0.25% Pd/SM(sc) under flow hydrogenation conditions were also evaluated. A pre-packed 5% Pd/SM cartridge could be used continuously for at least 72 h without any loss of catalyst activity. The 0.2% Pd/SM(sc) catalyst prepacked in a cartridge showed high catalyst activity for the flow hydrogenation of trisubstituted alkenes under mild reaction conditions.

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.

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.

Pummerer‐based annulation of alkenyl sulfoxides, mainly ketene dithioacetal monoxides (KDMs), with nitriles has been developed. By means of trifluoromethanesulfonic anhydride (Tf₂O) as an activator, additive Pummerer reaction and subsequent C−S‐bond‐forming cyclization from the nitrilium intermediates furnished the corresponding thiazoles. Moreover, the nitrilium intermediates proved to be interrupted intermolecularly by H₂O to afford oxazoles instead of thiazoles.

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.

The high reactivity of organolithium reagents often renders them too unstable to be used, thereby limiting their application in organic synthesis. This review highlights our approach to various synthetic multiple reactions for drug discovery mediated by organolithium reagents based on flash chemistry.

A synthesis process for the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride (BMIM.Cl) was developed using a flow microreactor (FMR) in this study. After the reaction rate analysis, the FMR was efficiently designed using computational fluid dynamics simulation, which can shorten the process development time by reducing trial-and-error experimentation. The designed FMR is composed of a V-shaped mixer and a tubular reactor having a millimeter-scale inner diameter. From the viewpoint of process operation and control, reactors with larger inner diameter are basically preferable. The influence of three inner diameters, 0.75, 2.16, and 4.35 mm, that satisfy temperature constraints on product quality, product yield, and production volume was investigated. It was found that as the inner diameter becomes large, the product yield becomes low because the mass transfer approaches the rate-limiting step of the reaction process. To avoid this problem, it was proposed that static mixers should be built in the reac...

In the anionic polymerization of styrene using a flow microreactor, there was a strong correlation between the molecular weight distribution (Mw/Mn) of the polymer and the mixing speed. By taking advantage of this relationship, a new type of mixability evaluation was developed using the flow microreactor system. The new method allowed the mixability to be evaluated at 0 °C or a lower temperature with high accuracy. With the ability to be applied for a wider range of reaction conditions, it offers a great advantage over other evaluation procedures such as the Dushman reaction, which requires reaction temperatures to be above 0 °C. The presented method is a promising alternative as a new evaluation technique for mixing efficiency.

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.

Successful transformations of 3-iodo-1-methyl-5,6-dihydropyridin-2(1H)-one into its derivatives by a halogen–lithium exchange and subsequent reactions in a flow microreactor system are described. The methylation of the organolithium compound generated from 3-iodo-1-methyl-5,6-dihydropyridin-2(1H)-one in the flow microreactor system afforded the desired methylated product in 68% yield, whereas the yield of the corresponding batch reaction was 23%. This superiority of the flow microreactor system was further emphasized in the reaction of the organolithium compound with methoxycarbonyl isocyanate, which gave the desired imide in 78% yield by using the flow microreactor system whereas the yield of the corresponding batch reaction was only 2%. The established flow microreactor system was also effectively used for the reaction of the organolithium compound with phenyl isocyanate to afford the desired product in 52% yield.

Triarylmethylium-o,o-dimers adopt a twisted geometry so that two diarylmethyliums are stacked in a slipped manner. Thus, chiral auxiliaries on the aryl groups induce a preference in the axial chirality of the central biphenyl unit. Strong circular dichroism is attained through exciton coupling, which can be used for additional spectral output in their electrochromic behavior. Diastereoselectivity based on π–π stacking exhibits unique solvent effects, thus endowing multifunctional response properties.

Thermally unstable (3,3,3-trifluoroprop-1-en-2-yl)lithium was generated by lithiation of 2-bromo-3,3,3-trifluoroprop-1-ene and successively underwent borylation in a flow microreactor system. Direct use of the 1-(trifluoromethyl)vinylborate thus formed for the Suzuki–Miyaura coupling in a batch system afforded α-(trifluoromethyl)styrenes in high yields.

Flow synthesis techniques have received a significant amount of attention due to their high productivity. However, when reaction condition is heterogeneous, it is usually difficult to adapt it to flow synthesis. Herein, by selecting appropriate reagents, the synthesis of phosphate esters, which is commonly heterogeneous, was made homogeneous, enabling synthesis in flow systems. In addition, reaction rate was accelerated compared to the batch system. It was demonstrated that not only can the high productivity of flow synthesis be achieved in flow, but also high productivity can be achieved by accelerating the reaction. Finally, we demonstrated the synthesis of the Akiyama-Terada catalyst, a chiral organocatalysts, in a short period.

This perspective article discusses the basic concept of time control by space based on flow and micro, some examples that realized extremely fast reactions which were difficult to achieve by conventional flask chemistry, and the future of this fascinating chemistry.

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.

The space integration of the lithiation of aryl halides, the borylation of aryllithiums, and Suzuki&ndash, Miyaura coupling using a Pd catalyst supported by a polymer monolith flow reactor without using an intentionally added base was achieved. To scale up the process, a series connection of the monolith Pd reactor was examined. To suppress the increase in the pressure drop caused by the series connection, a monolith reactor having larger pore sizes was developed by varying the temperature of the monolith preparation. The monolithic Pd reactor having larger pore sizes enabled Suzuki&ndash, Miyaura coupling at a higher flow rate because of a lower pressure drop and, therefore, an increase in productivity. The present study indicates that series connection of the reactors with a higher flow rate serves as a good method for increasing the productivity without decreasing the yields.