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α-Aryl-α,α-difluoroketones were synthesized via decarboxylative arylation using diaryliodonium salts under catalyst-free conditions without organometallic intermediates. The products can be transformed into various difluorinated functional groups.

Trimethoxyphenyliodonium(III) acetate [TMP-iodonium(III) acetate] functions as an efficient arylation reagent for N,O-protected hydroxylamines, generating aniline derivatives in the absence of transition metal catalysts. Various N-methoxysulfonamides participated in the amination reaction to produce the corresponding N-methoxysulfonylanilines. This amination reaction was compatible with several protecting groups, including Troc (2,2,2-trichloroethoxycarbonyl), Cbz (benzyloxycarbonyl), Boc (tert-butoxycarbonyl), benzyl, acetyl, and silyl groups. This method uses TMP-iodonium(III) acetate and efficiently synthesizes various aniline derivatives that are versatile synthetic intermediates for functional organic molecules.

Benzolactams have unique biological activity and high utility in the synthesis of valuable compounds with direct applicability to oxindole alkaloids and antibacterial agents. Despite recent advances in organic chemistry and the growing number of reported methods for synthesizing benzolactams, their preparation still requires a multistep process. C-H amination reactions can convert aromatic C(sp

The synthesis of 2-oxygenated dihydrobenzofurans involving the [3 + 2] coupling of quinone monoacetals with vinyl ethers has been realized by tetrabutylammonium triflate catalysis. The reaction involves a new activation method of the acetal moiety in quinone monoacetals under acid-free conditions affording the highly oxygenated dihydrobenzofurans. This new activation mode was achieved by using the triflate anion catalyst for stabilization of the highly reactive cationic intermediate.

Oligosaccharides are involved in numerous biological processes. Achieving optimal anomeric selectivity and regioselectivity remains challenging. Herein, we present a method for the oxidative glycosylation of thioglycosides with hypervalent iodine reagents derived from carboxylic acid to form C-O bonds. The reaction of thioglycosides with various hypervalent iodine carboxylates afforded acyl

C-H/N-H bond functionalization for direct intermolecular aryl C-N couplings is a useful synthetic process. In this study, we achieved metal-free cross-dehydrogenative coupling of phenols and anilines with phenothiazines using hypervalent iodine reagents. This method affords selective amination products under mild conditions. Electron-rich phenols and anilines could be employed, affording moderate-to-high yields of

Ketene acetal derivatives, such as 1-alkoxyvinyl esters and O-silyl ketene acetals, belong to the category of O-substituted enols of esters, which easily react with various types of nucleophiles, Nu-H, under neutral conditions to give the corresponding acylated and silylated products in excellent yields only by evaporation of the generated volatile esters. Silyl ketene acetals can be easily synthesized by various simple procedures, whereas 1-alkoxyvinyl esters require an equimolar or catalytic amount of a mercury salt to synthesize them. This drawback prevented the advancement of the chemistry of 1-alkoxyvinyl esters. In 1993, we developed a useful synthetic method of 1-alkoxyvinyl esters using a small amount (0.5-1 mol %) of a ruthenium catalyst. Encouraged by this discovery, we subsequently developed various reactions and applied them to the synthesis of natural products. It is noteworthy that the stereoselective total synthesis of fredericamycin A was achieved by the combined use of these reactions. Macrocyclization was variously utilized for the synthesis of natural macrolides by two types of approaches: direct macrolactonization of α,ω-hydroxy acids or intermolecular esterification between an acid and alcohol followed by a ring-closure step. Additionally, several new reactions using 1-alkoxyvinyl esters or their analogs as key intermediates on the basis of our methods were recently reported. In this paper, we introduce our efforts from the synthesis of 1-alkoxyvinyl esters to the application such as natural product syntheses and recent advancements.

Trifluoromethylphenyl substituted phthalimides (PIs) containing oligoselenophene and phenylselenophene substituents were synthesized. Spectroscopic studies show that increasing the number of selenophene units causes the UV-Vis and photoluminescence maxima of the selenophene substituted PIs to shift to longer wavelengths. Analysis of the single crystal structure shows that the biselenophene substituted derivative has a layered structure, no center of symmetry and a molecular network with close contacts between Se atoms. XRD patterns of the PI derivatives indicate they have similar layered structures. These substances were used to fabricate field-effect transistors (FET)s by using the vapor deposition method. The FET derived using the biselenophene substituted PI exhibits clear n-type characteristics with an electron mobility of ca. 10−4 cm2 V−1 s−1. The FET prepared using the more highly conjugated terselenophene derivative also displays n-type FET characteristics with a slightly higher threshold voltage. Moreover, n-type behavior is also displayed by a highly crystalline thin film generated from the phenylselenophene derivative. The LED light responsiveness of FET characteristics was investigated. While the FET formed from the terselenophene derivative maintains a saturation drain–source current (IDS) operation along with a three-fold increase of electron mobility upon irradiation, those derived from the biselenophene and phenylselenophene derivatives display Ohm's law-like IDS. The difference in light responses are discussed in terms of conductivity differences.

An efficient protocol for C–H condensation of hypervalent iodine compounds toward arenes in fluoroalcohols has been applied to the recyclable preparation of mesityl iodonium(III) salts. The electrophilicities of [hydroxy(tosyloxy)iodo]mesitylene (MesI(OH)OTs) and iodomesitylene diacetate (MesI(OAc)2) are suitably enhanced in 2,2,2-trifluoroethanol. A series of nucleophilic aromatic compounds react smoothly with MesI(OH)OTs and MesI(OAc)2 or in situ hypervalent iodine(III) species, generated from iodomesitylene, to provide the target mesityl iodonium(III) salts in good yields at room temperature with broad functional group tolerance. This C–H condensation strategy merits high para-regioselectivities during the diaryliodonium(III) salt formation, but the major limitation in the case of low-reactive aromatic substrates is byproduct formation resulting from the self-condensation of the nucleophilic mesitylene ring in MesI(OH)OTs and MesI(OAc)2.

It was determined that diaryliodonium(III) triflates bearing a trimethoxybenzene (TMP) auxiliary are more reactive than the reported selective aryl-transfer iodonium salts in the N-arylation of benzimidazoles and other types of azole compounds under catalytic conditions. The TMP-iodonium(III) salts can thus effectively facilitate the reaction at 50 °C or below, producing the corresponding N-arylated biaryls without the formation of TMP-derived coupling byproducts. Utilization of this TMP reagent under mild conditions would prevent the underlying problem of participation of the auxiliary group in the coupling reactions, which is observed while using the iodonium(III) salts that require elevated temperatures.

Oxidative coupling strategies that can directly convert the C–H group for chemical transformations are, in theory, ideal synthetic methods to reduce the number of synthetic steps and byproduct generation. Hypervalent iodine reagents have now become one of the most promising tools in developing oxidative couplings due to their unique reactivities that are replacing metal oxidants. As part of our continuous development of oxidative coupling reactions, we describe in this report highly efficient μ-oxo hypervalent iodine catalysts for the direct oxidative coupling of N-methoxyamides and related compounds with aromatic hydrocarbons. The excellent TONs, up to over 100 times, with a best catalyst loading of 0.5 mol% were determined for the oxidative C–H/N–H coupling method, which can provide the most straightforward route to obtaining these unique arylamide compounds.

An oxidation system comprising phenyliodine(III) diacetate (PIDA) and iodosobenzene with inorganic bromide, i.e., sodium bromide, in an organic solvent led to the direct introduction of carboxylic acids into benzylic C–H bonds under mild conditions. The unique radical species, generated by the homolytic cleavage of the labile I(III)–Br bond of the in situ-formed bromo-λ3-iodane, initiated benzylic carboxylation with a high degree of selectivity for the secondary benzylic position.

Cocrystals of N-4-trifluoromethylphenylphthalimides 1 a⊇2 a(1 %), composed of bromo (1 a) and dimethylamino (2 a) derivatives in a 99:1 ratio, display delayed photoluminescence (DPL) at λem=535 nm with a lifetime of 0.26 s. In contrast, pure materials 1 a and 2 a do not exhibit DPL. Similar DPL emission is also observed for cocrystals 1⊇2(1 %) of N-4-pyridyl, N-phenyl, and N-4-tolyl derivatives. X-Ray crystallographic analyses and the results of density functional theory calculations revealed that key for the occurrence of DPL is the formation of charge-transfer (CT) excited states 1(2 a⋅1 a)CT* and the existence of regularly aligned networks in the cocrystals, which leads to generation of the long-lived excited state 31 a via 3(2 a⋅1 a)CT* by intersystem crossing and localization of triplet energy.

Biaryl diamines are important building blocks in organic ­synthesis. Consequently, it is desirable to develop a general and mild synthetic approach to diverse biaryl diamines. Oxidative coupling is an efficient and promising strategy for the synthesis of these targets. We have now developed a direct formation of biaryl diamines by oxidative coupling using a hypervalent iodine(III) reagent.

A new type of binaphthyl-based chiral iodide functionalized at positions 8 and 8' of the naphthalene rings has been found as a promising structural motif for the asymmetric hypervalent iodine(III) oxidations, specifically, for the dearomatizing spirocyclization of naphthol carboxylic acids showing expectedly better enantioselectivities versus other atropisomeric biaryls, i.e., a conventionally used binaphthalene having the diiodides in the minor groove.

The metal-free arylative coupling of carboxylic acids using iodosoarenes without the use of a catalyst and base, which is applicable to even a highly-polar molecule bearing multiple alcohol groups, is reported. The in situ preparation of the reactive diaryliodonium(III) carboxylates is the important key to this approach, and the introduction of the trimethoxybenzene auxiliary enables both the smooth salt formations and the selective aryl transfer events during the couplings.

The C2-symmetric tetralin-fused 1,4-diiodo-1,3-butadiene derivatives, (Z,Z)-2,3-di(1-iodoalkylidene)tetralin 1a-c, are atropisomeric and can be resolved into the two persistent axially chiral enantiomers by HPLC on a chiral stationary phase. The enantiomerically pure compounds can serve as chiral organocatalysts for dearomatizing spirolactonization to show good performances in up to 73 % ee.

A simple and efficient synthesis of phenol biaryls by the cross-couplings of quinone monoacetals (QMAs) and phenols is reported. The Brønsted acid catalytic system in 1,1,1,3,3,3-hexafluoro-2-propanol was found to be particularly efficient for this transformation. This reaction can be extended to the synthesis of various phenol biaryls, including sterically hindered biaryls, with yields ranging from 58 to 90 % under mild reaction conditions and in a highly regiospecific manner.

The iron(III) chloride-catalyzed Friedel–Crafts arylation of 4-aryl-4-methoxy-2,5-cyclohexadienones, which were easily prepared by the phenyliodine(III) diacetate (PIDA)-mediated oxidation of 4-arylphenols in methanol, proceeded site-selectively to form meta-terphenyl (2,4-diarylphenol) derivatives in good yields. The subsequent PIDA-mediated oxidation and iron(III) chloride-catalyzed Friedel–Crafts arylation of the resulting products gave the corresponding 2,4,6-triarylphenol derivatives. The present method provides useful highly substituted polyarylated compounds.

Thioglycosides are available donors in glycosylation due to the stability of the anomeric C-S bond under general reaction conditions of protection and deprotection, and offer orthogonality in their activation. We report now that the hypervalent iodine effectively induced glycosylation reaction of thioglycosides with various alcohols. This method features a high efficiency, completion in a short time, and proceeding under very mild conditions.

Pyrrole-aryl derivatives are important due to their unique biological activities in medicinal chemistry. We now report a new oxidative biaryl coupling for pyrroles and indoles toward various arenes using a hypervalent iodine reagent and an appropriate stabilizer for pyrrolyl iodonium intermediates. The reactions readily provide a variety of desired coupling products in good yields.

Trifluoromethylphenyl-substituted phthalimide derivatives favorably form triboluminescence (TL) active noncentrosymmetric crystals. Oligothienyl-, oligophenyl-, and naphthyl-substituted phthalimide derivatives were successfully developed as a series of metal free TL compounds. X-ray crystal structure analyses of bithienyl and naphthyl derivatives revealed noncentrosymmetric layer structures in the same direction. Introduction of suitable electron rich π-units such as thienyl groups enhances their photoluminescence and TL characteristics, and the colors can be also controlled in the visible region. A rigid naphthyl-substituted imide derivative exhibits extremely high TL performance.

Quinone monoacetals (QMAs) were found to be convenient substrates for a unique arylation reaction of enol silyl ethers. This arylation process of QMAs typically proceeds through the acetal activation of the QMAs by a hydrogen-bond donor solvent, such as a fluoroalcohol, for the initiating step. The silyl transfer from silyl enol ethers to the carbonyl oxygen of the QMAs appears to be involved in the C–C coupling step, followed by QMA aromatization. By this method, valuable α-aryl carbonyl compounds containing o-phenol moieties can be obtained directly under mild conditions without lactone formation.

A combination of phenyliodine bis(trifluoroacetate) (PIFA) and trifluoromethanesulfonic acid was found to be an effective activator for the glycosylation reaction, of which the glycosyl donor was p-(octyloxy)phenyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-1-thio-D-glucopyranoside or p-(octyloxy)phenyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-1-thio-D-galactopyranoside. The reaction proceeded with good yields when naturally occurring and derived alkanols, such as cholestanol, (–)-menthol, 1- and 2-adamantanols and nor-kauranol, were employed as acceptor substrates. Interestingly, the glycosylation reaction of sterically hindered terpenoid alcohols, such as (–)- and (+)-borneols and (+)-fenchyl alcohol, with p-(octyloxy)phenyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-1-thio-D-glucopyranoside afforded the desired β-glycoside in quantitative yield. Moreover, the present reaction was useful to synthesize disaccharides of which the non-reducing end was composed of a D-glucosamine or D-galactosamine unit.

The benzylic positions of the phthalan and isochroman derivatives (1) as benzene-fused cyclic ethers effectively underwent gold-catalyzed direct azidation using trimethylsilylazide (TMSN3) to give the corresponding 1-azidated products (2) possessing the N,O-acetal partial structure. The azido group of the N,O-acetal behaved as a leaving group in the presence of catalytic iron(III) chloride, and 1-aryl or allyl phthalan and isochroman derivatives were obtained by nucleophilic arylation or allylation, respectively. Meanwhile, a double nucleophilic substitution toward the 1-azidated products (2) occurred at the 1-position using indole derivatives as a nucleophile accompanied by elimination of the azido group and subsequent ring opening of the cyclic ether nucleus produced the bisindolylarylmethane derivatives.

The facile and clean oxidative coupling reaction of pyrroles with azoles has been achieved using the recyclable hypervalent iodine(III) reagents having adamantane structures. These iodine(III) reagents could be recovered from the reaction mixtures by a simple solid-liquid separation, i.e., filtration, for reuse.

The gene encoding the chromatin remodeler CHD8 is the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Heterozygous mutations in CHD8 give rise to ASD that is often accompanied by macrocephaly, gastrointestinal complaints, and slender habitus. Whereas most phenotypes of CHD8 haploinsufficiency likely result from delayed neurodevelopment, the mechanism underlying slender habitus has remained unknown. Here, we show that CHD8 interacts with CCAAT/enhancer-binding protein β (C/EBPβ) and promotes its transactivation activity during adipocyte differentiation. Adipogenesis was impaired in Chd8-deleted preadipocytes, with the upregulation of C/EBPα and peroxisome-proliferator-activated receptor γ (PPARγ), two master regulators of this process, being attenuated in mutant cells. Furthermore, mice with CHD8 ablation in white preadipocytes had a markedly reduced white adipose tissue mass. Our findings reveal a mode of C/EBPβ regulation by CHD8 during adipogenesis, with CHD8 deficiency resulting in a defect in the development of white adipose tissue.

We have developed the iodoarene-catalyzed nucleophilic fluorination of β-dicarbonyl compounds and intramolecular aminofluorination of ω-amino-alkenes using the same reaction conditions. The key for this reaction is the in situ generation of a hypervalent iodine compound ArIF2 by hydrogen fluoride, mCPBA and a catalytic amount of iodoarene. Preliminary trials of catalytic asymmetric nucleophilic fluorination were conducted.

3-Borylbenzynes were generated in situ from 6-boryl-2-iodophenyl trifluoromethanesulfonates using i -PrMgCl·LiCl and applied to Diels–Alder reactions with substituted furans and pyrroles. The reactions allowed good functional group compatibility and produced the cycloadducts in high yields with high distal selectivities. Effective conversion of the boryl group of the products was achieved. A series of these reactions provides a new method for producing multifunctionalized benzo-fused aromatic compounds. Additionally, the regioselectivities of these Diels–Alder reactions were theoretically analyzed by DFT calculations to find that the reactions were mainly controlled by the electrostatic effect and aryne distortion caused by the boryl group.

Direct oxidative coupling is an attractive tool for environmentally benign green chemistry. We report the novel oxidative synthesis of hexahydroxytriphenylene by using a hypervalent iodine reagent. The reaction proceeds under very mild conditions for reducing acid waste and in a very short time at room temperature.

The hypervalent-iodine-mediated oxidative metal-free cross-coupling reaction of thiophenes with various pyrroles was developed. The corresponding thiophene–pyrrole derivatives were obtained in moderate to high yields (up to 85 %). This method features high efficiency and regioselectivity and broad functional group tolerance. We further determined the highly planar characteristics of the 3,4-ethylenedioxythiophene–pyrrole biaryls caused by intramolecular hydrogen bonding.

Thioglycosides are available donors in glycosylation due to the stability of the anomeric C-S bond under general reaction conditions of protection and deprotection, and offer orthogonality in their activation. We report now that the hypervalent iodine effectively induced glycosylation reaction of thioglycosides with various alcohols. This method features a high efficiency, completion in a short time, and proceeding under very mild conditions.

A hypervalent iodine(III)-catalyzed intermolecular oxidative cross-coupling reaction of electron-rich aromatic compounds is achieved by using a catalytic amount of an iodoarene and an inorganic oxidant.

Recently, hypervalent iodine reagents have been extensively used in organic synthesis. A variety of reactions available for natural product syntheses have been developed using phenyliodine(III) diacetate (PIDA), phenyliodine(III) bis(trifluoroacetate) (PIFA), and other iodine(III) and (V) reagents. These reactions are expected to have applications in pharmaceutical and agrochemical processes because of their safety, mild reaction conditions, and high yields of pure products. Under such considerations, this chapter focuses on the oxidative coupling reactions of hypervalent iodine reagents found in total syntheses of biologically active natural products and their related compounds.