立命館大学 薬学部 精密合成化学研究室 立命館大学 薬学部 精密合成化学研究室 立命館大学 薬学部 精密合成化学研究室

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2024

K. Kikushima, K. Komiyama, N. Umekawa, K. Yamada, Y. Kita, T. Dohi, Silver-catalyzed coupling of unreactive carboxylates: Synthesis of α-fluorinated O-aryl esters. Org. Lett. 2024, 26(25), 5347-5352. https://doi.org/10.1021/acs.orglett.4c01731 (selected as Cover Feature)


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.
Y. Yoto, R. Hatagochi, Y. Irie, N. Takenaga, R. Kumar, T. Dohi, Synthesis of heterocyclic sulfonium triflates by Cu-catalyzed selective S-arylation with aryl(mesityl)iodonium salts. Curr. Org. Chem. 2024, 21, in press.

An efficient method for synthesizing cyclic arylsulfonium salts has been developed by selective aryl transfer to the sulfur atom from aryl(mesityl)iodonium triflates, a recyclable series of diaryliodonium salts, in the presence of inorganic copper catalyst.
R. Kumar, T. Dohi, V. V. Zhdankin, Organohypervalent heterocycles. Chem. Soc. Rev. 2024, 53(9), 4786-4827. https://doi.org/10.1039/D2CS01055K

This review summarizes the structural and synthetic aspects of heterocyclic molecules incorporating an atom of a hypervalent main-group element. The term “hypervalent” has been suggested for derivatives of main-group elements with more than eight valence electrons, and the concept of hypervalency is commonly used despite some criticism from theoretical chemists. The significantly higher thermal stability of hypervalent heterocycles compared to their acyclic analogs adds special features to their chemistry, particularly for bromine and iodine. Heterocyclic compounds of elements with double bonds are not categorized as hypervalent molecules owing to the zwitterionic nature of these bonds, resulting in the conventional 8-electron species. This review is focused on hypervalent heterocyclic derivatives of nonmetal main-group elements, such as boron, silicon, nitrogen, carbon, phosphorus, sulfur, selenium, bromine, chlorine, iodine(III) and iodine(V).
N. Miyamoto, D. Koseki, K. Sumida, E. E. Elboray, N. Takenaga, R. Kumar, T. Dohi, Auxiliary strategy for the general and practical synthesis of diaryliodonium(III) salts with diverse organocarboxylate counterions. Beilstein J. Org. Chem. 2024, 20, 1020-1028 (Thematic Issue “Hypervalent halogen chemistry”). https://doi.org/10.3762/bjoc.20.90

Diaryliodonium(III) salts are versatile reagents that exhibit a range of reactions, both in the presence and absence of metal catalysis. In this study, we developed efficient synthetic methods for aryl(TMP)iodonium(III) carboxylates, by reaction of (diacetoxyiodo)arenes or iodosoarenes with 1,3,5-trimethoxybenzene in the presence of a diverse range of organocarboxylic acids. These reactions were conducted under mild conditions using the trimethoxyphenyl (TMP) group as an auxiliary, without the need for additives, excess reagents, or counterion exchange in further steps. These protocols are compatible with a wide range of substituents on (hetero)aryl iodine(III) compounds, including electron-rich, electron-poor, sterically congested, and acid-labile groups, as well as a broad range of aliphatic and aromatic carboxylic acids for the synthesis of diverse aryl(TMP)iodonium(III) carboxylates in high yields. This method allows for the hybridization of complex bioactive and fluorescent-labeled carboxylic acids with diaryliodonium(III) salts.
菊嶌孝太郎, 脱炭酸的アリール化によるα,α-ジフルオロカルボニル化合物のメタルフリー合成. 薬学雑誌 2023, 144(1), 7-14.(日本薬学会関西支部奨励賞受賞記念総説)https://doi.org/10.1248/yakushi.23-00143

Decarboxylative arylation of difluoroketoacid salts with diaryliodonium(III) salts has been developed to synthesize aryldifluoromethyl ketones, which are attractive synthetic intermediates for various difluorobenzyl units. This additive-free arylation represents an alternative approach to conventional synthetic methods that rely on transition metal catalysts and/or organometallic compounds. The reaction involves sequential ligand exchange of difluoroketoacid with tosylate ligand of diaryliodonium salt, followed by decarboxylative ligand coupling. Various functional groups, including ester, nitro, cyano, heteroarenes, and aryl halide groups, were tolerated during the present reaction. The resulting aryldifluoromethyl ketones can be transformed into the corresponding esters, amides, and difluoromethyl compounds, which are commonly found in biologically active compounds.
R. Kumar, R. R. Nair, R. Prakash, T. Bae, T. Dohi, O. Prakash, α,α-Dibromoketones as synthetic equivalents of α-bromoketones for the synthesis of thiazolo[3,2-a]benzimidazoles. Lett. Org. Chem. 2024, 21(2), 209-212. DOI: 10.2174/1570178620666230803123511 Flyer

Utilization of α,α-dihalocarbonyl compounds as synthetic equivalents to α-halocarbonyl compounds have been explored in the syntheses of a wide range of highly useful heterocycles and α-functionalized ketones. Continuously growing demand of α,α-dibromoketones, as highly reactive and mild synthetic precursors/intermediates, to carry out selective organic transformations, prompted us to investigate their potential application for the synthesis of thiazolo[3,2-a]benzimidazoles. In this paper, a remarkable application of α,α-dibromoacetophenones in the development of a facile protocol for the synthesis of thiazolo[3,2-a]benzimidazoles, avoiding the use of lachrymatory α-haloketones, is described. Although the mechanism for the debromination from the intermediate compound under these conditions is not confirmed, possible pathways have been suggested.

2023

L. Bouissane, J. Echeverria, T. Dohi, T. J. Müller, Editorial: Multicomponent reactions (MCRs) towards scaffolds with versatile application. Front. Chem. 2023, 11:1332672. (Special Topic Collections 2023)
doi: 10.3389/fchem.2023.1332672

In the Research Topic "Multicomponent Reactions (MCRs) Towards Scaffolds with Versatile Applications" we have compiled various aspects of modern MCR chemistry. Three contributions place a special emphasis on methodological developments by metal-free MCR syntheses of trifluoromethyl-1,2,4-triazole scaffolds (Wang et al.), by Pd-catalyzed asymmetric MCR synthesis of α-arylglycine derivatives (Jakob et al.), and by summarizing advancements of metal-mediated MCR syntheses in general (Sakthivel et al.). The fourth contribution takes a conceptual approach and summarizes and outlines the application of MCRs for accessing chromophores, which as functional π-systems are the molecular key constituents in photonic and electronic applications (Brandner et al.). We hope that this Research Topic will inspire to follow the exciting path of MCRs, which inevitably have become a playground for developing superior, sustainable methodologies allowing to tackle scientific challenges with tailored molecules in a broad scope from life to materials sciences.
H. Sasa, S. Hamatani, M. Hirashima, N. Takenaga, T. Hanasaki, T. Dohi, Efficient metal-free oxidative C–H amination for accessing dibenzoxazepinones via μ-oxo hypervalent iodine catalysis. Chemistry 2023, 5(2), 2155-2165. (Special Issue "Catalytic Organic Synthesis—a Special Issue in Honor of Professor Masahiro Miura") doi: 10.3390/chemistry5040145

Dibenzoxazepinones exhibit unique biological activities and serve as building blocks for synthesizing pharmaceutical compounds. Despite remarkable advancements in organic chemistry and recent developments in synthetic approaches to dibenzoxazepinone motifs, there is a strong demand for more streamlined synthesis methods. The application of catalytic C–H amination strategy, which enables direct transformation of inert aromatic C–H bonds into C–N bonds, offers a rapid route to access dibenzoxazepinone frameworks. Hypervalent-iodine-catalyzed oxidative C–H amination should become one of the effective approaches for synthesizing dibenzoxazepinones. In this study, we present our method of employing μ-oxo hypervalent iodine catalysis for intramolecular oxidative C–H amination of O-aryl salicylamides, facilitating the synthesis of target dibenzoxazepinone derivatives bearing various functional groups in a highly efficient manner.
E. E. Elboray, T. Bae, K. Kikushima, Y. Kita, T. Dohi, Transition metal-free O-arylation of N-alkoxybenzamides enabled by aryl(TMP)iodonium salts. Adv. Synth. Catal. 2023, 365(16), 2703-2710. (Special Issue: Iodine in Catalysis and Organic Synthesis) https://doi.org/10.1002/adsc.202300406

Herein, we develop a metal catalyst-free protocol for O-arylation of benzamide hydroxamate esters. The chemoselective O- versus N-arylation of the amides was tuned by varying the electronic and/or steric properties of the diaryliodonium salt and/or the substrate. The O-arylation reaction would preferentially occur for sterically and electronically diverse substrates. This study, which reveals the possibility of substituent- and reagent-controlled chemoselectivity, with diaryliodonium salts is expected to attract great interest in the area of hypervalent iodine chemistry.
K. Sakthivel, R. J. Gana, T. Shoji, N. Takenaga, T. Dohi, F. V. Singh, Recent progress in metal assisted multicomponent reactions in organic synthesis. Front. Chem. 2023, 11:1217744. (Special Issue: Multicomponent Reactions (MCRs) Towards Scaffolds with Versatile Applications)
doi: 10.3389/fchem.2023.1217744

To prepare complicated organic molecules, straightforward, sustainable, and clean methodologies are urgently required. Thus, researchers are attempting to develop imaginative approaches. Metalcatalyzed multicomponent reactions (MCRs) offer optimal molecular diversity, high atomic efficiency, and energy savings in a single reaction step. These versatile protocols are often used to synthesize numerous natural compounds, heterocyclic molecules, and medications. Thus far, the majority of metal-catalyzed MCRs under investigation are based on metal catalysts such as copper and palladium; however, current research is focused on developing novel, environmentally friendly catalytic systems. In this regard, this study demonstrates the effectiveness of metal catalysts in MCRs. The aim of this study is to provide an overview of metal catalysts for safe application in MCRs.
S. E. Shetgaonkar, J. Subbhiksha, T. Dohi, F. V. Singh, Iodine(V)-based oxidants in oxidation reactions. Molecules 2023, 28(13), 5250-5277. (Special Issue: Oxidative Reaction in Chemistry) https://doi.org/10.3390/molecules28135250

The chemistry of hypervalent iodine reagents has now become quite valuable due to their reactivity under mild reaction conditions and their resemblance in the chemical properties with transition metals. The environmentally friendly nature of these reagents makes them suitable reagents for Green Chemistry. These reagents showed the dual natures as iodine(III) reagents are capable electrophiles while the iodine(V) reagents are known for their strong oxidant behavior. Various iodine(V) reagents including IBX and DMP have been used as oxidants in organic synthesis either in stoichiometric or catalytic amounts. In this review article, we have covered various oxidation reactions induced by iodine(V) reagents in past one decade.
M. F. Radwan, E. E. Elboray, H. M. Dardeer, Y. Kobayashi, T. Furuta, S. Hamada, T. Dohi, M. F. Alya, 1,3-Dipolar cycloaddition of 3-chromonyl-substituted glycine imino esters with arylidenes and in situ diastereodivergent via retrocycloaddition. Chem.-Asian J. 2023, 18(10), e202300215. https://doi.org/10.1002/asia.202300215

1,3-Dipolar cycloaddition through in situ generation of azomethine ylide provides a straightforward and critically important sustainable approach for access to diverse pyrrolidine chemical space. Herein, we developed a metal-free AcOH-activated 1,3-dipolar cycloaddition protocol that permits the synthesis of uncommon pyrrolidine cycloadducts with excellent diastereoselectivity. The challenging substrates of 3-formylchromone, glycine ester.HCl and arylidene dipolarophile were reacted in the presence of AcONa, which played a dual role as a base and AcOH source, to deliver firstly endocycloadduct. Under prolonged reaction time at room temperature or heating; the endo-adduct underwent diastereodivergent via a sequence of retro-cycloaddition, stereomutation of the generated syndipole into anti-dipole and recycloaddition; to furnish the scarcely known exo′-cycloadduct with high diastereodivergency. The reaction worked well with a broad range of substrates and the stereochemistry of the obtained cycloadducts was determined without ambiguity using NMR- and X-ray analysis. Experimental and theoretical DFT calculation studies were performed to support the proposed reaction mechanism and elucidate the key role of AcOH in the process which seems more beneficial than other transition metal-catalyzed processes.
K. Kikushima, K. Yamada, N. Umekawa, N. Yoshio, Y. Kita, T. Dohi, Decarboxylative arylation with diaryliodonium(III) salts: Alternative approach for catalyst-free difluoroenolate coupling to aryldifluoromethyl ketones. Green Chem. 2023, 25(5), 1790-1796. (Green Chemistry themed collection on International Symposium on Green Chemistry 2022) DOI: 10.1039/D2GC04445E (selected as Cover Feature)


Catalyst‐free access to aryldifluoromethyl ketones has been achieved through decarboxylative arylation of α,α‐difluoro‐β‐ketoacid salts using diaryliodonium(III) salts. The products were successfully transformed into the corresponding esters, amides, and difluoromethyl compounds. This strategy provides access to fluorine‐containing drugs, thus contributing to drug design.
菊嶌孝太郎, 土肥寿文,「ジアリールヨードニウム塩を用いる求核剤のアリール化反応 ― リガンドによる反応性と選択性の制御 ―」有機合成化学協会誌 2023, 81(5), 463-473. (日本の誇るハロゲン資源:ハロゲンの反応と機能 特集号). https://doi.org/10.5059/yukigoseikyokaishi.81.463

Diaryliodonium(III) salts (Ar1Ar2I+X−) are hypervalent iodine(III) compounds that function as useful arylation agents forming aryl–carbon and aryl–heteroatom bonds with or without transition metal catalysts. The iodine(III) center of diaryliodonium salts has electrophilic properties, which induces the arylation reactions of nucleophiles. For the cases with Ar1≠Ar2 in diaryliodonium salts, the chemoselectivity of aryl-group transfers depends on the nature of the aryl ligands, including electronic and steric effects. This article describes ligand control strategy leading to unified aryl selectivity and enhanced reactivity for the arylation of various nucleophiles. Diaryliodonium(III) salts bearing trimethoxyphenyl (TMP) or mesityl (Mes) groups underwent the selective arylations, wherein TMP and Mes groups serve as “dummy ligand” to form aryl–carbon or aryl–heteroatom bonds with the other aryl groups. TMP-iodonium salts were employed for various types of arylation via single electron transfer process, metal-free ligand coupling, and metal-catalyzed coupling to afford the corresponding arylation products with unified selectivity. Furthermore, we found that TMP-iodonium acetates (Ar(TMP)I+AcO−) exhibit extremely high reactivities for metal-free arylation of phenols and hydroxylamines, wherein the interaction between the ortho-methoxy groups of TMP and the iodine(III) center presumably enhances the basicity of the acetate anion to cooperatively activate the nucleophiles. These effective metal-free arylations would provide practical methods for the synthesis of organic functional aromatic molecules.
Neena, V. Chaudhri, F. V. Singh, H. China, T. Dohi, R. Kumar, Synthetic utility of Vilsmeier-Haack reagent in organic synthesis. Synlett 2023, 34(7), 777-792. DOI: 10.1055/s-0042-1751421 (Special Issue: Chemical Synthesis and Catalysis in India)

The Vilsmeier-Hack reaction has historically been a topic of great interest to organic chemists, and it continues to attract considerable attention. The Vilsmeier-Hack reaction provides a facile entry into large numbers of aromatic and heteroaromatic systems. Vilsmeier reagents generated from amides and halides have been found to be very important in organic synthesis. This review highlights recent developments in synthetic utility of Vilsmeier-Haack reagent.

2022

K. Sakthivel, J. Subhiksha, A. Raju, R. Kumar, T. Dohi, F. V. Singh, Recent progress in hypervalent iodine-mediated fluorination of organic compounds. ARKIVOC 2022, vii, 138-165. https://doi.org/10.24820/ark.5550190.p011.996 (Prof. V. V. Zhdankin Hypervalent Iodine Special Issue)

Fluorine is an essential element for the protection of teeth and bones. Number of fluorinated drug molecules is available in the literature. Mainly, the addition of fluorine atom increases the lipophilicity of the drugs that makes it unique in the field of medicinal chemistry. In past two decades, hypervalent iodine chemistry has received a particular attention in organic synthesis mainly due to their mild reaction conditions and environmental friendly nature of hypervalent iodine reagents. Although their use is not just restricted to oxidation reactions, these reagents were primarily recognized for their oxidative properties. Due to their use in catalysis, the demand for these reagents has recently surged significantly for green chemistry. The hypervalent iodine reagents were also been used to achieve number of synthetically valuable organic transformations. Recently, hypervalent iodine reagents have been successfully employed to achieve various fluorination reactions. In this review recent development of fluorination of organic compounds using hypervalent iodine reagent are described.
T. Dohi, Editorial: Recent topics in iodine reagents and compounds in organic chemistry. Curr. Org. Chem. 2022, 26(21), 1915-1916. DOI: 10.2174/138527282621230123155131 (Special Issue Collections)

This Special Issue would cover the hot topics on recent synthetic interest in iodine reagents and related chemistry as well as the unique characteristics of hypervalent iodine compounds. The excellent reviews by the experts and eminent researchers engaged in the recent advances, i.e., preparations, reactions, and mechanistic studies of hypervalent iodine compounds, and their utilizations as reagents and organocatalysts in controlled reactions for synthesizing useful organic molecules, such as pharmaceutical compounds and organic materials, are provided in this Special Issue.
K. Kikushima, A. Morita, E. E. Elboray, T. Bae, N. Miyamoto, Y. Kita, T. Dohi, Transition-metal-free N-arylation of N-methoxysulfonamides and N,O-protected hydroxylamines with trimethoxyphenyliodonium(III) acetates. Synthesis 2022, 54(23), 5192-5202. DOI: 10.1055/a-1922-8846 (Feature Article) Organic Chemistry Portal

Trimethoxyphenyl (TMP) iodonium(III) acetate functionated 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.
K. Morimoto, K. Yanase, K. Toda, H. Takeuchi, T. Dohi, Y. Kita, Cyclic hypervalent iodine-induced oxidative phenol and aniline couplings with phenothiazines. Org. Lett. 2022, 24(32), 6088-6092. https://doi.org/10.1021/acs.orglett.2c02470

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 N-arylphenothiazines. Aniline amination proceeded efficiently at 20 °C, a previously unreported phenomenon.
T. Dohi, J.-W. Han, R. Kumar, Editorial: New hypervalent iodine reagents for oxidative coupling –Volume II. Front. Chem. 2022, 10:995702. (Special Topic Collections 2022) https://www.frontiersin.org/articles/10.3389/fchem.2022.995702/full

This collection of articles showcases different aspects of hypervalent iodine compounds towards achieving various valuable organic transformations. Irrespective of the fact that there are continuous expansions in this field, there are still many areas yet to be explored. By taking into account the advantages of hypervalent iodine-mediated oxidative coupling reactions, it seems certain that these reactions will be further utilized in the development of sustainable synthetic methods.
S. Soni, Rimi, V. Kumar, K. Kikushima, T. Dohi, V. V. Zhdankin, R. Kumar, Hypervalent iodine(V) catalyzed reactions. ARKIVOC 2022, vii, 27-56. DOI: https://doi.org/10.24820/ark.5550190.p011.800
(Prof. V. V. Zhdankin Hypervalent Iodine Special Issue)

The chemistry of hypervalent iodine compounds has been widely recognized in the synthetic community. The utilization of hypervalent iodine compounds as stoichiometric reagents as well as catalysts has tremendously been studied in recent decades. Hypervalent iodine(V)-catalyzed reactions are proven to be versatile catalytic systems to access various oxidative transformations. In this review, the versatility of hypervalent iodine(V)-catalyzed reactions have been discussed in detail. This review highlights the oxidation of various substrates using catalytic amounts of o-iodoxybenzoic acid (IBX), modified IBX derivatives, o-iodoxybenzenesulfonic acid (IBS), recyclable iodine(V), and non-cyclic/pseudocyclic iodine(V) compounds.
佐々裕隆, 土肥寿文,「高活性超原子価ヨウ素触媒および反応剤を用いる効率的芳香環アミノ化法の開発」月刊ファインケミカル (シーエムシー出版)51(8)、48-58. (2022年8月発行)

著者らは超原子価ヨウ素触媒および反応剤を用いることにより、芳香環C-N結合を形成し、効果的に芳香族アミドを合成する手法を開発した。本法により遷移金属が触媒する従来のC-N結合形成と同様の反応が、メタルフリーな条件下で達成された。本稿では著者らの反応開発の概要について記載した。
F. V. Singh, T. Dohi, R. Kumar, Editorial: Metal-free oxidative transformations in organic synthesis. Front. Chem. 2022, 10:956779 (Special Topic Collections 2021) doi: 10.3389/fchem.2022.956779

The tools of synthetic approaches must be continuously expanded and enriched to facilitate the sustainable production of chemicals. The development of processes with considerably superior environmental and industry-relevant credentials is one of the prime objectives for organic chemists. Most of the organic transformations, including C-C and C-X bond-forming cross-coupling reactions, and cross dehydrogenative-coupling reactions generally rely on the prerequisite of transition-metal catalysts and harmful organic solvents. Hence, there is a dire need of developing green synthetic strategies by avoiding the use of transition-metal catalysts and hazardous organic solvents. Metal-free oxidative transformations have emerged as an important alternative to metal catalysis in the past few decades. Even, in some cases, metal-free catalysis has more advantages over metal-catalyzed reactions, such as exceptional performance, better selectivity, recyclability, and higher substrate tolerance. This thematic issue includes research papers covering key aspects of metal-free transformations.
L. A. Segura-Quezada, K. R. Torres-Carbajal, K. A. Juárez-Ornelas, A. J. Alonso-Castro, R. Ortiz-Alvarado,T. Dohi, C. R. Solorio-Alvarado, Iodine(III) reagents for the oxidative aromatic halogenation. Org. Biomol. Chem. 2022, 20(25), 5009-5034. https://doi.org/10.1039/D2OB00741J (selected as Front Cover)

Iodine(III) reagents have covered relevance in organic synthesis by their use as safe, non-toxic, green and easy to handle reagents in different transformations. These characteristics make them important alternatives to procedures involving hazardous and harsh reaction conditions. Their versatility as oxidants has been exploited in the functionalization of different aromatic cores, which allow the introduction of several groups. The metal-free arylation using iodine(III) reagents is by far one of the most described topics in literature, however other highly relevant non-aromatic groups have been also introduced. Herein, we summarize the most representative developed procedures for the functionalization of aryls and heteroaryls by introducing to the halogens, using different iodine(III) reagents.
S. E. Shetgaonkar, R. Mamgain, K. Kikushima, T. Dohi, F. V. Singh, Palladium-catalyzed organic reactions involving hypervalent iodine reagents. Molecules 2022, 27(12), 3900-3960. (Special Issue: Applications of Palladium-Catalyzed in Organic Chemistry) https://doi.org/10.3390/molecules27123900

The chemistry of polyvalent iodine compounds has piqued the interest of researchers due to their role as important and flexible reagents in synthetic organic chemistry, resulting in a broad variety of useful organic molecules. These chemicals have potential uses in various functionalization procedures due to their non-toxic and environmentally friendly properties. Since they are also strong electrophiles and potent oxidizing agents, the use of hypervalent iodine reagents in palladium-catalyzed transformations have received a lot of attention in recent years. Extensive research has been conducted on the subject of C–H bond functionalization by Pd-catalysis with hypervalent iodine reagents as oxidants. Furthermore, iodine (III) reagent is now often used as an arylating agent in Pd-catalyzed C-H arylation or Heck-type cross-coupling processes. In this article, recent advances in palladium-catalyzed oxidative cross-coupling reactions employing hypervalent iodine reagents are reviewed in detail.
S. E. Shetgaonkar, A. Raju, H. China, N. Takenaga, T. Dohi, F. V. Singh, Non-palladium catalyzed oxidative coupling reactions using hypervalent iodine reagents. Front. Chem. 2022, 10, 909250. https://doi.org/10.3389/fchem.2022.909250 (Special Issue: New Hypervalent Iodine Reagents for Oxidative Coupling - Volume II)

Transition metal-catalyzed direct oxidative coupling reactions via C–H bond activation have emerged as a straightforward strategy for the construction of complex molecules in organic synthesis. The direct transformation of C–H bond into carbon–carbon and carbon-heteroatom bonds renders the requirement of prefunctionalization of starting materials and therefore represents a more efficient alternative to the traditional cross-coupling reactions. The key to the unprecedented progress made in this area has been the identification of appropriate oxidant that facilitates oxidation as well as provides heteroatom ligands at the metal centre. In this context, hypervalent iodine compounds have evolved as mainstream reagents particularly due to their excellent oxidizing nature, high electrophilicity and versatile reactivity. They are environmentally benign reagents, stable, non-toxic and relatively cheaper than inorganic oxidants. For many years, palladium catalysis has dominated these oxidative coupling reactions, but eventually other transition metal catalysts such as gold, copper, platinum, iron, etc. were found promising alternate catalysts for facilitating such reactions. This review article critically summarizes the recent developments in non-palladium-catalyzed oxidative coupling reactions mediated by hypervalent iodine(III) reagents with great emphasis on understanding the mechanistic aspects in details.
Rimi, S. Soni, B. Uttam, H. China, T. Dohi, V. V Zhdankin, R. Kumar, Recyclable hypervalent iodine reagents in modern organic synthesis. Synthesis 2022, 54(12), 2731-2748. DOI: 10.1055/s-0041-1737909

Hypervalent iodine (HVI) reagents have gained much attention as versatile oxidants because of their low toxicity, mild reactivity, easy handling, and availability. Despite their unique reactivity and other advantageous properties, stoichiometric HVI reagents are associated with the disadvantage of generating non-recyclable iodoarenes as waste/coproducts. To overcome these drawbacks, the synthesis and utilization of various recyclable hypervalent iodine reagents have been established in recent years. This review summarizes the development of various recyclable non-polymeric, polymer-supported, ionic-liquid-supported, and MOF-hybridized HVI reagents.
K. Kikushima, E. E. Elboray, J. O. C. Jiménez-Halla, C. R. Solorio-Alvarado, T. Dohi, Diaryliodonium(III) salts in one-pot double functionalization of C–I(III) and ortho C–H bonds. Org. Biomol. Chem. 2022, 20(16), 3231-3248. DOI: 10.1039/D1OB02501E (selected as Front Cover)

Since the 1950s, diaryliodonium(III) salts have been demonstrated to participate in various arylation reactions, forming aryl–heteroatom and aryl–carbon bonds. Incorporating the arylation step into sequential transformations would provide access to complex molecules in short steps. This focus review summarizes the double functionalization of carbon–iodine(III) and ortho carbon–hydrogen bonds using diaryliodonium(III) salts. This involves arylation/intramolecular rearrangement, arylation followed by electrophilic aromatic substitution, three-component [2 + 2 + 2] cascade annulation, sequential metalcatalyzed arylations, and double functionalization via aryne formation.
N. Takenaga, Y. Yoto, T. Hayashi, N. Miyamoto, H. Nojiri, R. Kumar, T. Dohi, Catalytic and non-catalytic selective aryl transfer from mesityliodonium(III) salts to diarylsulfide compounds. ARKIVOC 2022, vii, 7-18. DOI: https://doi.org/10.24820/ark.5550190.p011.732 (Prof. V. V. Zhdankin Hypervalent Iodine Special Issue)

We report a facile synthesis of triarylsulfonium triflates by selective aryl transfer from readily available mesityl iodonium(III) salts to diarylsulfides in the presence of a copper catalyst. The advantage of our protocol is that the iodonium(III) salts bearing a mesitylene (Mes) auxiliary efficiently promote selective S-arylation of diarylsulfides to produce the desired triarylsulfonium triflates without the formation of Mes-derived byproduct salts.
K. Kikushima, N. Miyamoto, K. Watanabe, D. Koseki, Y. Kita, T. Dohi, Ligand- and counterion-assisted phenol O-arylation with TMP-iodonium(III) acetates. Org. Lett. 2022, 24(10), 1924-1928. https://doi.org/10.1021/acs.orglett.2c00294 (selected as Cover Feature) EurekAlert! 大学HP
Organic Chemistry Portal

The high reactivity of trimethoxyphenyl (TMP)-iodonium(III) acetate for phenol O-arylation was achieved. It was first determined that the TMP ligand and acetate anion cooperatively enhance the electrophilic reactivity toward phenol oxygens. The proposed method provides access to various diaryl ethers in significantly higher yields than the previously reported techniques. Various functional groups, including aliphatic alcohol, boronic ester, and sterically hindered groups, were tolerated during O-arylation, verifying the applicability of this ligand- and counterion-assisted strategy.
R. Kumar, F. V. Singh, N. Takenaga, T. Dohi, Asymmetric direct/stepwise dearomatization reactions involving hypervalent iodine reagents. Chem.-Asian J. 2022, 17(4), e202101115(1)-e202101115(20).
DOI: https://doi.org/10.1002/asia.202101115
(selected as Cover Feature and Frontispiece)



A remarkable growth in hypervalent iodine-mediated oxidative transformations as stoichiometric reagents as well as catalysts have been well-documented due to their excellent properties, such as, mildness, easy handling, high selectivity, environmentally friendly nature, and high stability. This review aims at highlighting the asymmetric oxidative dearomatization reactions involving hypervalent iodine compounds. The present article summarizes asymmetric intra- and intermolecular dearomatization reactions using chiral hypervalent iodine reagents/catalysts as well as hypervalent iodine-mediated dearomatization reactions followed by desymmetrization.
H. Sasa, K. Mori, K. Kikushima, Y. Kita, T. Dohi, μ-Oxo hypervalent iodine-catalyzed oxidative C-H amination for synthesis of benzolactam derivatives. Chem. Pharm. Bull. 2022, 70(2), 106-110. DOI: https://doi.org/10.1248/cpb.c21-00980

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.
H. China, T. Dohi, R. Kumar, Comprehensive Chemistry for Electrochemical Enzyme Biosensors. Multifaceted Bio-sensing Technology (Editors:Smita S Kumar, Lakhveer Singh, Durga Madhab Mahapatra), Elsevier (2022)

In 1956, Clark's invention of the "oxygen electrode" provided an important impetus for the development of biosensors. Herein, we focus on enzyme sensors, which mark the origin of biosensors. They are widely used in various fields, including food science, environmental science, and medicine. Enzyme sensors for various molecules, such as sugars (e.g., glucose, sucrose, lactose, galactose, and fructose), amino acids (e.g., glutamate, glutamine, and lysine), alcohols (e.g., ethanol, methanol, and glycerol), lactate, ascorbate, choline, acetylcholine, and xanthine, are commercially available.
T. Dohi, Y. Kita, Catalytic and Asymmetric Dearomatization Reactions Employing Hypervalent Iodine Reagents. Iodine Catalysis in Organic Synthesis (Editors:Kazuaki Ishihara and Kilian Muniz), John Wiley & Sons Ltd (2022)


Recently, hypervalent iodine reagents have been extensively employed in organic syntheses. A variety of reactions employing phenyliodine(III) diacetate (PIDA), phenyliodine(III) bis(trifluoroacetate) (PIFA), and other iodine(III) and (V) reagents are available for the syntheses of natural products. These reactions can be applied to pharmaceutical and agrochemical processes owing to their favorable characteristics, mild reaction conditions, and high yields of pure products. Here, the history and recent investigations of these hypervalent iodine reagents in asymmetric dearomative couplings of phenols, especially the catalytic reactions involving specific chiral hypervalent iodine(III) species, are introduced.

2021

T. Kamitanaka, Y. Tsunoda, Y. Fujita, T. Dohi, Y. Kita, [3+2] Coupling of quinone monoacetals with vinyl ethers effected by tetrabutylammonium triflate: Regiocontrolled synthesis of 2-oxygenated dihydrobenzofurans. Org. Lett. 2021, 23(23), 9025-9029. DOI: https://doi.org/10.1021/acs.orglett.1c02792 (selected as Inside Cover)

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.
T. Shoji, K. Fukushima, T. Menjo, Y. Yamada, T. Hanasaki, K. Kikushima, N. Takenaga, T. Dohi, Triflimide-promoted nucleophilic C-arylation of halopurines to access N7-substituted purine biaryls. Chem. Pharm. Bull. 2021, 69(9), 886-891. DOI: https://doi.org/10.1248/cpb.c21-00380

Functionalized nucleobases are utilized in a wide range of fields; therefore, the development of new synthesis methods is essential for their continued application. With respect to the C6-arylation of halopurines, which possess a substituent at the N7-position, only a small number of successful cases have been reported, which is predominately a result of large steric hinderance effects. Herein, we report efficient and metal-free C6-arylations and SNAr reactions of N7-substituted chloropurines in aromatic and heteroatom nucleophiles promoted by triflimide (Tf2NH) in fluoroalcohol.
H. China, N. Kageyama, H. Yatabe, N. Takenaga, T. Dohi, Practical synthesis of 2-iodosobenzoic acid (IBA) without contamination by hazardous 2-iodoxybenzoic acid (IBX) under mild conditions. Molecules 2021, 26(7), 1897-1914. (Special Issue: Exclusive Papers of the Editorial Board Members of the Organic Chemistry Section of Molecules) DOI: https://doi.org/10.3390/molecules26071897

We report a convenient and practical method for the preparation of nonexplosive cyclic hypervalent iodine(III) oxidants as efficient organocatalysts and reagents for various reactions using Oxone® in aqueous solution under mild conditions at room temperature. The thus obtained 2-iodosobenzoic acids (IBAs) could be used as precursors of other cyclic organoiodine(III) derivatives by the solvolytic derivatization of the hydroxy group under mild conditions of 80 °C or lower temperature. These sequential procedures are highly reliable to selectively afford cyclic hypervalent iodine compounds in excellent yields without contamination by hazardous pentavalent iodine(III) compound.
N. Ohtaguro, H. Matsuo, K. Iwasaki, S. Ueda, K. Nakagawa, T. Tsuchiya, N. Imamura, T. Dohi, Y. Yamada, S. Shiota, Isolation and identification of a compound showing anti-staphylococcal activity. 就実薬学雑誌 2021, 8, 70-74.

Staphylococci are one of the major causes of bloodstream infections via medical devices. The development of new anti-Staphylococcal drugs is urgently needed. We isolated tryptanthrin from a traditional Japanese dye sukumo made from fermented Polygonum tinctorium. The minimum inhibitory concentration against gram-positive and gram-negative bacteria were measured. It showed anti-Staphylococcal activity against Staphylococcus aureus, S. epidermidis, S. saprophyticus and S. warneri.
K. Kikushima, H. Koyama, K. Kodama, T. Dohi, Nucleophilic aromatic substitution of polyfluoroarene to access highly functionalized 10-phenylphenothiazine derivatives. Molecules 2021, 26(5), 1365-1378. (Special Issue: 25th Anniversary of Molecules - Recent Advances in Organic Synthesis) DOI: https://doi.org/10.3390/molecules2605136510.3390/molecules25246007 (Preprints 2021, 2021020563. DOI: 10.20944/preprints202102.0563.v1)

Nucleophilic aromatic substitution (SNAr) reactions can provide metal‐free access to synthesize mono‐substituted aromatic compounds. We have developed efficient SNAr conditions for p‐selective substitution of polyfluoroarenes with phenothiazine in the presence of a mild base to afford the corresponding 10‐phenylphenothiazine (PTH) derivatives. The resulting polyfluoroarene‐bearing PTH derivatives were subjected to a second SNAr reaction to generate highly functionalized PTH derivatives with potential applicability as photocatalysts for the reduction of carbon–halogen bonds.
T. Dohi, Prefece to HETEROCYCLES issue honoring the 77th birthday of Professor Dr. Yasuyuki Kita. Heterocycles 2021, 103(1), 11-14. (Prof. Kita's Special Issue) DOI: 10.3987/COM-20-S(K)Foreword_3

Professor Yasuyuki Kita, an Emeritus Professor in Osaka University and currently an Invited Research Professor and Director of the Research Center for Drug Discovery and Pharmaceutical Development Science of Ritsumeikan University, has turned 76 years on March 2, 2021. It is my great pleasure and honor to celebrate his Kiju by contributing to this special issue of Heterocycles.
K. Kikushima, K. Matsuki, Y. Yoneda, T. Menjo, K. Kaneko, T. Hanasaki, T. Dohi, Polyfluoroarene-capped thiophene derivatives via fluoride-catalyzed nucleophilic aromatic substitution. Heterocycles 2021, 103(2), 878-892. (Prof. Kita's Special Issue) DOI: 10.3987/COM-20-S(K)54

Arylthiophene derivatives are potential components of functional materials, including organic electronics. Herein, we describe a nucleophilic aromatic substitution reaction of polyfluoroarenes using silylthiophenes as nucleophiles in the presence of a catalytic amount of a fluoride salt. Various polyfluoroarene-capped thiophene derivatives were synthesized via double arylation under transition metal-free conditions. A fluoride ion activates a silylthiophene to trigger a nucleophilic aromatic substitution, subsequently affording the coupling product along with elimination of the fluoride ion, which serves as a promoter of the catalytic reaction.
N. Takenaga, H. China, R. Kumar, T. Dohi, Azido, cyano, nitrato cyclic hypervalent iodine(III) reagents in heterocycle synthesis. Heterocycles 2021, 103(1), 144-164. (Prof. Kita's Special Issue) DOI: 10.3987/REV-20-SR(K)5

In recent years, synthetic applications of cyclic hypervalent iodine reagents have undergone significant developments. Among them, benziodoxol(on)es containing azido, cyano, and nitrato ligands have been found to be useful synthetic tools for the preparation of functionalized heterocyclic compounds. This review aims to summarize recent synthetic applications of benziodoxol(on)es as effective heteroatom-introducing reagents.
K. Kikushima, R. Kumar, T. Dohi, Progress in [18F]fluorination by using aryliodonium(III) compounds and application for PET tracer syntheses. Mini Rev. Org. Chem. 2021, 18(2), 173-195. (Special Issue: Hypervalent Iodine in Organic Synthesis) DOI: 10.2174/1570193X17999200629155733 (Editor's Choice Artcle)

[18F]-labeled drugs and radioligands are most frequently used in positron-emission tomography (PET) radiopharmaceuticals for both clinical and preclinical research. Various methods for the introduction of [18F] into complex molecules through fluorination reactions have been reported. Herein, recent advances in [18F]-fluorination utilizing aryliodonium(III) compounds are highlighted.
R. Kumar, T. Dohi, Editorial: Special Issue on hypervalent iodine reagents in organic synthesis. Mini Rev. Org. Chem. 2021, 18(2), 136-137 (Special Issue Collections) DOI: 10.2174/1570193X1802210210122955

Hypervalent iodine compounds formally feature expanded valence shells at iodine. These reagents are broadly used in synthetic chemistry due to the ability to participate in well‐defined oxidation–reduction processes and because the ligand‐exchange chemistry intrinsic to the hypervalent center allows hypervalent iodine compounds to be applied to a broad array of oxidative substrate functionalization reactions. The current Research Topic is to cover the recent advances in the oxidative coupling using hypervalent iodine reagents. Areas to be covered in this Research Topic may include, but are not limited to: Photochemical Transformations, Rearrangements, Heterocyclic Synthesis, Fluorination Reactions and theoretical and computational aspects related to the these reagents.
T. Dohi, J.-W. Han, R. Kumar, Editorial: New hypervalent iodine reagents for oxidative coupling. Front. Chem. 2021, 9:642889 (Special Topic Collections) DOI: 10.3389/fchem.2021.642889

One of the innovative research fronts in hypervalent iodine chemistry, that has appeared in the past decade, is the advance of the oxidative coupling. This Research Topic collections is to cover the recent advances of oxidative couplings using hypervalent iodine reagents and related reactions, guiding the versatility of these reagents and their continuous development.

2020

H. China, K. Kikushima, R. Kumar, T. Dohi, Halogen-induced controllable cyclizations as diverse heterocycle synthetic strategy. Molecules 2020, 25(24), 6007-6040. (Special Issue: Halogen-controlled synthesis of useful organic molecules) DOI: 10.3390/molecules25246007 (Preprints 2020, 2020120295. DOI: 110.20944/preprints202012.0295.v1)

In organic synthesis, due to their high electrophilicity and leaving group properties, halogens play pivotal roles in the activation and structural derivations of organic compounds. Recently, cyclizations induced by halogen groups that allow the production of diverse targets and the structural reorganization of organic molecules have attracted significant attention from synthetic chemists. Electrophilic halogen atoms activate unsaturated and saturated hydrocarbon moieties via the generation of halonium intermediates, followed by the attack of carbon-, nitrogen-, oxygen-, and sulfur-containing nucleophiles to give highly functionalized carbo- and heterocycles. Interestingly, new transformations of halogenated organic molecules that can control the formation and stereoselectivity of the products according to the difference in the size and number of halogen atoms have recently been discovered. These unique cyclizations may possibly be used as efficient synthetic strategies with future advances. In this review, innovative reactions controlled by halogen groups are discussed as a new concept in the field of organic synthesis.
N. Takenaga, R. Kumar, T. Dohi, Heteroaryliodonium(III) salts as highly reactive electrophiles. Front. Chem. 2020, 8, 599026. (Special Issue: New Hypervalent Iodine Reagents for Oxidative Coupling) DOI: 10.3389/fchem.2020.599026

In recent years, the chemistry of heteroaryliodonium(III) salts has undergone significant developments. Heteroaryliodonium(III) salts have been found to be useful synthetic tools for the transfer of heteroaryl groups under metal-catalyzed and metal-free conditions for the preparation of functionalized heteroarene-containing compounds. Synthetic transformations mediated by these heteroaryliodonium(III) salts are classified into two categories: (i) reactions utilizing the high reactivity of the hypervalent iodine(III) species, and (ii) reactions based on unique and new reactivities not observed in other types of conventional diaryliodonium salts. The latter feature is of particular interest, and so has been intensively investigated in recent decades. This mini-review therefore aims to summarize the recent synthetic applications of heteroaryliodonium(III) salts as highly reactive electrophiles.
T. Dohi, Editorial: Recent topics in organohalogen reagents and compounds. Curr. Org. Chem. 2020, 24(18), 2029-2030. (Special Issue Collections)
DOI: 10.2174/138527282418201106141610

This Special Issue covers the hot topics on recent synthetic interest in halogen and related chemistry as well as the unique characteristics of halogen compounds. The excellent reviews by the experts and eminent researchers engaged in the recent advances, i.e., preparations, reactions, and mechanistic studies of unique organohalogen compounds, halogen bond interaction as the catalysis, and halogen-controlled unique reactions for synthesizing useful organic molecules, such as pharmaceutical compounds and organic materials, are provided in this Special Issue.
K. Komiyama, S. Kobayashi, T. Shoji, K. Kikshima, T. Dohi, Y. Kita, Practical synthesis of diaryliodonium(III) triflates using ArI(OAc)2/TfOH/CH3CN reaction system. Russ. Chem. Bull. 2020, 69(12), 2328—2332. (150th Mendeleev Special Issue) DOI: https://doi.org/10.1007/s11172-020-3035-9

Diaryliodonium(III) triflates were synthesized in a safe manner using aryliodine(III) diacetates (ArI(OAc)2) with triflic acid (TfOH) in acetonitrile (ACN) under mild exothermic conditions. This method provides access to a variety of diaryliodonium(III) triflates with high purity by direct condensation of the hypervalent iodine reagent with an equimolar amount of a nucleophilic aromatic compound.
H. China, H. Yatabe, N. Kageyama, M. Fujitake, K. Kikushima, T. Dohi, New syntheses of haloketo acid methyl esters and their transformation to halolactones by reductive cyclizations. Russ. Chem. Bull. 2020, 69(9), 1804-1810. (150th Mendeleev Special Issue) https://doi.org/10.1007/s11172-020-2965-6

A new method for haloketo acid methyl ester synthesis is reported on the basis of the ring-opening of cyclic α,β-unsaturated ketones followed by halogenation under mild conditions. Di- and tri-haloketo acid methyl esters are conveniently synthesized via the hydrolytic ring-opening reaction through this method. Halolactones can be readily obtained from these haloketo acid methyl esters by reductive cyclization employing NaBH4 and trifluoroacetic acid. Derivatizations of this obtained halolactone utilizing the exo-halomethylene moiety were also demonstrated.
H. China, K. Tanihara, H. Sasa, K. Kikushima, T. Dohi, Regiodivergent oxygenations of alkoxyarenes by new hypervalent iodine/Oxone system. Catal. Today 2020, 348, 2-8. (Special Issue for Invited Contributors in 1st International Conference on Applied Catalysis & Chemical Engineering) DOI: org/10.1016/j.cattod.2019.08.060

We have found that the combination of Oxone® with an organoiodine compound, i.e., 2-iodobenzoic acid (2-IB), selectively yields p-quinones from monomethoxyarenes under mild conditions. In this reaction system, an organoiodine compound is immediately oxidized by Oxone® to generate cyclic hypervalent iodine (III) species in situ, which serves as the specific mediator for the selective p-quinone synthesis, preventing o-quinone formation.
T. Dohi, K. Komiyama, S. Ueda, N. Yamaoka, M. Ito, Y. Kita, Benzylic oxidation and functionalizations of xanthenes by ligand trasfer reactions of hypervalent iodine reagents. Heterocycles 2019, 100(1), 85-103 (100th Memorial Special Issue). DOI: 10.3987/COM-19-14139

The benzylic oxidation, amidation, and unprecedented heteroarylation proceed at room temperature using iodosobenzene, (sulfonylimido)iodobenzenes, and diaryliodonium(III) salts are described for the direct Csp3-H functionalizations of xanthene molecules. This study has demonstrated that hypervalent iodine reagents serve as unified synthetic tools for versatile xanthene Csp3-H transformations based on the radical and SET oxidation processes.

2019

K. Kikushima, H. China, T. Dohi, Asymmetric construction of heterocycles via dearomative coupling and addition reactions of phenol and aniline derivatives. Heterocycles 2019, 98(12), 1489-1511. (Invited Review) DOI: 10.3987/REV-19-916

Efficient methods for the formation of chiral heterocycles are considerably important in the synthesis of naturally-occurring compounds and pharmaceutical products. This review highlights the formation of chiral heterocycles through dearomative bond-formations as the key reactions, wherein the phenol or aniline derivatives serve as the nucleophiles. Transition-metal-catalyzed intramolecular coupling reactions in the presence of chiral ligands afford the enantioenriched multicyclic compounds bearing heterocycles. Chiral bifunctional organocatalysts induce the formation of dearomative coupling products, which could be converted to heterocycles through further transformations.
N. Takenaga, T. Shoji, T. Menjo, A. Hirai, S. Ueda, K. Kikushima, T. Hanasaki, T. Dohi, Nucleophilic arylation of halopurines facilitated by Bronsted acid in fluoroalcohol. Molecules 2019, 24(21), 3812-3821 (Modern Strategies for Heterocycle Synthesis). DOI: 10.3390/molecules24213812

Various aryl-substituted purine derivatives were synthesized through the direct arylation of halopurines with aromatic compounds, facilitated by the combination of triflic acid and fluoroalcohol. This metal-free method is complementary to conventional coupling reactions using metal catalysts and reagents for the syntheses of aryl-substituted purine analogues.
T. Dohi, K. Morimoto, Y. Kita, 高リサイクル型ならびに高活性超原子価ヨウ素反応剤の開発 ChemGrowing 2019, 7, 2-5. https://labchem-wako.fujifilm.com/jp/melmaga/019779.html

ヨウ素反応剤は基質や触媒を酸化した後に、1価のヨードベンゼンとなる。近年では精密化学製品の合成に高純度が要求され、この副生するヨードベンゼンの除去が実用化への問題となる。また、有機ヨウ素化合物を等量用いることは工業的な利用には大きな制約があるので、回収・再利用可能なリサイクル型反応剤の開発や遷移金属のような高活性な触媒の開発が重要である。
T. Dohi, T. Hayashi, S. Ueda, T. Shoji, K. Komiyama, H. Takeuchi, Y. Kita, Recyclable synthesis of mesityl iodonium(III) salts. Tetrahedron 2019, 75, 3617-3627. DOI: org/10.1016/j.tet.2019.05.033

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.
T. Moriuchi, K. Kikushima, ハロゲン化物塩をハロゲン源とする酸化的ハロゲン化反応 有機合成化学協会誌 2019, 77, 227-235. https://doi.org/10.5059/yukigoseikyokaishi.77.227

The bromination reaction of organic compounds is one of the important reactions in organic synthesis, providing bromination products which are key precursors for various transformations. Conventional bromination reaction is carried out using toxic and hazardous elemental bromine. Oxidative bromination reaction by utilization of a bromide ion as a bromide source instead of bromine has attracted a great deal of attention to develop environmentally friendly bromination method. In this account, catalytic oxidative halogenation and aromatization by using halide salt as a halide source are described. An environmentally benign catalytic oxidative bromination reaction was demonstrated by the combination of the redox properties of a commercially available inexpensive vanadium compound and molecular oxygen as a terminal oxidant, wherein vanadium-catalyzed oxidative bromination was promoted by Brønsted acid or Lewis acid. The catalytic chlorination reaction of ketones and alkenes was achieved by using a vanadium catalyst in the presence of Bu4NI and AlCl3 under molecular oxygen. The vanadium-catalyzed oxidation system, which consists of a vanadium catalyst, a bromide source, and an acid under molecular oxygen, could be applied to the catalytic oxidative aromatization of 2-cyclohexen-1-ones, affording the corresponding phenol derivatives. Metal-free oxidative bromination reactions was also performed in aqueous media under mild conditions with a combination of tetrabutylammonium bromide as a bromide source, trifluoroacetic acid as an acid, and hydrogen peroxide as an oxidant.
H. China, D. Koseki, K. Samura, K. Kikushima, Y. In, T. Dohi, Dataset on synthesis and crystallographic structure of phenyl(TMP)iodonium(III) acetate. Data Brief 2019, 25, 104063. DOI: org/10.1016/j.dib.2019.104063

The data in this article are related to research article ‘‘Efficient N-arylation of azole compounds utilizing selective aryl-transfer TMP-iodonium (III) reagents (Koseki et al., 2019). For the title compound, phenyl(2,4,6-trimethoxyphenyl)iodonium(III) acetate (Ph(TMP)IOAc), the single-crystal X-ray diffraction measurement together with NMR analysis, like also the method of synthesis and crystallization are presented. The X-ray structure analysis has revealed that the two types of geometries regarding the acetate anion attached to phenyl (TMP)iodonium (III) cation are found in the crystal states.
N. Takenaga, T. Hayashi, S. Ueda, H. Satake, Y. Yamada, T. Kodama, T. Dohi, Synthesis of uracil-iodonium(III) salts for practical utilization as nucleobase synthetic modules. Molecules 2019, 24(17), 3034.(Advances in the Chemistry of Hypervalent Iodine Compounds) DOI: 10.3390/molecules24173034

Iodonium(III) salts bearing uracil moieties have recently appeared in the literature, but their structural scope and utilization are limited because of their hygroscopic characteristics. In this study, we describe our detailed investigations for synthesizing a series of uracil iodonium(III) salts derived with various structural motifs and counterions. These new compounds have been utilized as attractive synthetic modules in constructing functionalized nucleobase and nucleosides.
T. Kamitanaka, K. Morimoto, T. Dohi, Y. Kita, Controlled-coupling of quinone monoacetals by new activation methods: Regioselective synthesis of phenol-derived compounds. Synlett 2019, 30, 1125-1143. (Invited Review) DOI: 10.1055/s-0037-1611735

We have studied for a long time the reaction of quinone acetal type compounds, such as quinone monoacetals, quinone O,S-acetals, and iminoquinone monoacetals, and have reported the regioselective introduction of various nucleophiles. Quinone monoacetals show various types of reactivities toward nucleophiles due to their unique structures. In this study, we found that aromatic and alkene nucleophiles can be regioselectively introduced into the α-position of the carbonyl group on quinone monoacetals by specific activation of the acetal moiety. These reactions enabled the metal-free synthesis of highly functionalized aromatic compounds by the regioselective introduction of nucleophiles. In this account, we describe our recent studies of the coupling of quinone monoacetals.
N. Takenaga, S. Ueda, T. Hayashi, T. Dohi, S. Kitagaki, Vicinal functionalization of uracil heterocycles with base activation of iodonium(III) salts. Heterocycles 2019, 99, 865-874. (Tohru Fukuyama’s Special Issue) DOI: 10.3987/COM-18-S(F)93

We describe a new approach for the construction of bicyclic uracil systems and vicinal functionalization by utilizing uracil-iodonium(III) salts. Our method efficiently furnishes various multi-functionalized uracil derivatives in a single step.
D. Koseki, E. Aoto, T. Shoji, K. Watanabe, Y. In, Y. Kita, T. Dohi, Efficient N-arylation of azole compounds utilizing selective aryl-transfer TMP-iodonium(III) reagents. Tetrahedron Lett. 2019, 60, 1281-1286. DOI: org/10.1016/j.tetlet.2019.04.012

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.
T. Dohi, H. Sasa, M. Dochi, C. Yasui, Y. Kita, Oxidative Coupling of N-Methoxyamides and Related Compounds toward Aromatic Hydrocarbons by Designer μ-Oxo Hypervalent Iodine Catalyst. Synthesis 2019, 51, 1185-1195. (50th Anniversary Golden SYNTHESIS Special Issue) DOI: 10.1055/s-0037-1611661

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.

2018

T. Dohi, Y. Kita, Oxidative C-C Bond Formation (Couplings, Cyclizations, Cyclopropanation, etc.). PATAI'S Chemsitry of Functional Groups (Hypervalent Halogen Compounds) John Wiley & Sons Ltd (2018) https://onlinelibrary.wiley.com/doi/abs/10.1002/9780470682531.pat0952
Oxidative coupling that can directly convert C-H group for chemical transformations is, in theory, an ideal strategy in organic synthesis as it reduces the number of synthetic steps and possible by‐products. Hypervalent iodine reagent has become one of the most promising tools in developing oxidative coupling due to its unique reactivity similar to metal oxidants. We have pioneered the metal‐free oxidative coupling chemistry using the hypervalent iodine reagents, that is, phenyliodine(III) diacetate (PIDA, PhI(OAc)2) and bis(trifluoroacetate) (PIFA), in the past decades. As an introduction, we briefly mention the research backgrounds regarding the establishment of their fundamental reactivities with representative achievements in this area.
N. Takenaga, S. Ueda, T. Hayashi, T. Dohi, S. Kitagaki, Facile Synthesis of Stable Uracil-Iodonium(III) Salts with Various Counterions. Heterocycles 2018, 97(2), 1248-1256. (Kiyoshi Tomioka's Special Issue) DOI: 10.3987/COM-18-S(T)80
Aryliodonium(III) salts, one of the useful and important classes of hypervalent iodine compounds, have a wide range of applicability, i.e., photoacid generator, active bactericides, and coupling agents for reacting a wide range of nucleophiles even under metal-free conditions. In this report, we present an approach to the design of stable uracil-iodonium(III) salts with various counterions. Uracil is an important substructure that exists in many biologically active compounds and the introduction of such a moiety in iodonium(III) salts would be of high utility in organic chemistry.
K. Morimoto, T. Kamitanaka, T. Dohi, Y. Kita, Metal-free Oxidative Cross-Coupling of Pyrroles with Electron-Rich Arenes Using Recyclable Hypervalent Iodine(III) Reagent. Heterocycles 2018, 97(1), 632-645. (Kiyoshi Tomioka's Special Issue) DOI: 10.3987/COM-18-S(T)52
The facile and clean oxidative cross-coupling reaction of pyrroles has been developed using the recyclable hypervalent iodine(III) reagents having an adamantane core. The recyclable iodine(III) reagent could be recovered from the reaction mixtures as the corresponding reduced forms, i.e., the tetraiodide 2, by a simple solid-liquid separation. By re-oxidizing the recovered 2 to the initial reagent 1a using m-chloroperbenzoic acid (mCPBA), the reagent 1a can be reused.
T. Dohi, S. Ueda, K. Iwasaki, Y. Tsunoda, K. Morimoto, Y. Kita, Selective carboxylation of reactive benzylic C-H bonds by a hypervalent iodine(III)/inorganic bromide oxidation system. Beilstein J. Org. Chem. 2018, 14, 1087-1094. DOI: 10.3762/bjoc.14.94
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.

2017

T. Dohi, H. Sasa, K. Miyazaki, M. Fujitake, N. Takenaga, Y. Kita, Chiral Atropisomeric 8,8’-Diiodobinaphthalene for Asymmetric Dearomatizing Spirolactonizations in Hypervalent Iodine Oxidations. J. Org. Chem. 2017, 82(22), 11954-11960. DOI: 10.1021/acs.joc.7b02037

A new type of binaphthyl-based chiral iodide functionalized at the 8,8’-positions of the naphthalene rings has been found as a promising structural motif for the asymmetric hypervalent iodine(III) oxidations, specifically, for dearomatizing the 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.
T. Dohi, D. Koseki, K. Sumida, K. Okada, S. Mizuno, A. Kato, K. Morimoto, Y. Kita, Metal-Free O-Arylation of Carboxylic Acid by Active Diaryliodonium(III) Intermediates Generated in situ from Iodosoarenes. Adv. Synth. Catal. 2017, 359, 3503-3508. DOI: 10.1002/adsc.201700843

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.
M. Ogasawara, H. Sasa, H. Hu, Y. Amano, H. Nakajima, N. Takenaga, K. Nakajima, Y. Kita, T. Takahashi, T. Dohi, Atropisomeric chiral diiododiene (Z,Z)-2,3-di(1-iodoalkylidene)tetralin: Synthesis, enantiomeric resolution, and application in asymmetric catalysis. Org. Lett. 2017, 19 (15), 4102–4105. DOI: 10.1021/acs.orglett.7b01876

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 performance in up to 73% ee.
K. Morimoto, D. Koseki, T. Dohi, Y. Kita, Oxidative biaryl coupling of N-aryl anilines using hypervalent iodine(III) reagent. Synlett 2017, 28(20), 2941-2945. DOI: 10.1055/s-0036-1590875

The biaryl diamines are important building blocks in organic synthesis. Thus, it is desirable to develop a general and mild synthetic approach to diverse biaryl diamines. The oxidative coupling is an efficient and promising strategy to synthesize these targets. We have now developed the direct formations of biaryl diamines by an oxidative coupling using the hypervalent(III) iodine reagent.
K. Morimoto, T. Dohi, Y. Kita, Metal-free Oxidative Cross-Coupling Reaction of Aromatic Compounds Containing Heteroatoms. Synlett 2017, 28, 1680-1694. DOI: 10.1055/s-0036-1588455

The biaryl unit containing a heteroatom is a key structure in a large number of natural products and π-conjugated organic systems. The cross-couplings can provide powerful methods for the construction of biaryls and heterobiaryls; thus the development of a new coupling method has been intensively studied by synthetic chemists. Therefore, the oxidative biaryl coupling reaction of arenes containing a heteroatom is a significantly attractive, convenient, and straightforward route to the synthesis of biaryls due to its operational simplicity avoiding the preparation of the corresponding halogenated and metallated arenes. In this report, recent progress in the field of metal-free oxidative cross-coupling reactions of aromatic compounds using hypervalent iodine(III) reagents, is presented.
T. Dohi, S. Ueda, A. Hirai, Y. Kojima, K. Morimoto, Y. Kita, Selective aryl radical transfers into N-heteroaromatics from diaryliodonoium salts with trimethoxybenzene auxiliary. Heterocycles 2017, 95, 1272-1284. (Masakatsu Shibasaki Special Issue) DOI: 10.3987/COM-16-S(S)90

We have found that a series of trimethoxybenzene-based diaryl- iodonium(III) salts I (ArI+Ar’X-, where Ar = various aryl groups, Ar’ = 2,4,6- trimethoxyphenyl, X- = counterion) can exclusively cause Ar-transfers during the base-induced radical couplings with N-heteroaromatic compounds 1 by working the trimethoxybenzene ring (Ar’) as an inert coupling auxiliary. By the treatment with N-heteroaromatics 1 as the solvent, the ​metal-free arylations utilizing the specific salts I initiated by solid NaOH upon heating selectively produced the corresponding biaryls 2 in good yields without the formation of the trimethoxy- benzene (Ar’) coupling product.

2016

T. Kamitanaka, H. Takamuro, K. Shimizu, Y. Aramaki, T. Dohi, Y. Kita, New synthesis of tetrahydrobenzodifurans by interative coupling of quinone monoacetals and alkene nucleophiles. Heterocycles 2016, 93, 295-309. (Lutz F. Tietze Special Issue) DOI: 10.3987/COM-15-S(T)41

A new efficient synthetic strategy of tetrahydrobenzodifurans has been developed by the repetitive [3+2] couplings of quinone monoacetals with alkene nucleophiles. Both the symmetrical and unsymmetrical tetrahydrobenzodifurans can be easily synthesized by this continuous method by altering the type of alkenes. These tetrahydrobenzodifurans have also become a useful precursor of highly-substituted benzofurans by dehydrogenation.
T. Kamitanaka, K. Morimoto, K. Tsuboshima, D. Koseki, T. Dohi, Y. Kita, Efficient Coupling Reaction of Quinone Monoacetal with Phenols Leading to Phenol Biaryls. Angew. Chem., Int. Ed. 2016, 55, 15535-15538.DOI: 10.1002/anie.201608013
Reported is the efficient synthesis of unsymmetrical phenol biaryls by MeSO3H-catalyzed couplings of quinone monoacetals (QMAs) and phenols. The unsymmetrical phenol biaryls are the major products and can be obtained just by tuning the acids in this reaction system. This novel method, which is employs inexpensive reagents and has good tolerance to air, proceeds without using an expensive catalysts.
S. Sawama, M. Masuda, R. Nakatani, H. Yokoyama, Y. Monguchi, T. Dohi, Y. Kita, H. Sajiki, Site-selective Iron(III) Chloride-Catalyzed Arylation of 4-Aryl-4-methoxy-2,5-cyclohexadienones for Synthesis of Poly-arylated Phenols. Adv. Synth. Catal. 2016, 358, 3683-3687. DOI: 10.1002/adsc.201600577

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.
K. Morimoto, Y. Ohnishi, D. Koseki, A. Nakamura, T. Dohi, Y. Kita, Stabilized pyrrolyl iodonium salts and metal-free oxidative cross- coupling. Org. Biomol. Chem. 2016, 14, 8947-8951. DOI:10.1039/C6OB01764A

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.
K. Morimoto, A. Nakamura, T. Dohi, Y. Kita, Metal-Free oxidative cross-coupling reaction of thiophene iodonium salts with pyrroles. Eur. J. Org. Chem. 2016, 4294-4297. DOI: 10.1002/ejoc.201600791

The efficient hypervalent-iodine-induced oxidative cross-coupling reaction of 3,4-ethylenedioxythiophene (EDOT) with various pyrroles is made successful by optimizing the reagents. The corresponding EDOT–pyrrole derivatives are obtained in moderate to high yields (up to 85 %). This method features high efficiency and regioselectivity and broad functional group tolerance.
T. Kajimoto, K. Morimoto, R. Ogawa, T. Dohi, Y. Kita, Glycosylation reaction of thio-glycosides by using hypervalent iodine(III) reagent as an excellent promoter. Chem. Pharm. Bull. 2016, 64, 838-844. DOI: org/10.1248/cpb.c16-00203

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.
K. Morimoto, K. Sakamoto, T. Oshika, T. Dohi, Y. Kita, Organo-iodine(III) catalyzed oxidative phenol-arene and phenol-phenol cross-coupling reaction. Angew. Chem., Int. Ed. 2016, 55, 3652-3656. DOI: 10.1002/anie.201511007

Criss-cross phenol: An organocatalytic intermolecular oxidative cross-coupling reaction of phenols uses a catalytic amount of an iodoarene with a stoichiometric amount of an inorganic oxidant. The reaction proceeds smoothly at room temperature, thereby enabling the efficient formation of biaryls from phenols without over-oxidation of the coupling products.
T. Dohi, Y. Kita, Hypervalent iodine-induced oxidative couplings (New metal-free coupling advances and their applications in natural product syntheses). Top. Curr. Chem. 2016, 373, 1-23. DOI: 10.1007/128_2016_667

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.
T. Dohi, Y. Kita, Metal-free oxidative biaryl coupling by hypervalent iodine reagents.Curr. Org. Chem. 2016, 20, 580-615. DOI: 10.2174/1385272819666150716173142

In green chemistry, the most ideal synthetic route to biaryl compounds, which are important in manufacturing fine chemicals, from non-functionalized starting aromatic materials appears to be the oxidative couplings that directly use two molecules of C–H groups for a new bond-forming event to reduce the synthetic steps and byproduct generation. However, these methods for reacting non-activated aromatic substrates are known to have difficulty in achieving selective cross-biaryl-couplings because of the over-oxidation of the products and competitive homodimer formations by undesired coupling between the same aryl substrates. In order to realize an efficient cross-coupling, therefore, unique chemoselective nature of the oxidant for the aromatic rings that discriminate aromatic substrates is required together with the sufficient oxidation ability. Using hypervalent iodine reagent, we have recently pioneered a number of new metal-free oxidative aromatic coupling methods for providing several types of mixed biaryls in high yields with perfect cross-coupling selectivities. They are classified into three types of the aromatic ring activation modes based on the pattern of the reaction mechanisms, which involve i) the aromatic cation radicals, ii) diaryliodonium salts, and iii) C-reactive phenoxenium ions and their N-analogues. As a result, the strategies now cover a wide range of the aromatic substrates. Hypervalent iodine reagents having low toxicities, mild reactivities, ready availability, high stabilities, easy handling, and ease of recovery and recyclability are useful alternatives to metal-based oxidants and catalysts for performing metal-free synthesis. We fully summarize the outcomes and clarify the synthetic values of our hypervalent iodine methods among the oxidative crosscoupling area.
Y. Kita, T. Dohi, 「CSJ Current Review 有機分子触媒の最前線」 化学同人、京都(Editor:寺田眞浩、秋山隆彦、竹本佳司、林雄二郎、丸岡啓二、岩澤伸治)、超原子価ヨウ素触媒反応 ~メタルフリー酸化的カップリング反応への触媒設計~

有機分子触媒は,取扱いの容易さだけでなく,環境負荷の軽減やレアメタルの枯渇・高騰といった社会的な問題に応えうる「元素戦略」の観点からも注目を集めている。精巧な分子設計のもとに選択性(立体選択性,位置選択性,官能基選択性など)の高度な制御を目指して設計開発され,多彩な反応系で大きく進展している。
K. Morimoto, T. Dohi, Y. Kita,「超原子価ヨウ素試薬の新展開-有機ヨウ素触媒酸化的ビアリールカップリング-」月刊ファインケミカル (シーエムシー出版)45、7-15. (2016年12月発行)

筆者らは最近、超原子価ヨウ素種を触媒とする芳香環の酸化的クロスカップリングの開発に成功した。本結果は有機触媒を用いるメタルフリーな初めての例であり、ここでは超原子価ヨウ素反応剤の触媒的利用研究と、反応開発と並行してここ数年行っている触媒設計が鍵となっている。本稿では、その一連の研究の経緯について紹介する。
T. Dohi, K. Morimoto, Y. Kita,「超原子価ヨウ素を用いる芳香環酸化的クロスカップリングの基本戦略」SISニュースレター(ヨウ素学会)17、 2-10. (2016年5月発行)
T. Dohi, JACIニュースレター(新化学技術協会)57、7. (2016年1月発行)

酸化的カップリングは、炭素-水素結合を直接、官能基化や結合形 成に用いるといった点で魅力的な合成戦略である。ここでは、超原 子価ヨウ素触媒を持いたメタルフリーな芳香族酸化的クロスカップ リングの最初の発見について紹介する。このグリーンな合成法は、 様々なファインケミカルにみられる重要なビアリール化合物の生産 に貢献できる新しいクロスカップリング戦略となる。

2015

K. Morimoto, R. Ogawa, D. Koseki, Y. Takahashi, T. Dohi, Y. Kita, Clean synthesis of N-pyrrolyl azoles by metal-free oxidative cross-coupling using recyclable hypervalent iodine reagent. Chem. Pharm. Bull. 2015, 63, 819-824. DOI: org/10.1248/cpb.c15-00469

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.
H. China, Y. Okada, T. Dohi, The multiple reactions in the monochlorodimedone assay: Discovery of unique dehalolactonizations under mild conditions. Asian J. Org. Chem. 2015, 4, 1065-1074. DOI: 10.1002/ajoc.201500210 (Cover Picture; Asian J. Org. Chem. 2015, 4, 977)

Lose the halo: It was clarified that spontaneous decomposition of the assumed product in the monochlorodimedone assay for halogenating enzymes occurs. The unique dehalolactonization of halogenated δ-keto acids, which was discovered from among many reactions in the assay, are selective cyclizations without any sacrificial reagent and external catalyst in aqueous solution.
H. China, Y. Okada, T. Dohi, Suppression mechanism for enol–enol isomerization of 2-substituted dimedones. Asian J. Org. Chem. 2015, 4, 952-962. DOI: 10.1002/ajoc.201500069 (Cover Picture; Asian J. Org. Chem. 2015, 4, 821)

Sommer days: Dynamic NMR spectroscopy of the intramolecular chemical exchange in enol–enol isomerism of cyclic β-diketones showed a link between the isomerization rate and intermolecular hydrogen bond formation in solution. Suppression of isomerizations that have negative activation energy enabled the analysis of several 2-substituted enolic dimedones, for which equalization of two resonance signals in the isomerism interferes with the usual NMR analysis.
T. Dohi, T. Kamitanaka, H. Takamuro, Y. Mishima, N. Washimi, Y. Kita, A new arylation of silyl enol ethers by quinone monoacetal substitution. Tetrahedron Lett. 2015, 56, 3046-3051. DOI:org/10.1016/j.tetlet.2014.11.085

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.
T. Kajimoto, K. Morimoto, R. Ogawa, T. Dohi, Y. Kita, Phenyliodine bis(trifluoroacetate) (PIFA) as an excellent promoter of 2-deoxy-2-phthalimido-1-thio-glycosides in the presence of triflic acid in glycosylation reaction. Eur. J. Org. Chem. 2015,10, 2138-2142. DOI: 10.1002/ejoc.201500186

Glycosylation reactions using p-(octyloxy)phenyl 2-deoxy-2-phthalimido-1-thio-D-glucopyranoside or p-(octyloxy)phenyl 2-deoxy-2-phthalimido-1-thio-D-galactopyranoside as the donor substrate afforded β-glycosylated products in good to excellent yields by activating the thioglycosides with PIFA (1 equiv.) and TfOH (2 equiv.).
T. Dohi, Y. Toyoda, T. Nakae, D. Koseki, H. Kubo, T. Kamitanaka, Y. Kita, Phenol and aniline oxidative coupling with alkenes by using hypervalent iodine dimer for the rapid access to dihydrobenzofurans and indolines. Heterocycles 2015, 90, 631-644. DOI: 10.3987/COM-14-S(K)14

A highly reactive hypervalent iodine dimer, [Ph(CF3COO)I]-O-[I(OCOCF3)Ph], is utilized as successful promoter in the oxidative phenolic coupling with styrenes leading to 2-aryldihydrobenzofurans. The extensions of the substrates in this study have led to the development of a new expeditious construction of the pyrroloindoline structure from aniline and enamide derivatives.
Y. Kita, T. Dohi, Pioneering metal-free oxidative coupling strategy of aromatic compounds using hypervalent iodine reagent. Chem. Rec. 2015, 15, 886-906. DOI: 10.1002/tcr.201500020

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.
T. Dohi, Y. Kita,“Iodine: Chemistry and Application” 2015, Wiley-Blackwell、Hoboken, New Jersey (Editor:Kaiho Tatsuo), Chapter 7「Hypervalent Iodine」(pp103-157), Chapter 15「Oxidizing Agents」(pp277-301), Chapter 16「Reaction of iodo compounds」(pp303-327).

This book comprehensively covers iodine, its chemistry, and its role in functional materials, reagents, and compounds.
  • Provides an up-to-date, detailed overview of iodine chemistry with discussion on elemental aspects: characteristics, properties, iodides, and halogen bonding
  • Acts as a useful guide for readers to learn how to synthesize complex compounds using iodine reagents or intermediates
  • Describes traditional and modern processing techniques, such as starch, cupper, blowing out, and ion exchange resin methods
  • Includes seven detailed sections devoted to the applications of iodine: Characteristics, Production, Synthesis, Biological Applications, Industrial Applications, Bioorganic Chemistry and Environmental Chemistry, and Radioisotopes
  • Features hot topics in the field, such as hypervalent iodine-mediated cross coupling reactions, agrochemicals, dye sensitized solar cells, and therapeutic agents
T. Dohi,「酸化的カップリングにおける新規超原子価ヨウ素触媒法」化学と工業(日本化学会)、68、1111. (2015年12月発行)

 酸化的カップリングは,炭素-水素結合を直接,官能基化や結合形成に用いるといった点で,グリーンケミストリーに合致した魅力的な合成戦略である。本法に基づく新しい合成法として,芳香環をあらかじめ官能基化することなくカップリングさせる反応が実現し,ここ数年,注目を集めている。
 筆者らは2008 年に,芳香環に関して優れた選択性を示す超原子価ヨウ素反応剤を用いた,世界初のメタル触媒フリーな新法を報告した。この成功を契機に,二量体や過剰酸化のため難しいと思われてきた酸化的クロスカップリングが,様々な基質でうまくいくことが明らかになった。一方,超原子価ヨウ素反応剤の触媒化についての例はなく,その実現には高活性なヨウ素触媒の設計が不可欠であった。
 反応開発と並行して行っているヨウ素触媒設計の中で,最近,高い反応性と化学選択性を併せ持つ新規架橋型超原子価ヨウ素種1 を同定した。そこで,メタクロロ過安息香酸(mCPBA)を再酸化剤として,これを触媒に用いると,アニリン類と様々な芳香族化合物との酸化的カップリングが効果的に進行することがわかった。ここでは触媒1 の使用に加えて,酸化により発生するアニリン環上の正電荷を,アニリン窒素上のアルキルスルホニル(Ms =メシル)酸素原子がn-p*相互作用を通じて安定化することが,重要となる。本法は有機触媒を用いる初のメタルフリーな芳香環酸化的カップリングの例であり,このように超原子価ヨウ素種は,炭素,窒素,酸素などの典型元素から成る有機分子触媒とは性質が大きく異なり,金属元素と近い反応性を示す。

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