µ-Oxo-Hypervalent-Iodine-Catalyzed Oxidative C-H Amination for Synthesis of Benzolactam Derivatives.

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(sp2)-H bonds directly to C(sp2)-N bonds, and this direct approach to C-N bond formation offers effective access to benzolactams. Hypervalent iodine reagents are promising tools for achieving oxidative C-H amination. Motivated by our ongoing research efforts toward the development of useful hypervalent-iodine-mediated oxidative transformations, we herein describe an effective intramolecular oxidative C-H amination reaction based on µ-oxo hypervalent iodine catalysis for the synthesis of benzolactams bearing various functional groups.

1-Alkoxyvinyl Ester as an Excellent Acyl Donor: Efficient Macrolactone Synthesis.

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.

Selective carboxylation of reactive benzylic C-H bonds by a hypervalent iodine(III)/inorganic bromide oxidation system.

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.

Chiral Atropisomeric 8,8'-Diiodobinaphthalene for Asymmetric Dearomatizing Spirolactonizations in Hypervalent Iodine Oxidations.

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.

Hypervalent Iodine-Induced Oxidative Couplings (New Metal-Free Coupling Advances and Their Applications in Natural Product Syntheses).

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.

Phthalimide Compounds Containing a Trifluoromethylphenyl Group and Electron-Donating Aryl Groups: Color-Tuning and Enhancement of Triboluminescence.

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.

Stabilized pyrrolyl iodonium salts and metal-free oxidative cross-coupling.

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.

Glycosylation Reaction of Thioglycosides by Using Hypervalent Iodine(III) Reagent as an Excellent Promoter.

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.

Organo-Iodine(III)-Catalyzed Oxidative Phenol-Arene and Phenol-Phenol Cross-Coupling Reaction.

The direct oxidative coupling reaction has been an attractive tool for environmentally benign chemistry. Reported herein is that the hypervalent iodine catalyzed oxidative metal-free cross-coupling reaction of phenols can be achieved using Oxone as a terminal oxidant in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP). This method features a high efficiency and regioselectivity, as well as functional-group tolerance under very mild reaction conditions without using metal catalysts.

Efficient Coupling Reaction of Quinone Monoacetal with Phenols Leading to Phenol Biaryls.

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.

Pioneering Metal-Free Oxidative Coupling Strategy of Aromatic Compounds Using Hypervalent Iodine Reagents.

We started our hypervalent iodine research about 30 years ago in the mid-1980s. We soon successfully developed the single-electron-transfer oxidation ability of a hypervalent iodine reagent, specifically, phenyliodine(III) bis(trifluoroacetate) (PIFA), toward aromatic rings of phenyl ethers for forming aromatic cation radicals. This was one of the exciting and unexpected events in our research studies so far, and the discovery was reported in 1991. It also led to the next challenge, developing the metal-free oxidative couplings for C-H functionalizations and direct couplings between the C-H bonds of valuable aromatic compounds in organic synthesis. In order to realize the effective oxidative coupling, pioneering new aromatic ring activations was essential and several useful methodologies have been found for oxidizable arenes. The achievements regarding this objective obtained in our continuous research are herein summarized with classification of the aromatic ring activation strategies.

Clean Synthesis of N-Pyrrolyl Azoles by Metal-Free Oxidative Cross-Coupling Using Recyclable Hypervalent Iodine Reagent.

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.

Gold-Catalyzed Benzylic Azidation of Phthalans and Isochromans and Subsequent FeCl3-Catalyzed Nucleophilic Substitutions.

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.

Silver-Catalyzed Coupling of Unreactive Carboxylates: Synthesis of α-Fluorinated O-Aryl Esters.

α-Fluorinated aryl esters pose a challenge in synthesis via O-arylation of α-fluorinated carboxylates owing to their low reactivities. This limitation has been addressed by combining a silver catalyst with aryl(trimethoxyphenyl)iodonium tosylates to access α-fluorinated aryl esters. We envision that the catalytic system involves high-valent aryl silver species generated via the oxidation of silver(I) salt. The present method provided a synthetic protocol for various α-fluorinated aryl esters including fluorinated analogs of drug derivatives.

Organocatalytic C­H/C­H' cross-biaryl coupling: C-selective arylation of sulfonanilides with aromatic hydrocarbons.

The hypervalent iodine-mediated C-C selective coupling of N-methanesulfonyl anilides with aromatic hydrocarbons has been developed. The first organocatalytic oxidative cross-biaryl-coupling was achieved by the catalyst control in defining specific 2,2'-diiodobiphenyls for the direct C-C bond formations.

Asymmetric dearomatizing spirolactonization of naphthols catalyzed by spirobiindane-based chiral hypervalent iodine species.

This report details the development of a spirobiindane-based chiral hypervalent iodine reagent, especially focusing on its structural elucidation for effective asymmetric induction of the chiral spiro center during the oxidative dearomatizing spirolactonization of naphthols. In this study we synthesized a new series of ortho-functionalized spirobiindane catalysts and demonstrated that the enantioselectivity can be dramatically improved by the presence of the substituents ortho to the iodine atom. The structural elucidation of a spirobiindane-based hypervalent iodine catalyst has led to further improvement in the stereoselective construction of the spiro center during the oxidative dearomatizing spirolactonization of naphthols. Thus, catalytic oxidation with the highest reported level of enantioselectivity in hypervalent iodine chemistry has been achieved with also an excellent level of asymmetric induction (92% ee for substrate 3a). As a result, this study, dealing with a series of modified iodine catalysts, can provide important clues about the transition state and reaction intermediate to help scientists understand the origin of the stereoselectivity. A plausible transition-state model and intermediate in the reaction for the stereoselective formation of spirolactone products are postulated by considering the ortho-substituent effect and the results of X-ray analysis. In this reaction model, the high enantiomeric excess obtained by using the spirobiindane catalysts could be well explained by the occupation of the equatorial site and extension of the surroundings around the hypervalent iodine bonds by the introduced ortho-substituent. Thus, this study would contribute to estimation of the chiral hypervalent iodine compounds in asymmetric reactions.

Identification of CHD7S as a novel splicing variant of CHD7 with functions similar and antagonistic to those of the full-length CHD7L.

CHD7 is one of the nine members of the chromodomain helicase DNA-binding family of ATP-dependent chromatin remodeling enzymes. Mutations in CHD7 give rise to CHARGE syndrome, a human condition characterized by malformation of various organs. We have now identified a novel transcript of CHD7 that is generated by alternative splicing of exon 6. The protein encoded by this variant transcript (termed CHD7S) lacks one of the two chromodomains as well as the helicase/ATPase domain, DNA-binding domain and BRK domains of the full-length protein (CHD7L). CHD7S was found to localize specifically to the nucleolus in a manner dependent on a nucleolar localization signal. Over-expression of CHD7S, as well as that of CHD7L, resulted in an increase in 45S precursor rRNA production. Conversely, depletion of both CHD7S and CHD7L by RNA interference inhibited both 45S precursor rRNA production and cell proliferation to a greater extent than did depletion of CHD7L alone. Furthermore, we found that, like CHD7L, CHD7S binds to Sox2 in the nucleoplasm. Unexpectedly, however, whereas over-expression of CHD7L promoted Sox2-mediated transcriptional regulation, over-expression of CHD7S suppressed it. These results indicate that CHD7S functions cooperatively or antagonistically with CHD7L in the nucleolus and nucleoplasm, respectively.

Efficient synthesis of a regioregular oligothiophene photovoltaic dye molecule, MK-2, and related compounds: a cooperative hypervalent iodine and metal-catalyzed synthetic route.

We have successfully established an efficient route to the core structure of donor-acceptor head-to-tail (H-T)-linked regioregular oligothiophenes, which includes the following key synthetic steps, that is, hypervalent iodine induced direct and regioselective coupling of thiophenes and the use of the obtained bithiophenes as excellent coupling substrates for the Suzuki and Stille couplings. The versatility of this new approach is highlighted in the dramatic improvement of the yield (ca. 59 % overall yield) of MK-2, a high-performance organic dye, for photovoltaic applications.

Single-electron-transfer (SET)-induced oxidative biaryl coupling by polyalkoxybenzene-derived diaryliodonium(III) salts.

Metal-free oxidative C-C coupling by using polyalkoxybenzene-derived diaryliodonium(III) salts as both the oxidant and aryl source has been developed. These salts can induce single-electron-transfer (SET) oxidation to yield electron-rich arenes and subsequently transfer the polyalkoxyphenyl group into in situ generated aromatic radical cations to produce biaryl products. The reaction is promoted by a Lewis acid that activates the iodonium salts. It has been revealed that the reactivity of the salts under acidic conditions is quite different to their known behavior under basic conditions. The reactivity preference of a series of iodonium salts in the SET oxidation and their ligand transfer abilities have been systematically investigated and the results are summarized in this report.

Brønsted acid-controlled [3 + 2] coupling reaction of quinone monoacetals with alkene nucleophiles: a catalytic system of perfluorinated acids and hydrogen bond donor for the construction of benzofurans.

We have developed an efficient Brønsted acid-controlled strategy for the [3 + 2] coupling reaction of quinone monoacetals (QMAs) with nucleophilic alkenes, which is triggered by the particular use of a specific acid promoter, perfluorinated acid, and a solvent, fluoroalcohol. This new coupling reaction smoothly proceeded with high regiospecificity in regard with QMAs for introducing π-nucleophiles to only the carbon α to the carbonyl group, thereby providing diverse dihydrobenzofurans and derivatives with high yields, up to quantitative, under mild conditions in short reaction times. The choice of Brønsted acid enabled us to avoid hydrolysis of the QMAs, which gives quinones, and the formation of discrete cationic species from the QMAs. Notably, further investigations in this study with regard to the acid have led to the findings that the originally stoichiometrically used acid could be reduced to a catalytic amount of 5 mol % loading or less and that the stoichiometry of the alkenes could be significantly improved down to only 1.2 equiv. The facts that only a minimal loading (5 mol %) of perfluoroterephthalic acid is required, readily available substrates can be used, and the regioselectivity can be controlled by the acid used make this coupling reaction very fascinating from a practical viewpoint.