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 (ΔEH-L) 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 ΔEH-L 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 ΔEH-L 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. The energy difference between the HOMO of the anion and the LUMO of the cation (ΔED-A) and the interplanar angle between them (φDA) have a crucial effect on ΔEH-L, and hence, on the electronic structures and optoelectronic properties of these zwitterions. The zwitterions with small ΔED-A and large φDA have a small ΔEH-L of ca. 1 eV and show amphoteric redox properties and near-infrared (NIR) electronic absorption exceeding λ = 1000 nm. The NIR absorption responds to solvent polarity, temperature, and acid addition. This molecular design will generate small π-conjugated donor-acceptor molecules with small ΔEH-L values.

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. As a proof of concept, we use our approach to generate a benzoxazinone scaffold that gained attention as a starting structure against castrate-resistant prostate cancer. Further improvement of the structure led to significantly increased cancer cell line toxicity. Thus, exploiting environmentally benign electrooxidation, we present a new versatile and powerful method based on direct C-H activation that is applicable for example the production of medicinally relevant compounds.

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. This review focuses on the latter approach and provides a concise overview of the current methods for the generation and accumulation of cationic reactive intermediates as a pool using modern techniques of electrochemistry and their reactions with subsequently added nucleophilic reaction partners.

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.

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.

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. The aminating reagent was also prepared by the flow method. Based on stopped-flow NMR analysis, the reaction time for the preparation of the aminating reagent was quickly optimized without the necessity of work-up. Integrated one-flow synthesis consisting of the generation of an aryllithium, the preparation of an aminating reagent, and their combined reaction was successfully achieved to give the desired amine within 5 minutes of total reaction time.

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 N-acyliminium ions using the indirect cation pool method: Elucidation of stereoselectivity by spectroscopic conformational analysis and DFT calculations.

In this study, six-membered N-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 N-acyliminium ions were studied by low temperature NMR analyses and DFT calculations and were found to be consistent with the Steven's hypothesis.

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. The presented electrochemical protocol can be applied to a broad scope of alkylated substrates. Even tert-butyl moieties or halogen substituents are compatible with this versatile method.

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.

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 (MeN3) 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 NaN3 and Me2SO4 in a flow reactor gave a MeN3 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.

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. The absence of crossover products indicates the intramolecular nature of the carbamoyl group migration.

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.

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. The electrochemical oxidation of aromatic substrates in the presence of the heterocycles followed by chemical reaction under nonoxidative conditions gave the desired coupling products.

Electrochemical intramolecular C-H amination: synthesis of benzoxazoles and benzothiazoles.

A new method for metal-free intramolecular C-H amination has been developed. Electrochemical oxidation of 2-pyrimidyloxybenzenes and 2-pyrimidylthiobenzenes, which can be easily prepared from phenols and thiophenols, respectively, followed by the treatment of the resulting pyrimidinium ions with piperidine gives 2-aminobenzoxazoles and 2-aminobenzothiazoles, respectively.

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.