Regioselective Synthesis of α-Functional Stilbenes via Precise Control of Rapid - Isomerization in Flow.

The rapid - isomerization of α-anionic stilbene was regioselectively controlled by using flow microreactors, and its reaction with various electrophiles was conducted. The reaction time was precisely controlled within milliseconds to seconds at -50 °C to selectively give the - or -isomer in high yields. This synthetic method in flow was well-applied to synthesize precursors of commercial drug compound, ()- and ()-tamoxifen with high regioselectivity and productivity.

HOMO-LUMO Energy-Gap Tuning of π-Conjugated Zwitterions Composed of Electron-Donating Anion and Electron-Accepting Cation.

π-Conjugated molecules with small highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gaps (Δ) have been extensively studied because of their unique optoelectronic properties. Although the expansion of π-conjugation is one of the well-known approaches for designing molecules with small Δ values, such an approach inevitably gives large π-conjugated molecules sometimes suffering from synthetic difficulty and low solubility toward organic solvents. To develop relatively small donor-acceptor molecules with small Δ values, we have designed and synthesized π-conjugated zwitterions composed of electron-donating anions, such as phenoxide and anthroxide, and electron-accepting cations, such as pyridinium and acridinium.

Metal-Free Twofold Electrochemical C-H Amination of Activated Arenes: Application to Medicinally Relevant Precursor Synthesis.

The efficient production of many medicinally or synthetically important starting materials suffers from wasteful or toxic precursors for the synthesis. In particular, the aromatic non-protected primary amine function represents a versatile synthetic precursor, but its synthesis typically requires toxic oxidizing agents and transition metal catalysts. The twofold electrochemical amination of activated benzene derivatives via Zincke intermediates provides an alternative sustainable strategy for the formation of new C-N bonds of high synthetic value.

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.

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.

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.

Alkyllithium Compounds Bearing Electrophilic Functional Groups: A Flash Chemistry Approach.

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.

Metal- and Oxidant-Free Alkenyl C-H/Aromatic C-H Cross-Coupling Using Electrochemically Generated Iodosulfonium Ions.

A three-step transformation consisting of 1) addition of electrochemically generated iodosulfonium ions to vinylarenes to give (1-aryl-2-iodoethoxy)sulfonium ions, 2) nucleophilic substitution by subsequently added aromatic compounds to give 1,1-diaryl-2-iodoethane, and 3) elimination of HI with a base to give 1,1-diarylethenes was developed. The transformation serves as a powerful metal- and chemical-oxidant-free method for alkenyl C-H/aromatic C-H cross-coupling.

Stereoselective nucleophilic addition reactions to cyclic -acyliminium ions using the indirect cation pool method: Elucidation of stereoselectivity by spectroscopic conformational analysis and DFT calculations.

In this study, six-membered -acyliminium ions were generated by the "indirect cation pool" method and reacted with several nucleophiles. These reactions afforded disubstituted piperidine derivatives with high diastereoselectivities and good to excellent yields. The conformations of the obtained -acyliminium ions were studied by low temperature NMR analyses and DFT calculations and were found to be consistent with the Steven's hypothesis.

A Catalyst-Free Amination of Functional Organolithium Reagents by Flow Chemistry.

Reported is the electrophilic amination of functional organolithium intermediates with well-designed aminating reagents under mild reaction conditions using flow microreactors. The aminating reagents were optimized to achieve efficient C-N bond formation without using any catalyst. The electrophilic amination reactions of functionalized aryllithiums were successfully conducted under mild reaction conditions, within 1 minute, by using flow microreactors.

Control of tandem isomerizations: flow-assisted reactions of o-lithiated aryl benzyl ethers.

Tandem chemical changes are often difficult to control at will, because they proceed rapidly through multiple unstable reactive intermediates. It is desirable to develop a novel method for controlling such tandem changes to obtain desired products with high selectivity. Herein, we report a flow microreactor platform for controlling tandem isomerizations of o-lithiated aryl benzyl ethers based on precise residence time control.

Electrogenerated Cationic Reactive Intermediates: The Pool Method and Further Advances.

Electrochemistry serves as a powerful method for generating reactive intermediates, such as organic cations. In general, there are two ways to use reactive intermediates for chemical reactions: (1) generation in the presence of a reaction partner and (2) generation in the absence of a reaction partner with accumulation in solution as a "pool" followed by reaction with a subsequently added reaction partner. The former approach is more popular because reactive intermediates are usually short-lived transient species, but the latter method is more flexible and versatile.

Liquid Quinones for Solvent-Free Redox Flow Batteries.

Liquid benzoquinone and naphthoquinone having diethylene glycol monomethyl ether groups are designed and synthesized as redox active materials that dissolve supporting electrolytes. The Li-ion batteries based on the liquid quinones using LiBF /PC show good performance in terms of voltage, capacity, energy efficiency, and cyclability in both static and flow modes. A battery is constructed without using intentionally added organic solvent, and its high energy density (264 W h L ) demonstrates the potential of solvent-free organic redox flow batteries using liquid active materials.

Generation of hazardous methyl azide and its application to synthesis of a key-intermediate of picarbutrazox, a new potent pesticide in flow.

Generation and reactions of methyl azide (MeN) 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 and MeSO in a flow reactor gave a MeN 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.

New Approach to 1,4-Benzoxazin-3-ones by Electrochemical C-H Amination.

1,4-Benzoxazin-3-ones are important structural motifs in natural products and bioactive compounds. Usually, the synthesis of benzoxazinones requires transition-metal catalysts and pre-functionalized substrates such as aryl halides. However, the anodic C-H amination of phenoxy acetates offers a very efficient and sustainable access to these heterocycles.

Harnessing [1,4], [1,5], and [1,6] Anionic Fries-type Rearrangements by Reaction-Time Control in Flow.

A series of anionic Fries-type rearrangements of carbamoyl-substituted aryllithium intermediates were controlled by using flow microreactor systems. For the [1,4] and [1,5] rearrangements, the aryllithium intermediate formed before carbamoyl migration and the lithium alkoxide formed after carbamoyl migration can be selectively subjected to subsequent reactions with electrophiles by precisely controlling the residence time and temperature (-25 to -50 °C). In contrast, the [1,6] rearrangement is rather slow even at -25 °C.

Metal-Free Benzylic C-H Amination via Electrochemically Generated Benzylaminosulfonium Ions.

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.

The Stabilized Cation Pool Method: Metal- and Oxidant-Free Benzylic C-H/Aromatic C-H Cross-Coupling.

Electrochemical oxidation of toluene derivatives in the presence of a sulfilimine gave benzylaminosulfonium ions as stabilized benzyl cation pools, which reacted with subsequently added aromatic nucleophiles to give the corresponding cross-coupling products. The transformation serves as a powerful metal- and chemical-oxidant-free method for benzylic C-H/aromatic C-H cross-coupling. The method has been successfully applied to synthesis of TP27, an inhibitor of PTPase.

Submillisecond organic synthesis: Outpacing Fries rearrangement through microfluidic rapid mixing.

In chemical synthesis, rapid intramolecular rearrangements often foil attempts at site-selective bimolecular functionalization. We developed a microfluidic technique that outpaces the very rapid anionic Fries rearrangement to chemoselectively functionalize iodophenyl carbamates at the ortho position. Central to the technique is a chip microreactor of our design, which can deliver a reaction time in the submillisecond range even at cryogenic temperatures.

Generation and Reaction of Carbamoyl Anions in Flow: Applications in the Three-Component Synthesis of Functionalized α-Ketoamides.

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.

Heterocyclization Approach for Electrooxidative Coupling of Functional Primary Alkylamines with Aromatics.

A new approach for electrooxidative coupling of aromatic compounds and primary alkylamines bearing a functional group such as a hydroxyl group and an amino group was developed. The key to the success of the transformation is heterocyclization of functional primary alkylamines. Treatment of primary alkylamines bearing a functional group with nitriles or their equivalents gives the corresponding heterocycles.

Low temperature in situ Raman spectroscopy of an electro-generated arylbis(arylthio)sulfonium ion.

A low temperature in situ Raman spectroscopic method was developed for the detection of unstable intermediates in electro-organic chemistry. It was effective for monitoring the generation of ArS(ArSSAr)(+) by the electrochemical oxidation of ArSSAr (Ar = p-FC6H4) in Bu4NBF4/CH2Cl2 at 195 K. The intensity of a Raman band at 427 cm(-1), which is attributable to the S-S vibration of ArS(ArSSAr)(+), increased with an increase in the electricity until 2/3 F of the electricity was consumed, whereas decreased with a further increase in the electricity indicating the decomposition of ArS(ArSSAr)(+).

Benzyllithiums bearing aldehyde carbonyl groups. A flash chemistry approach.

Reductive lithiation of benzyl halides bearing aldehyde carbonyl groups followed by reaction with subsequently added electrophiles was successfully accomplished without affecting the carbonyl groups by taking advantage of short residence times in flow microreactors.

Switching the reaction pathways of electrochemically generated β-haloalkoxysulfonium ions - synthesis of halohydrins and epoxides.

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.