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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 Introduction 2 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 [ABSTRACT FROM AUTHOR]

This article explores the potential of using volatile organic compounds (VOCs) in environmentally friendly industrial processes. It discusses the challenges associated with working with VOCs and presents a study on their reaction with organolithium species in a flow microreactor system. The study demonstrates successful molecular transformations with high yields and purity, suggesting that this approach could lead to the development of novel, environmentally friendly industrial processes. Additionally, the article discusses the development of a flow microreactor system for selective formylation of organolithium species, which significantly improves yield compared to a batch reaction system and allows for safe and precise handling of VOCs. This approach has the potential to contribute to the sustainable development of organic synthesis using VOCs. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

The lithiation of 5,5′‐dibromo‐2,2′‐bithiophene with one equivalent of an alkyllithium such as n‐BuLi or s‐BuLi was studied by varying the residence time in flow microreactors. With a short residence time, the product 2,2′‐bithiophene (3) derived from dilithiation was obtained preferentially and a significant amount of the starting material 5,5′‐dibromo‐2,2′‐bithiophene remained unchanged. An increase in the residence time caused a higher yield of the product 5‐bromo‐2,2′‐bithiophene derived from monolithiation with expense in the yields of 2,2′‐bithiophene and 5,5′‐dibromo‐2,2′‐bithiophene. The lithiation using MeLi gave the product 5‐bromo‐2,2′‐bithiophene preferentially even with a very short residence time. [ABSTRACT FROM AUTHOR]

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. Selective synthesis of ketones can be achieved by extremely fast 1:1 micromixing of acid halides and organolithiums using a flow microreactor system. Moreover, the chemoselective reactions of acid chlorides bearing electrophilic functional groups with functionalized organolithiums were also carried out in this controlled system to give the corresponding functionalized ketones (see scheme). [ABSTRACT FROM AUTHOR]

Flash chemistry based on flow microreactor systems allowed alkyllithiums bearing electrophilic functional groups to be successfully generated and used for subsequent reactions. The series of reactions with high reactivity was achieved by extremely accurate control over residence time in a controlled and selective manner. In a flash: Flash chemistry using flow microreactor systems enables the generation and reaction of alkyllithium compounds bearing electrophilic functional groups. High‐resolution control of the residence time is responsible for the successful transformations. Micromixers=M1 and M2, microtube reactors=R1 and R2, LiNp=lithium naphthalenide. [ABSTRACT FROM AUTHOR]

Flash chemistry based on flow microreactor systems allowed alkyllithiums bearing electrophilic functional groups to be successfully generated and used for subsequent reactions. The series of reactions with high reactivity was achieved by extremely accurate control over residence time in a controlled and selective manner. [ABSTRACT FROM AUTHOR]

Generation and reactions of methyl azide (MeN 3 ) were successfully performed by using a flow reactor system, demonstrating that the flow method serves as a safe method for handling hazardous explosive methyl azide. The reaction of NaN 3 and Me 2 SO 4 in a flow reactor gave a MeN 3 solution, which was used for Huisgen reaction with benzoyl cyanide in a flow reactor after minimal washing. The resulting 1-methyl-5-benzoyltetrazole serves as a key intermediate of picarbutrazox (IX), a new potent pesticide. [ABSTRACT FROM AUTHOR]

Using a flow microreactor system, carbamoyllithium compounds were successfully generated and used for reactions with electrophiles to give various amides, including α-ketoamides. The present method could be applied to the three-component synthesis of functionalized α-ketoamides using a carbamoyllithium compound, methyl chloroformate, and a functionalized organolithium reagent. [ABSTRACT FROM AUTHOR]

Using a flow microreactor system, carbamoyllithium compounds were successfully generated and used for reactions with electrophiles to give various amides, including α-ketoamides. The present method could be applied to the three-component synthesis of functionalized α-ketoamides using a carbamoyllithium compound, methyl chloroformate, and a functionalized organolithium reagent. [ABSTRACT FROM AUTHOR]

Cationic polymerization of vinyl ethers initiated by an electrogenerated dendritic diarylcarbenium ion in the presence of 2,6-di- tert -butylpyridine was developed using a flow microreactor. The carbocationic polymer end generated by polymerization of isobutyl vinyl ether was effectively trapped by various nucleophiles such as trimethyl(1-phenylvinyloxy)silane and allyltrimethylsilane to give polymers with very narrow molecular weight distribution. The block copolymerization of two vinyl ethers followed by trapping with nucleophiles was successfully accomplished to give structurally well-defined macromolecules. [ABSTRACT FROM AUTHOR]

Flash chemistry using flow microreactors enables highly chemoselective reactions of difunctional electrophiles with functionalized aryllithium compounds by virtue of extremely fast micromixing. The approach serves as a powerful method for protecting-group-free synthesis using organolithium compounds and opens a new possibility in the synthesis of polyfunctional organic molecules. [ABSTRACT FROM AUTHOR]

Flash chemistry using flow microreactors enables highly chemoselective reactions of difunctional electrophiles with functionalized aryllithium compounds by virtue of extremely fast micromixing. The approach serves as a powerful method for protecting-group-free synthesis using organolithium compounds and opens a new possibility in the synthesis of polyfunctional organic molecules. [ABSTRACT FROM AUTHOR]

Carboxylation of short-lived organolithiums bearing electrophilic functional groups such as nitro, cyano, and alkoxycarbonyl groups with CO2 to give carboxylic acids and active esters was accomplished in a flow microreactor system. The successful reactions indicate that gas/liquid mass transfer and the subsequent chemical reaction with CO2 are extremely fast. [ABSTRACT FROM AUTHOR]

Flow on: Flow microreactors enable the generation of aryl lithium compounds and subsequent electrophilic fluorination with NFSI and N ‐ fluorosultam. The reaction can be successfully accomplished to synthesize various aryl fluorides involving an electron ‐ withdrawing, an electron ‐ donating, and a sterically hindered functional group in good yields. [ABSTRACT FROM AUTHOR]

Living anionic polymerization of tert-butyl acrylate initiated by 1,1-diphenylhexyllithium is conducted in a flow microreactor system in the presence of lithium chloride. A high degree of control over the molecular weight distribution is achieved under easily accessible conditions, for example at −20 °C. The subsequent reaction of a reactive polymer chain end with an alkyl methacrylate in an integrated flow micoreactor system leads to the formation of a block copolymer with a narrow molecular weight distribution. [ABSTRACT FROM AUTHOR]

Abstract: Tricyclic sulfonamides were synthesized by the generation of aziridinyllithiums from N-tosylaziridines followed by an intramolecular nucleophilic reaction and the subsequent reaction with electrophiles using a flow microreactor system. The reactions could be carried out at 0°C, although much lower temperatures such as −78°C are needed for batch macro reactors. [Copyright &y& Elsevier]

A flow microreactor method for the synthesis of disubstituted pyridines by generation of pyridyllithiums followed by reactions with electrophiles has been developed. By using a short residence time and efficient temperature control, the cryogenic conditions required for conventional batch macro processes can be avoided. Sequential introduction of two different electrophiles into dibromopyridines has been achieved using an integrated flow microreactor system composed of four micromixers and four microtube reactors, to obtain disubstituted pyridine compounds. [ABSTRACT FROM AUTHOR]

A flow microreactor method for the synthesis of disubstituted pyridines by generation of pyridyllithiums followed by reactions with electrophiles has been developed. By using a short residence time and efficient temperature control, the cryogenic conditions required for conventional batch macro processes can be avoided. Sequential introduction of two different electrophiles into dibromopyridines has been achieved using an integrated flow microreactor system composed of four micromixers and four microtube reactors, to obtain disubstituted pyridine compounds. [ABSTRACT FROM AUTHOR]

We found that a flow microreactor system enables the generation of a configurationally unstable chiral organolithium intermediate and allows for its use in a reaction with an electrophile before it epimerizes. Based on this method, the enantioselective carbolithiation of conjugated enynes followed by the reaction with electrophiles was accomplished to obtain enantioenriched chiral allenes. [ABSTRACT FROM AUTHOR]

Abstract: Living anionic polymerization of alkyl methacrylates initiated by 1,1-diphenylhexyllithium was conducted in a flow microreactor system. A high level of molecular-weight distribution control was achieved under easily accessible conditions, such as at −28°C (MMA: Mw/Mn=1.16), 0°C (BuMA: Mw/Mn=1.24) and 24°C (Bu t MA: Mw/Mn=1.12). The molecular weight (Mn) increased with an increase in the monomer/initiator ratio. The subsequent reaction of a reactive polymer chain end with a second alkyl methacrylate in integrated flow micoreactor systems led to the formation of a block copolymer having narrow molecular-weight distribution. [Copyright &y& Elsevier]

[Display omitted] 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. [ABSTRACT FROM AUTHOR]

Friedel-Crafts reactions of aromatic and heteroaromatic compounds with an N-acyliminium ion pool were studied. The reaction of 1,3,5-trimethylbenzefle in a batch reactor gave rise to the selective formation of a monoalkylation product (69%). Presumably, the second alkylation is slower than the first alkylation because of the protonation of the monoalkylation product that decreases its reactivity. The reaction of 1,3,5-trimethoxybenzene, however, gave rise to the formation of both monoalkylation (37%) and dialkylation (32%) products. Disguised chemical selectivity due to faster reaction than mixing seems to be responsible for the lack of selectivity. The use of micromixing was found to be quite effective to solve this problem to increase the selectivity. The monoalkylation product was obtained in 92% yield together with a small amount of the dialkylation product (4%). The reaction with various aromatic and heteroaromatic compounds revealed that the low mono/dialkylation selectivity was observed only for highly reactive aromatics. In such cases, the use of micromixing was quite effective to improve the selectivity. On the basis of micromixing, the selective sequential dialkylation using two different N-acyliminium ions was achieved. CFD simulations using a laminar flow and finite-rate model are consistent with the experimental observations and clearly indicate the importance of mixing. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Reactions of functionalized aryllithiums with dialkyl oxalates were achieved using a flow microreactor to obtain α-keto esters with high selectivity by virtue of fast 1 : 1 micromixing. [ABSTRACT FROM AUTHOR]

B A few-millisecond chemistry approach b , conducting a series of reactions with short-lived intermediates in a flow microreactor, enabled chemical conversions involving alkyllithiums bearing an electrophilic functional group, which are virtually impossible with conventional macro batch reactors. B A few-millisecond chemistry approach b , conducting a series of reactions with short-lived intermediates in a flow microreactor, enabled chemical conversions involving alkyllithiums bearing an electrophilic functional group, which are virtually impossible with conventional macro batch reactors. [Extracted from the article]

Invited for the cover of this issue is the group of Aiichiro Nagaki at Kyoto University. The image depicts the reaction in the flow microreactor reported in the paper. Read the full text of the article at10.1002/chem.201902867. [ABSTRACT FROM AUTHOR]

• Reaction involving unstable intermediates based on reaction time control. • Chemical transformations via electrophilic-functionalized organolithiums. • Reaction integration via functional organolithiums. Examples in this mini-review illustrate the potential of flow microreactor chemistry in chemical science and chemical production. Flow microreactors provide a powerful method for novel transformations via functional organolithiums that cannot be achieved using a conventional macro batch reactor. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This article explores a manufacturing strategy for producing consistent and scalable PEGylated bioconjugates, which are proteins linked to polyethylene glycol (PEG) for improved therapeutic efficacy and safety. The study compares the use of a continuous-flow reaction system to the traditional batch-mode approach and finds that continuous-flow offers advantages in terms of selectivity and conversion rates. The study also analyzes the differences in solvent-accessible surface area (SASA) between two proteins, lysozyme and IL-6, and suggests that this may contribute to variations in selectivity. The authors conclude that continuous-flow chemistry has potential for protein modifications but further research is needed for optimization. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

The space integration of the lithiation of aryl halides, the borylation of aryllithiums, and Suzuki–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–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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In einem Mikrofließreaktor wurden wenig stabile Carbamoylanionen, spezifisch Carbamoyllithiumspezies, erzeugt und umgesetzt, was mithilfe herkömmlicher Batch‐Methoden nahezu unmöglich ist. J. Yoshida, A. Nagaki und Y. Takahashi beschreiben in ihrer Zuschrift auf S. 5413 ff. eine Anwendung der Methode in einer Dreikomponentensynthese funktionalisierter α‐Ketoamide, darunter auch das biologisch aktive Triazinderivat GW356194. [ABSTRACT FROM AUTHOR]

The article presents a study on oxiranyl anion methodology. It focuses on the chemical and configurational stabilities of oxiranyllithiums as well as the application to preparative scale synthesis of substituted epoxides through the microflow systems. It explores the two important aspects of the methodology, as well as the importance of gaining deeper insights on the two aspects to further develop the usefulness of the method.

Application of a flow microreactor system allows for the generation of benzyllithium compounds endowed with carbonyl substituents which further react with various electrophiles such as aldehydes, ketones, isocyanates, trimethylsilyl derivatives, and methanol. [ABSTRACT FROM AUTHOR]

Different types of products are obtained from a single parent compound in a flow microreactor system by control of the residence times. [ABSTRACT FROM AUTHOR]

This article focuses on living polymerization. The discovery of controlled/living polymerization is an epoch-making event in polymer science and technology, and the control of molecular weight and molecular weight distribution is still at the forefront in this field. Molecular weight control is possible when the exchange between the active and dormant species is faster than propagation. The major drawback of the presence of such an equilibrium is a slow propagation because the concentration of active species is very low.

Carboxylation of organolithium compounds bearing electrophilic functional groups such as nitro, cyano, and alkoxycarbonyl groups, with CO2 to give carboxylic acids and active esters is accomplished in a flow microreactor system consisting of three micromixers and three microtube reactors. [ABSTRACT FROM AUTHOR]

Review: 80 refs. [ABSTRACT FROM AUTHOR]

New methods for the synthesis of functionalized aryl fluorides (II) (18 examples) based on organo-lithium chemistry in flow microreactors and use of electrophilic fluorinating reagents are developed. [ABSTRACT FROM AUTHOR]

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 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. [ABSTRACT FROM AUTHOR]

A continuous flow microreactor method for generating and carrying out reactions on pyridyllithiums is developed. [ABSTRACT FROM AUTHOR]