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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.

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.

The dopaminergic system is essential for the function of the brain in health and disease. Therefore, detailed studies focused on unraveling the mechanisms involved in dopaminergic signaling are required. However, the lack of probes that mimic dopamine in living tissues, owing to the neurotransmitter's small size, has hampered analysis of the dopaminergic system. The current study aimed to overcome this limitation by developing alkyne-tagged dopamine compounds (ATDAs) that have a minimally invasive and uniquely identifiable alkyne group as a tag. ATDAs were established as chemically and functionally similar to dopamine and readily detectable by methods such as specific click chemistry and Raman scattering. The ATDAs developed here were verified as analogue probes that mimic dopamine in neurons and brain tissues, allowing the detailed characterization of dopamine dynamics. Therefore, ATDAs can act as safe and versatile tools with wide applicability in detailed studies of the dopaminergic system. Furthermore, our results suggest that the alkyne-tagging approach can also be applied to other small-sized neurotransmitters to facilitate characterization of their dynamics in the brain.

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

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.

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.

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.

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.

Electrochemical oxidation of toluene derivatives in the presence of N-tosyldiphenylsulfilimine gave the corresponding benzylaminosulfonium ions, which were treated with tetrabutylammonium iodide under non-electrolytic conditions to give N-tosylbenzylamines. The transformation serves as a metal- and chemical-oxidant-free method for benzylic C-H amination. Because of high oxidation potential of N-tosyldiphenylsulfilimine the present method can be applied to synthesis of various benzylamines from functionalized toluene derivatives.

Reaction integration which combines multiple reactions in a single operation in one pot or in a flow system without isolating intermediates enhances the power and speed of organic synthesis to meet...

β-Haloalkoxysulfonium ions generated by the reaction of electrogenerated Br+ and I+ ions stabilized by dimethyl sulfoxide (DMSO) reacted with sodium hydroxide and sodium methoxide to give the corresponding halohydrins and epoxides, respectively, whereas the treatment with triethylamine gave α-halocarbonyl compounds.

Halogen and chalcogen cations (X(+) = Br(+), I(+), ArS(+), and ArSe(+)) were generated by low-temperature electrochemical oxidation in the presence of dimethyl sulfoxide (DMSO) and were accumulated in the solution. DFT calculations indicated that DMSO stabilizes these cations by coordination. The complexes of I(+) with one and two DMSO molecules were observed by cold-spray-ionization MS analyses. The stability of the resulting cation pools of X(+) increased in the order of Br(+)I(+)ArS(+)ArSe(+), which could be explained in terms of the electronegativity of X. The cation pools served as versatile reagents for organic synthesis; the reactions with alkenes gave β-X-substituted alkoxysulfonium ions, which were converted to the corresponding carbonyl compounds by the treatment with triethylamine, whereas the treatment with methanol gave the corresponding alcohols. The reactions with aminoalkenes and 1,6-dienes gave the cyclized products.

Arylbis(arylthio)sulfonium ions (ArS(ArSSAr)+), which were generated and accumulated by the low-temperature electrolysis of diaryl disulfide (ArSSAr), were found to serve as ArS+ equivalent in electrophilic substitution reactions of aromatic compounds, enolizable ketones, enol acetates, ketene silyl acetals and allylsilanes to give the corresponding arylthiolated products.

Oxidative hydroxylation of toluene derivatives via alkoxysulfonium ion intermediates was achieved by integration of anodic oxidation and hydrolysis to give benzyl alcohols which are also susceptible to oxidation. Alkenes were also oxidized to give 1,2-diols without overoxidation. The integration of electrochemical oxidative cyclization and hydrolysis was achieved using alkenes bearing a nitrogen atom in an appropriate position to give cyclic β-amino-substituted alcohols.

The reaction of electrochemically generated N-acyliminium ion pools with alkenes bearing a heteroatom nucleophilic functionality such as a hydroxy group, a carboxy group, and an oxime moiety led to...

Reaction integration which combines multiple reactions in a single operation in one pot or in a flow system without isolating intermediates enhances the power and speed of organic synthesis to meet...

By modification of the procedure, also the corresponding alcohols are accessible in a diastereoselective one-pot reaction [viz.

Photoredox-mediated ring-opening metathesis polymerization (Photo-ROMP) is an emerging polymerization method. In contrast to traditional ROMP, which uses a well-defined metal initiator (typically Ru, W, or Mo) that covalently bonds in stoichiometric amounts with each polymer chain end, Photo-ROMP utilizes a photo-oxidant to oxidize an organic polymerization initiator. This obviates the need for purification processes to remove the metal initiator for use of the resulting polymer in biomedical, electronics, and optics applications. We have recently studied the efficacy of a variety of photo-oxidants and expanded the monomer scope to include polar functionality. In an evaluation of pyrylium and thiopyrylium photo-oxidants, more electron-rich photo-oxidants (weaker photo-oxidants) achieved higher conversion to polynorbornene. Additionally, thiopyrylium photo-oxidants displayed higher rates of conversion than similarly functionalized pyryliums. While our previous studies identified 2,4,6-tris(4-methoxyphenyl)pyrylium tetrafluoroborate as an effective photo-oxidant for Photo-ROMP, in our recent evaluation of additional pyryliums and thiopyryliums, the correspondingly functionalized thiopyrylium emerged as a successful alternative for achieving rapid polymerization. In addition to evaluating various pyrylium and thiopyrylium photo-oxidants, we recently identified a variety of monomers and co-monomers with polar functionality for Photo-ROMP. Our previous studies identified norbornene, dicyclopentadiene, and dihydrodicyclopentadiene as effective monomers for Photo-ROMP. Recently, we've identified several new monomers. Remarkably, a TBS-ether-funtioncalized norbornene was co-polymerized with norbornene and homopolymerized in good yields. The resulting polymer was successfully deprotected to give the corresponding alcohol-functionalized polynorbornene. Additionally, a Boc-functionalized copolymer with norbornene was successfully synthesized and the Boc groups subsequently thermally removed. Interestingly, while 2-chloro-2,3-dihydro-endo-dicylopentadiene was precluded from copolymerization with norbornene due to slow initiation kinetics, it did successfully homopolymerize via Photo-ROMP to give the resulting homopolymer in moderate yields. These functionalized monomers could facilitate post-polymerization modification. In addition to these recent developments in expanding the methods and scope of Photo-ROMP, ongoing work in evaluating alternative photo-oxidants and monomers will also be discussed in this presentation.

We have recently discovered a method of performing ring-opening metathesis polymerization (ROMP) via an electrochemically-mediated process involving electron rich olefin initiators and norbornene-based monomers. The method expands upon the powerful, metal-mediated approaches toward ROMP that have been successful for the production of polymers with precise structure and function. A key distinction is our ability to integrate organocatalysis and electro-organic synthesis to circumvent the need for metal-based initiators. In this way, electromediated ROMP has opened the doorway to metal-free protocols that have the potential to provide materials with unique optical, electronic, and materials properties. Inspired by the pioneering work of Chiba and coworkers, we explored the hypothesis that anodic oxidation of vinyl ethers could be used to initiate and mediate polymerization of strained cycloalkenes via a ROMP mechanism. Toward this end, we evaluated vinyl ethers in combination with norbornene as a common ROMP monomer to determine the viability of electromediated ROMP. Although initial conversions of norbornene to polynorbornene were low, we were able to confirm initiation by the vinyl ether and successful polymer formation. Consideration of the key limiting factors in our initial electromediated ROMP conditions, which appeared to be poor solubility of norbornene and polynorbornene, led us to consider photoredox and indirect electrolysis approach. We will discuss recent successes with organic photo-oxidants capable of facilitating metal-free ROMP in high conversions with excellent temporal control. In addition, we will present our latest results on the use of organic mediators to facilitate metal-free ROMP via indirect electrolysis.

Ring-opening metathesis polymerization (ROMP) is widely used for the synthesis of polymers, typically using a transition-metal-based initiator. Much effort based on improvement of catalyst design and polymerization techniques has led to breakthrough applications in diverse areas, including high-performance plastics, drug delivery, bioengineering, and organic photovoltaics. We reported an electrochemical polymerization technique using a vinyl ether as an initiator, which is directly oxidized to a radical cation at a carbon anode during bulk electrolysis. However, polymerization was only observed on the electrode surface, resulting in low yields. We hypothesized the low efficiency was due to the heterogeneous nature of the direct oxidation. Herein we report on the development of a method for the indirect electrochemical oxidation of the initiator via an electrochemical mediator to achieve metal-free-ROMP. Preliminary cyclic voltammetry analyses predicted the feasibility of electron transfer between the mediator and the initiator. In addition to these recent results, ongoing work will developing electrochemical ROMP methods via indirect oxidation of the initiator will be discussed.

Halogen cations such as I+ and Br+ are highly unstable species, although some of them are identified in the gas phase. The electrochemical oxidation provides a powerful method for generating and accumulating highly reactive cationic species in the solution, whereas the chemical methods are not effective because of reversibility of cation generation. We have already reported that some carbocations and onium ions can be generated and accumulated as cation pools at low temperatures (the “cation pool” method). However, halogen cations are very difficult to accumulate in the solution as “cation pools” because they are too unstable. We envisioned that the use of a stabilizing agent that coordinates the cation being generated would solve the problem. Coordination of a neutral molecule gives a positively charged species and coordination of an anionic species gives a neutral species, although the halogen is the +1 oxidation state in both cases. Some stabilizing agents have already been reported. For example, Miller and co-workers reported the generation and accumulation of “I+” cation in acetonitrile (CH3CN), and later we reported the detection of CH3CN−I+ and (CH3CN)2I+ by cold-spray-ionization mass spectroscopy. Shono and co-workers reported that “I+” could be accumulated in trimethyl orthoformate (TMOF). In this paper we report that dimethyl sulfoxide (DMSO) serves as a neutral stabilizing agent and that TfO− anion serves as a negatively charged stabilizing agent in the electrochemical generation and accumulation of halogen cations such as I+ and Br+. We also report their reactions with organic molecules to give the corresponding halogen-containing products, which serve as useful transformations in organic synthesis.

Arylbis(arylthio)sulfonium ions (ArS(ArSSAr)+), which were generated and accumulated by the low-temperature electrolysis of diaryl disulfide (ArSSAr), were found to serve as ArS+ equivalent in electrophilic substitution reactions of aromatic compounds, enolizable ketones, enol acetates, ketene silyl acetals and allylsilanes to give the corresponding arylthiolated products.

Anodic oxidation of toluene derivatives in the presence of DMSO followed by hydrolysis of the alkoxysulfonium ion intermediates allows a new and selective access to benzylic alcohols.

Generation of carbocations by the “cation pool” method followed by reaction with dimethyl sulfoxide (DMSO) gave the corresponding alkoxysulfonium ions. Alkoxysulfonium ions could also be generated by in situ DMSO trapping of electrochemically generated carbocations. The resulting alkoxysulfonium ions were transformed into carbonyl compounds by treatment with triethylamine. The present integrated electrochemical–chemical oxidation can be applied to the oxidation of diarylmethanes to diaryl ketones, toluenes to benzaldehydes, and aryl-substituted alkenes to 1,2-diketones. Moreover, the oxidation of unsaturated compounds bearing a nucleophilic group in an appropriate position gives cyclized carbonyl compounds.

Generation of carbocations by the “cation pool” method followed by reaction with dimethyl sulfoxide (DMSO) gave the corresponding alkoxysulfonium ions. Alkoxysulfonium ions could also be generated by in situ DMSO trapping of electrochemically generated carbocations. The resulting alkoxysulfonium ions were transformed into carbonyl compounds by treatment with triethylamine. The present integrated electrochemical–chemical oxidation can be applied to the oxidation of diarylmethanes to diaryl ketones, toluenes to benzaldehydes, and aryl-substituted alkenes to 1,2-diketones. Moreover, the oxidation of unsaturated compounds bearing a nucleophilic group in an appropriate position gives cyclized carbonyl compounds.

Electro-initiated coupling reactions of N-acyliminium ion with arylthiomethylsilanes and aryloxymethylsilanes were developed. Pulse electrolyses with intervals were found to be quite effective for the initiation. A chain mechanism involving cation, radical cation, and radical intermediates has been proposed.

Alkene difunctionalization via three-membered ring halonium ion intermediates is an important transformation in organic synthesis. The most straightforward method to generate the halonium intermediates is to use halogen cations, which are usually too unstable to accumulate in solution. Recently, we reported that halogen cations stabilized by dimethyl sulfoxide (DMSO) were successfully generated and accumulated in solution by low-temperature electrochemical oxidation. Reactions of DMSO-stabilized halogen cations such as Br+ and I+ with alkenes gave b-haloalkoxysulfonium ions. Subsequent treatment of the b-haloalkoxysulfonium ions with triethylamine gave α-halocarbonyl compounds via Swern−Moffatt type oxidation. Here, we report that treatment of the b-haloalkoxysulfonium ions with different bases gives different products, i.e. the use of sodium hydroxide and sodium methoxide gives halohydrins and epoxides, respectively.

Organosulfur compounds have received much attention because they serve as useful building blocks in organic synthesis and exhibit interesting physical properties in materials chemistry. To synthesize such compounds, the addition of ArSSAr to carbon-carbon multiple bonds is one of the most efficient methods. We have recently reported the reactions of alkenes with a stoichiometric amount of ArS(ArSSAr)+, which is generated by electrochemical oxidation and accumulated as a cation pool of ArSSAr.1) Thiiranium ions are generated as initial intermediates. Quenching with hard nucleophiles such as MeOH and H2O leads to the addition of an ArS group and RO group (R = Me or H) across the carbon-carbon double bond. In contrast, the use of soft nucleophiles such as ketene silyl acetals, allylsilanes, and Et3N leads to the addition of two ArS groups across the carbon-carbon double bond. Presumably, soft nucleophiles assist nucleophilic attack of ArSSAr on the thiiranium ion intermediate. We envisioned that the addition reaction of ArSSAr to alkenes may proceed with a catalytic amount of ArS(ArSSAr)+ if another molecule of ArSSAr plays a role of a soft nucleophile. This is indeed the case, if we use Bu4NB(C6F5)4 as a supporting electrolyte, and herein, we report this chemistry (Scheme 1).2) We focused on the reaction of ArSSAr (Ar = p-FC6H4) and (E)-β-methylstyrene with a catalytic amount of electrochemically generated ArS(ArSSAr)+ (Ar = p-FC6H4), as a model reaction. The reaction gave the addition product in 78% yield (Scheme 1). The addition took place anti-selectively, which was confirmed by the comparison of the NMR spectra of the product with those reported in the literature.1a) The present reaction seems to proceed by a cation chain mechanism. In the prsentation, the details of optimization conditions and the scope and limitations of the present reaction will be discussed. References 1) (a) Fujie, S.; Matsumoto, K.; Suga, S.; Nokami, T.; Yoshida, J. Tetrahedron 2010, 66, 2823-2829. See also, (b) Matsumoto, K.; Suga, S.; Yoshida, J. Org. Biomol. Chem. 2011, 9, 2586-2596. 2) Matsumoto, K.; Sanada, T.; Shimazaki, H.; Shimada, K.; Hagiwara, S.; Fujie, S.; Ashikari, Y.; Suga, S.; Kashimura, S.; Yoshida, J. Asian J. Org. Chem. 2013, 2, 325-329.

From functional materials to biologically active compounds, the role of organic synthesis has been expanding continuously. Accordingly, the power and speed of organic synthesis should be enhanced to meet future demands for synthesis of various organic molecules. In this context, conventional step-by-step synthesis is being supplemented with integrated synthesis that combines multiple reactions in a single operation in one pot or in a flow system without isolating the intermediates. In this presentation we report on time integration of electrochemical oxidation and chemical oxidation based on the “cation pool” method. For example, electrochemically generated carbocations are reacted with dimethylsulfoxide to give the corresponding alkoxysulfonium ions, which are well-known as key intermediates of Swern—Moffatt oxidation. The subsequent treatment with triethylamine gives the corresponding carbonyl compounds. Moreover, the reactions of halogenuim and arylchalcogenium cation pools stabilized by dimethoxysulfoxide with alkenes followed by treatment with triethylamine give a-halo and arylchalcogen-substituted carbonyl compounds, respectively.

Electro-initiated coupling reactions of N-acyliminium ion with arylthiomethylsilanes and aryloxymethylsilanes were developed. Pulse electrolyses with intervals were found to be quite effective for the initiation. A chain mechanism involving cation, radical cation, and radical intermediates has been proposed.

An integration of electrooxidative cyclization and chemical oxidation was achieved. Electrochemical oxidation of alkenes having a nucleophilic moiety in the presence of DMSO gave cyclized alkoxysulfonium ions, which were converted to the corresponding ketones by treatment with triethylamine in a one-pot sequential manner. The method is also an effective tool for cyclization of 1,6-dienes affording five-membered ring diketones in high stereoselectivity.