Continuous-flow synthesis using heterogeneous catalysts has attracted considerable attention as it enables safer, more productive, and highly reactive processes compared to batch methods. However, the development of easily separable and reusable heterogeneous catalysts has lagged behind that of homogeneous catalysts. Supported metal catalysts, such as those based on metal nanoparticles, hold promise as high-activity and long-lifetime heterogeneous catalysts due to their physical stability and ease of preparation. Nevertheless, the range of organic reactions achievable with these heterogeneous catalysts has been limited compared to those catalyzed by homogeneous catalysts. To address this, we focused on nitrogen-doped carbon (NDC) as a support, which can strongly coordinate with and activate metal species. NDC-supported metal catalysts, easily prepared by pyrolyzing nitrogen- and metal-containing precursors, have shown promise in catalyzing various reactions beyond simple redox processes, such as asymmetric catalysis and electrochemical synthesis. This paper highlights the development of NDC-supported metal catalysts for precise organic synthesis and their application in continuous-flow systems.

In the development of small molecule drugs, a strategy that aims to adjust the physical and pharmaceutical properties of drug candidates without significantly changing their pharmacological activity is attracting attention, in which a structural unit that shows the same biological response with the original partial structure (i.e. bioisostere) is frequently employed to create a molecule with superior medicinal properties. Cubane is a caged hydrocarbon known as a bioisostere of the benzene ring due to its structural similarity. Furthermore, when cubane is treated with silver(I) or palladium(II), it undergoes isomerization to a wedge-shaped hydrocarbon called cuneane. The potential for medicinal applications of these caged hydrocarbons has been hindered by limitations in the types of cubane and cuneane compounds that can be synthesized. We have approached these issues using precise organic synthesis chemistry from two perspectives: 1) developing a methodology for introducing functional groups by converting the C-H bonds of cubane, and 2) proposing the utility of cuneane as a bioisostere of m-substituted benzenes.

Herein, we summarize the electrosynthetic approach toward nitrogen-containing compounds using a nitromethane-lithium perchlorate (MeNO₂-LiClO₄) electrolyte system. The reactivity of anodically generated cationic intermediates was significantly enhanced in the MeNO₂-LiClO₄ electrolyte system due to its weak donating nature. This electrolyte promoted various glycosidation and dehydrogenative cross-coupling reactions, yielding N-, C-azanucleosides and (pyrrolo)phenanthridone alkaloids with high regio- and stereoselectivity.

Hexafluorocyclopentene derivatives produced by the reaction of octafluorocyclopentene (OFCP) with nucleophiles are promising functional materials, such as diarylethene-type photochromic molecules, electrochromic molecules, turn-on/turn-off fluorescent switching molecules, and heat-resistant polymers. Although many reactions of OFCP with heteroatom nucleophiles, like alcohols, amines, and thiols, have been reported, the systematic reactivity with carbon nucleophiles has not yet been fully elucidated. Reactivity studies of OFCP with various carbon nucleophiles revealed that the reaction with Griganrd reagent efficiently produces monosubstituted products, whereas the reaction with organolithium reagents preferentially produces 1,2-disubstituted products. Reactions with excess amounts of stable carbanions, such as diethyl sodiomalonate and methylidenetriphenylphosphorane, were found to proceed in a unique addition-elimination/1,4-HF-elimination/addition-elimination sequence to produce the corresponding 1,3-disubstituted products in high yields. During these systematic studies, it was found that 1,2-bis(arylethynyl)-3,3,4,4,5,5-hexafluorocyclopentene, formed in the reaction of OFCP with arylethynyllithium, is available as a dual-state fluorescent molecule that fluoresces in solution as well as in solid state. Furthermore, the products obtained in the reaction with phosphonium ylides, namely merophosphinines and phosphinines, also proved to be promising functional dyes as analogues of merocyanine and cyanine dyes. These achievements demonstrate that the reaction of OFCP with nucleophiles is a useful synthetic approach for incorporating cyclic fluorinated alkene backbones into functional molecules.

In 2002, Ciminiello and Fattorusso reported structure of mytilipin C, a member of the chlorosulfolipid (CSL) family characterized by chlorides and hydroxy groups on a linear alkyl chain. Toward total synthesis, a key step was the addition reaction of functionalized acetylide to an α,β-dichlorinated Weinreb amide to form an α,β-dichlorinated ketone, despite concerns about a potential side β-elimination reaction. To achieve this addition reaction, model studies were conducted. After several attempts, it was found that quenching procedures were critical in obtaining the desired ketone. Quenching the reaction with a saturated NH₄Cl solution resulted in the formation of an undesired elimination product. However, using 4 M HCl in dioxane effectively produced the desired ketone. Various nucleophiles were employed in the addition reaction with anti-α,β-dichlorinated Weinreb amide. In contrast, syn-α,β-dichlorinated Weinreb amide exhibited different reactivity compared to the anti-amide, which was attributed to the stability of the intermediates. With the developed reaction conditions, two fragments, chlorinated Weinreb amide and functionalized alkyne, were synthesized in a stereoselective manner. Despite initial failures in the key reaction with these two fragments, optimizations led to success. When aldehyde was used as an electrophile, the treatment of functionalized iodoalkyne with turbo-Grignard proceeded to produce the target adduct in high yield, with the acetate protecting group present. The study also identified characteristic coupling constants in the ¹H NMR spectra of anti- and syn-α,β-dichlorinated carbonyl compounds. Syntheses and considerations were described in detail.

Optically active carboxylic acid derivatives are important in the field of medicinal chemistry and pharmaceuticals. Preparation of these chiral carboxylic acids from naturaly abundant CO₂ would be highly valuable, however, the synthetic methodologies have been limited. Transition metal-catalyzed asymmetric synthesis has opened a new window for the direct access to enantio-enriched carboxylic acid derivatives. Herein, recent processes of transition metal-catalyzed asymmetric carboxylation reactions will be discussed.