Radical addition/β-fragmentation sequence has long been utilized for alkenylation and allylation of alkyl halides, in which key alkyl radicals are generated from alkyl halides by S_H2 reaction typically using tributyltin radical. In this article, we describe modernized alkenylation and allylation of alkyl halides, in which alkyl radical generation is carried out by electron transfer under photoirradiation with the use of transition metal catalyst, which enables us to carry out the radical alkenylation and allylation without the use of radical initiators nor chain transfer reagents. Indeed, radical alkenylation of alkyl iodides using alkenyl bromides proceeded well by the use of a Pd/light combined system involving Hantzsch ester. Alkenyl and allyl sulfones worked better, since the system can obviate the use of Hantzsch ester. Mechanistically spontaneous reductive elimination of PhSO₂I is suggested to recover the Pd catalyst. We also discuss allylation of gem-difluoromethy-lene-containing alkyl halides using allyl sulfones, which is best performed by the use of a visible light photoredox system based on Ru-catalyst.

In recent years, photoredox catalysis with ruthenium and iridium polypyridine complexes and organic dyes has received great attention as a powerful tool for radical reactions because it promotes single electron transfer (SET) processes under mild reaction conditions, i.e., at room temperature under visible light irradiation. An appropriate combination of radical precursors and photoredox catalysis enables efficient and selective generation of various organic and heteroatom-centered radicals, leading to a variety of radical functionalization. Conventional radical initiating systems often have disadvantages such as the need to use toxic or explosive reagents, the need for high-energy UV irradiation, or the formation of considerable amounts of waste derived from oxidants or reductants. In contrast, protocols for photoredox reactions are easier and safer to use. We have developed photocatalytic (i) Giese-type reaction with organoborates, (ii) radical fluoroalkylation, and (iii) radical introduction of N- and O-functionalities so far. In this article, basic concept and design of our photocatalytic systems will be described in each of the reactions. Then, we will present the several representative results of them.

Nitroxyl radicals (N-oxyls or nitroxides), as exemplified by TEMPO (2,2,6,6-tetramethylpiperidinyl-1-oxy), AZADO (2-azaadamantane N-oxyl), and PINO (phthalimidiy N-oxyl), represent a stable class of organic radicals that exhibit unique properties and reactivity. The diverse and exotic chemistry of these compounds has been found versatile use in electron spin resonance (ESR) studies as spin labels, in biological studies as antioxidants, as charge carriers for energy storage, as mediators in polymerization reactions, and as catalysts in chemical and electrochemical oxidation reactions. This article describes recent synthetic applications of the two most prominent classes of N-oxyl compounds, namely, aminoxyl and imidoxyl species, to effect useful oxidative transformations.

The cross-coupling reaction of aryl halides with various organometallic reagents has been found to proceed in the absence of a transition metal catalyst, which has been considered to be indispensable to promote the cross-coupling reaction. Here an electron works as a catalyst instead of a transition metal, giving coupling products derived from arylmagnesium, arylzinc, alkylzinc, alkynylzinc and arylboron reagents as well as magnesium amides.

Electron has long been recognized for its potential to catalyze chemical reactions, which is referred to as redox catalysis. While acid/base catalysis involves addition/removal of a positively charged atomic particle, proton, an electronically opposite mode of activation is enabled by redox catalysis. Although acid/base catalysis can only trigger polarity-driven reactions, both polarity-driven and radical-driven reactions are made possible by redox catalysis, since single electron transfer (SET) should be involved. Radical-driven reactions were somewhat less familiar in the field of synthetic organic chemistry, however, recent developments in photocatalysis and electrocatalysis have brought them to the forefront. Redox-catalyzed reactions can be categorized into two groups, one is the reactions triggered by oxidative SET and the other is those triggered by reductive SET, while both processes are net redox neutral. In this article, we focus on oxidative SET-triggered cycloadditions, including [2+2] and Diels-Alder.

Oxidative SET from bench stable neutral molecules produces radical cation species, which can be used as unique reactive intermediates. Electron-rich arenes and alkenes are common precursors for the production of radical cations, generating aryl radical cations and alkenyl radical cations by oxidative SET. We have developed oxidative SET-triggered [2+2] and Diels-Alder cycloadditions, where enol ether radical cations and styrene radical cations are used as reactive intermediates. Our reactions are designed based on redox tag processes, where the importance of an intramolecular SET is highlighted. Both [2+2] and Diels-Alder cycloadditions are triggered by oxidative SET from electron-rich alkenes, producing enol ether radical cations and styrene radical cations, respectively. After the intermolecular trapping, they form aryl radical cations through intramolecular SET, which are finally reduced by starting alkenes to complete net redox neutral processes and run catalytic cycles. Intramolecular SET in redox tag processes is further studied by density functional theory (DFT) calculations.

This account describes convergent total synthesis of bioactive cardenolides, 19-hydroxysarmentogenin-3-O-α-ʟ-rhamnoside, trewianin and ouabagenin. The highly oxygenated structures of the target cardenolides were assembled by applying a convergent and unified strategy. The AB-ring and the D-ring were coupled via formation of the acetal tether and 6-exo radical cyclization. The subsequent aldol reaction enabled the introduction of the three new stereocenters, giving rise to the steroid framework with the cis-fused CD-ring. Attachment of the C17-butenolide by Stille coupling and installation of the ʟ-rhamnose completed the total syntheses of the target cardenolides. The structure-activity relationship study using the synthesized natural and unnatural cardenolides demonstrated the biological importance of the hydroxy groups, the monosaccharide moiety, and the butenolide substructure.

The chemical labeling of proteins with synthetic small compound is an important technique in chemical biology. To achieve reliable bioconjugation, rapid reactions in aqueous under physiological pH and mild temperature are required. In the attempt to covalently label native proteins, various biorthogonal chemical reactions targeting not only nucleophilic amino acid residues such as lysine and cysteine, but also tyrosine, tryptophan, methionine, N- and C-terminal positions have been developed. The radical protein labeling reaction proceeds rapidly even in intracellular and physiological environment, and high reactivity of radical species enables local reaction control on the nanometer scale. In this paper, we introduce our recent studies on the labeling of protein tyrosine residues via single electron transfer initiated radical reaction, especially using ruthenium photocatalyst. We found the protein labeling at tyrosine residues with small compounds such as N’-acyl-N,N-phenylenediamine and 1-methyl-4-aryl-urazole under the reaction condition using ruthenium photocatalyst and visible light irradiation. Target-selective labeling using ligand-conjugated ruthenium photocatalysts, and target-selective-purification and labeling from protein mixture using catalyst-functionalized affinity beads were achieved.

The present review describes our endeavor to access agelastatin alkaloids wherein new means of radical nitrogenation of carbon-carbon double bonds have been developed. The first topic presents the development of intramolecular iron(II)-mediated radical aminohalogenation reactions of allyl azido formates and allyl N-tosyloxy carbamates, which culminated in the establishment of the 2nd- and 3rd-generation approaches to (−)-agelastatin A (AA). The second topic deals with the radial azidation reaction of carbon-carbon double bond with KMnO₄/BnEt₃NCl/TMSN₃, a new reagent that produces an azido radical, by which the 4th-generation synthesis of AA has been successfully accomplished.

In recent years, the cooperative interaction between photons and molecules, “photosynergetic” effect, has received increased attention. Chemists have extensively explored photofunctional materials from fundamental and applicative perspectives to establish attractive molecular systems for efficient light energy conversion. However, the conventional photochemical reaction cannot fully utilize the photon energy absorbed by matter because a higher exited state thermally deactivates to a lowest excited state, which is well-known as Kasha’s rule. Therefore, one of the important challenges in recent photochemistry is to establish a basic principle and systems based on advanced photoresponse beyond a one-photon reaction of a single chromophore. Photochromic molecules are one of the molecular classes which show reversible color changes arising from the molecular structural isomerization upon light irradiation. We have developed fast switchable photochromic molecular systems based on imidazolyl radicals, bridged imidazole dimer, pentaarylbiimidazole, and phenoxyl-imidazolyl radical complex. The tunable thermal back reaction rate from microsecond to second time scales enables the applications as a light trigger to various research fields. In addition, we have recently developed the stepwise two-photon induced fast photochromism by using the electron transfer from a higher excited state of sensitizer or the effective electronic interaction between the photogenerated transient radicals. The development of stepwise photochromic compounds based on the above concepts will offer various attractive photofunctional materials. This article overviews the studies about fast photochromic molecules based on imidazole radicals and recent development of the high-performance fast photochromic molecules by photosynergetic effect.

Recently, long-lived organic radical species have attracted much attention of chemists and material scientists because of their unique electronic properties derived from magnetic spin and singly occupied molecular orbitals. Most stable and persistent organic radicals are hetero-atom centered radicals, whereas carbon-centered radicals are generally very reactive, and therefore, have been far from application. Because physical properties of carbon-centered radicals depend predominantly on the topology of the π-electron array, the development of new carbon-centered radicals is key to new basic molecular skeletons that promise novel and diverse applications of spin materials. This article describes our recent studies on the development of novel carbon-centered radicals, including phenalenyl, fluorenyl, and triarylmethyl radicals.

Localized singlet diradicals are key intermediates in bond-homolyses. Thorough studies of the reactive species are essential to clarify the mechanisms of the homolytic bond-cleavage and -formation processes. In general, the singlet diradicals are quite short-lived due to the fast radical-radical coupling reactions. The short-lived characteristic has retarded the thorough study on bond-homolyses. In the last two decades, the author and his research group have enjoyed conducting fundamental studies of generating spectroscopically detectable singlet diradicals to clarify the chemistry of localized singlet diradicals. Recently, a new series of long-lived singlet diradicals, viz. 1,2-diazacyclopentane-3,5-diyl and singlet diradical having macrocyclic structures, have been identified, and their electronic structures and novel reactivities were thoroughly studied using laser-flash photolysis (LFP), product analysis, emission analyses, and computational studies. During the research study, two new concepts in chemistry have emerged; (1) π-single bonding (C-π-C) and (2) the third isomer in bond-homolysis processes, i.e. puckered singlet diradicals. This article describes first a short history of localized diradicals, then, the nitrogen-atom effect on the reactivity of singlet diradicals, the chemistry of π-single bonded species, the stereoselectivity in the photochemical denitrogenation reactions, and the adiabatic bond-homolysis process in the electronically excited states.

This review summarizes organic transformations enabled by the hydrosilane-alkoxide system. These transformations include dehydrogenative C-H silylation of aromatic heterocycles, reductive C-O and C-S bond cleavage, and debenzylation of N-benzylindole.