Papers - Kumagai, Naoya

DiQuinoline-MonoQuinazoline: A Flat Proton Binder and its Application as a Polyaromatic Hydrocarbon Scavenger and G4 Ligand

Karimata T., Xu W., Kumagai N.

Chemistry - A European Journal  2025

Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  09476539

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A new miniaturized framework for graphitic material featuring three neighboring pyridinic nitrogen atoms is disclosed. The quinoline/quinazoline hybridized pseudo trimeric macrocycle, DiQuinoline(Q)-MonoQuinazolines(Qz), Q2Qz1, was readily synthesized from the key macrocyclic amide precursor in a modular fashion. Its central cavity strongly captures a proton, and the thus-formed positively charged, highly planar architecture exhibits supramolecular complexation through π-interactions. Q2Qz1, with its unique properties, was applied as a scavenger for toxic polyaromatic hydrocarbons and as a G-quartet ligand for potential therapeutic agent for cancer chemotherapy.

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Recent Advances in Quinoline-Based Macrocycles: Synthesis, Properties, and Applications in Catalytic Reactions

Xu W., Kumagai N.

Synthesis (Germany) 56 ( 11 ) 1765 - 1774 2024.05

Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  00397881

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Macrocyclic compounds exhibit unique properties due to their large ring-shaped structures, which have captivated chemists in recent decades. These molecules exert specific functions in various applicable fields, such as chemistry, materials science, and biology. Crown ethers, calixarenes, and porphyrinoids, which contain several ether/phenol/pyrrole subunits, represent these molecular categories with unparalleled functional diversity. In contrast, quinoline-based macrocycles comprising the quinoline unit as a key element to construct specific ring shapes have received limited attention. In this minireview, we summarize the recent advances in oligoquinoline macrocycles TriQuinoline (TQ), oxa-TriQuinoline (o-TQ), TEtraQuinoline (TEQ), and other bridged quinoline-based macrocycles. Emphasis is placed on the synthesis, structure, and application of these molecules in organometallic and supramolecular chemistry, which may guide new molecular designs in the quinoline-based macrocycle family. 1 Introduction 2 Quinoline-Based Macrocycles 2.1 TriQuinoline (TQ) 2.2 Oxa-TriQuinoline (o-TQ) 2.3 TEtraQuinoline (TEQ) 2.4 Larger Quinoline-Based Macrocycles with Bridges 3 Conclusion.

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In2Q2: A New Entry of 16-Membered Tetraazamacrocycle Concatenating Indole and Quinoline Units

Kihara K., Kobayashi T., Xu W., Kumagai N.

Chemistry - A European Journal 30 ( 25 )  2024.05

Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  09476539

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A new family of 16-membered macrocycles comprising two indole (In) and two quinoline (Q) units, coined In2Q2, was synthesized. Each unit is diagonally located and concatenated in a head-to-tail fashion, furnishing a non-flat saddle-shaped architecture with C2 symmetry. The synthetic protocol utilizing macrocyclic diamide as a pivotal precursor allowed us to access a series of In2Q2 derivatives bearing various substituents on the periphery. The In2Q2 derivatives and their Zn2+ complexes were emissive in both solution phase and solid state. While the entire architecture of In2Q2 is similar to that of quinoline tetramer TEtraQuinoline, a couple of contrasting physicochemical properties were revealed.

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Chemoselective Catalytic Dehydrogenation of Benzylic Amines Driven by the TEtraQuinoline/FeCl<inf>2</inf> Complex

Nishiwaki M., Xu W., Kumagai N.

Asian Journal of Organic Chemistry (Asian Journal of Organic Chemistry)  12 ( 9 )  2023.09

Last author, Corresponding author, Accepted,  ISSN  21935807

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A chemoselective dehydrogenation protocol for benzylic amines catalyzed by the TEtraQuinoline (TEQ)/FeCl2 complex is described. In combination with 2 equiv of tert-butyl hydroperoxide, as little as 0.1 mol% of catalyst loading was sufficient to convert primary and secondary benzylic amines to the corresponding imines and dimerized imines, respectively. Subsequent hydrolysis of the imines allowed for removal of the benzyl group on the nitrogen atom. Nonaromatic carbon-carbon multiple bonds and the O-Bn group remained intact in the present protocol, providing a complementary deprotection procedure to reductive removal conditions exerted by Pd catalysis.

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Oxa-TriQuinoline: A New Entry to Aza-Oxa-Crown Architectures**

Kobayashi T., Kumagai N.

Angewandte Chemie - International Edition (Angewandte Chemie - International Edition)  62 ( 32 )  2023.08

Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  14337851

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A new 15-membered-macrocyclic molecular entity, oxa-TriQuinoline (o-TQ), was designed and synthesized. In o-TQ, three oxygen atoms were joined onto three quinoline units at the 2- and 8-positions in a head-to-tail fashion by three-fold SNAr reactions, giving rise to the characteristic N3O3 aza-oxa-crown architecture. o-TQ can serve as a new tridentate nitrogen ligand to capture a CuI cation and adopt a bowl shape, before supramolecular complexation with corannulene and [12]cycloparaphenylene (CPP) occurs through π–π and CH–π interactions. In the presence of the CuI cation, the non-emissive o-TQ becomes a highly emissive material in the solid state, whereby the emission wavelengths depend on the ancillary ligand on the CuI cation. The o-TQ/CuI complex is able to promote carbene catalysis to provide a range of enamines with a gem-difluorinated terminus.

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A brief introduction to highly symmetric N-heteroarene-based macrocycles

Xu W., Kumagai N.

Tetrahedron (Tetrahedron)  141 2023.07

Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  00404020

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Nitrogen-containing macrocycles have attracted sustained attention because of their fascinating structures and extensive applications in organic chemistry, therapeutic developments, and materials science. The nitrogen atoms in the macrocycles play important roles in the interaction with metal cations or small molecules, endowing their potential in catalysis, fluorescent sensors, and host–guest chemistry. In this context, herein we summarize highly symmetric nitrogen-containing N3/N4/N6 macrocycles comprising pyrroles, pyridines, quinolines, and (iso)indoles as key N-heteroarenes. The direct and indirect connectivity of N-heteroarene subunits allows for the construction of both flat and non-flat cyclic architectures. The synthesis, structure, and properties of these macrocycles are highlighted.

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Expeditious Access to the B<inf>3</inf>NO<inf>2</inf> Heterocycle Enabling Modular Derivatization

Tsutsumi R., Kashiwagi N., Kumagai N.

Journal of Organic Chemistry (Journal of Organic Chemistry)  88 ( 9 ) 6247 - 6251 2023.05

Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  00223263

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DATB (1,3-dioxa-5-aza-2,4,6-triborinane) is a unique six-membered heterocycle exhibiting proficient catalytic activity in direct dehydrative amidation. Reported herein is an improved synthetic protocol for DATB derivatives featuring a concise two-step chromatography-free process. Suzuki-Miyaura coupling assembled 2,6-dibromoaniline derivatives and 1,2-phenylenediboronic acid to afford dimeric B-spiroborate salts. Acidic untying of the spiroborates gave rise to the DATB ring system with various substituents.

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Less Is More: N(BOH)<inf>2</inf> Configuration Exhibits Higher Reactivity than the B<inf>3</inf>NO<inf>2</inf> Heterocycle in Catalytic Dehydrative Amide Formation

Opie C.R., Noda H., Shibasaki M., Kumagai N.

Organic Letters (Organic Letters)  25 ( 4 ) 694 - 697 2023.02

Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  15237060

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Diboron substructures have emerged as a promising scaffold for the catalytic dehydrative amidation of carboxylic acids and amines. This Letter describes the design, synthesis, and evaluation of the first isolable N(BOH)2 compound as an amidation catalyst. The new catalyst outperforms the previously reported B3NO2 heterocycle catalyst, with respect to turnover frequency, albeit the former gradually decomposes upon exposure to amines. This work opens up an avenue for designing a better catalyst for direct amidation.

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Azo-Tagged C4N4 Fluorophores: Unusual Overcrowded Structures and Their Applications to Fluorescent Imaging

Miki Kohei, Naoki Takizawa, Ryosuke Tsutsumi, Wei Xu, and Naoya Kumagai*

Org. Biomol. Chem.  2023.01

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted

TEtraQuinolines: A Missing Link in the Family of Porphyrinoid Macrocycles

Wei Xu, Yuuya Nagata, and Naoya Kumagai*

J. Am. Chem. Soc. (Journal of the American Chemical Society)  145 ( 4 ) 2609 - 2618 2023.01

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted,  ISSN  00027863

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Porphyrin contains four inwardly oriented nitrogen atoms. It is arguably the most ubiquitous multifunctional naturally occurring macrocycle that has inspired the design of novel nitrogen-containing heterocycles for decades. While cyclic tetramers of pyrrole, indole, and pyridine have been exploited as macrocycles in this category, quinoline has been largely neglected as a synthon. Herein, we report the synthesis of TEtraQuinoline (TEQ) as a ‘missing link’ in this N4 macrocycle family. In TEQs, four quinoline units are concatenated to produce an S4-symmetric architecture. TEQs are characterized by a highly rigid saddle shape, wherein the lone-pair orbitals of the four nitrogen atoms are not aligned in a planar fashion. Nevertheless, TEQs can coordinate a series of transition-metal cations (Fe2+, Co2+, Ni2+, Cu2+, Zn2+, and Pd2+). TEQs are inherently fluorescence-silent but become strongly emissive upon protonation or complexation of Zn(II) cations (ϕ = 0.71). TEQ/Fe(II) complexes can catalyze dehydrogenation and oxygenation reactions with catalyst loadings as low as 0.1 mol %.

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Less Is More: N(BOH)2 Configuration Exhibits Higher Reactivity than the B3NO2 Heterocycle in Catalytic Dehydrative Amide Formation

Christopher R. Opie, Hidetoshi Noda,* Masakatsu Shibasaki, and Naoya Kumagai*

Org. Lett.  2023.01

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted

Azo-tagged C4N4 fluorophores: unusual overcrowded structures and their application to fluorescent imaging

Kohei M., Takizawa N., Tsutsumi R., Xu W., Kumagai N.

Organic and Biomolecular Chemistry (Organic and Biomolecular Chemistry)  21 ( 14 ) 2889 - 2893 2023

Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  14770520

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The C4N4 fluorophore is an intense fluorescence emitter featuring a 2,5-diaminopyrimidine core comprising four carbon and four nitrogen atoms. A series of C4N4 derivatives was photochemically dimerized at the 5-amino group, furnishing overcrowded ortho-tetraaryl-substituted diaryl azo compounds with a characteristic skewed structure revealed by X-ray crystallography. The photoquenched azo-C4N4s are useful for fluorescently visualizing cells under hypoxic conditions.

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Peripheral Modification of Tripodal Aza-Oxa-Crown Oxa-TriQuinoline

Kobayashi T., Sakurai T., Kumagai N.

Bulletin of the Chemical Society of Japan (Bulletin of the Chemical Society of Japan)  96 ( 10 ) 1139 - 1143 2023

Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  00092673

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Oxa-TriQuinoline (o-TQ) is a new entry in the collection of aza-oxa-crown compounds featuring a semi-rigid flexible conformation and a tripodal ligation capability through three quinoline units. Herein, we describe the installation of functional groups and aromatic substituents on the outer edge of o-TQ to modulate its physicochemical properties. Amino and bromo substituents were regioselectively introduced at the 5-position, forming bowl-shaped Cu(I) complexes in which three quinoline units coordinated to Cu(I). X-ray crystallography indicated that these o-TQ derivatives preferred an almost identical geometry in both the absence and presence of Cu(I). In contrast to o-TQ, some new o-TQ derivatives exhibited photoluminescent properties in solution and/or in the solid state depending on the substituents.

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Oxygen-Fueled Iterative Hydride Transfer Driven by a Rigid Planar Architecture

Karimata T., Adachi S., Shibasaki M., Kumagai N.

Chemical and Pharmaceutical Bulletin (Chemical and Pharmaceutical Bulletin)  70 ( 9 ) 595 - 598 2022.09

Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  00092363

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An iterative hydride reduction/oxidation process was promoted under ambient conditions by a quasi-planar iminium cation rigidified by two concatenated quinoline units. The iminium proton was fixed by hydrogen bonding from neighboring quinoline nitrogen atoms, rendering the imine highly susceptible to hydride reduction with weak reductants, e.g., 1,4-dihydropyridines. The thus-formed amine was readily oxidized by molecular oxygen to regenerate the quasi-planar iminium cation under ambient conditions. This process was exploited for catalytic oxidation of 1,4-dihydropyridines as well as 9,10-dihydroacridine to highlight an intriguing rigidity- driven catalysis.

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Strategic Synthesis of Asymmetrically Substituted C4N4 Fluorophores

Xu W., Kohei M., Shibasaki M., Kumagai N.

Synthesis (Germany) (Synthesis (Germany))  53 ( 18 ) 3355 - 3360 2021.09

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted,  ISSN  00397881

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C4N4 fluorophores comprise a recently disclosed new class of emissive organic molecules with modular synthetic capabilities. Herein, we report a new synthetic protocol toward asymmetrically di arylated C4N4 fluorescent materials. Direct monoarylation of 1-naphthol is exploited to suppress undesired diarylation and to provide a free phenolic hydroxy group for prospective linking to a molecule of interest. Installation of the second aromatic unit in order to acquire fluorescent properties is achieved by Suzuki-Miyaura cross-coupling.

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Direct Catalytic Asymmetric Addition of Alkylnitriles to Aldehydes with Designed Nickel–Carbene Complexes

Saito A., Adachi S., Kumagai N., Shibasaki M.

Angewandte Chemie - International Edition (Angewandte Chemie - International Edition)  60 ( 16 ) 8739 - 8743 2021.04

Research paper (scientific journal), Joint Work, Corresponding author, Accepted,  ISSN  14337851

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A direct catalytic asymmetric addition of acetonitrile to aldehydes that realizes over 90 % ee is the ultimate challenge in alkylnitrile addition chemistry. Herein, we report achieving high enantioselectivity by the strategic use of a sterically demanding NiII pincer carbene complex, which afforded highly enantioenriched β-hydroxynitriles. This highly atom-economical process paves the way for exploiting inexpensive acetonitrile as a promising C2 building block in a practical synthetic toolbox for asymmetric catalysis.

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Highly Enantio- And Diastereoselective Synthesis of 1,2,3-Trisubstituted Cyclopropanes from α,β-Unsaturated Amides and Stabilized Sulfur Ylides Catalyzed by a Chiral Copper(I) Complex

Pagire S.K., Kumagai N., Shibasaki M.

ACS Catalysis (ACS Catalysis)     11597 - 11606 2021

Research paper (scientific journal), Joint Work, Corresponding author, Accepted

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The stereoselective preparation of 1,2,3-substituted cyclopropanes from α,β-unsaturated carbonyl compounds in the carboxylic acid oxidation state through Michael addition-initiated ring-closure reactions is a significant challenge in organic synthesis. Herein, the previously elusive catalytic asymmetric cyclopropanation of α,β-unsaturated amides with stabilized sulfur ylides has been efficiently accomplished utilizing a chiral Cu(I) complex. This Lewis acid catalytic system effectively converts a wide range of electron-deficient alkenes into the corresponding 1,2,3-trisubstituted cyclopropanes under mild reaction conditions in good to excellent yields with both high to excellent enantio- and diastereoselectivities. The resulting enantiomerically enriched cyclopropane amides can be readily diversified into promising synthetic intermediates such as β-aminocyclopropanecarboxylic acids with the facile recovery of the 7-azaindoline auxiliary without influencing the optical purity of the cyclopropane unit, which highlights the synthetic efficacy of this catalytic approach.

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Direct Catalytic Asymmetric Addition of α-Fluoronitriles to Aldehydes

Balaji P.V., Li Z., Saito A., Kumagai N., Shibasaki M.

Chemistry - A European Journal (Chemistry - A European Journal)  26 ( 67 ) 15524 - 15527 2020.12

Research paper (scientific journal), Joint Work, Corresponding author, Accepted,  ISSN  09476539

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A fluorine-containing tetrasubstituted stereogenic center is a highly valued structural feature in medicinal chemistry. Herein, we describe the direct coupling of racemic α-fluoronitriles and aldehydes promoted by a chiral CuI/Barton's base catalytic system, delivering α-tetrasubstituted α-fluoro-β-hydroxynitriles with satisfactory stereoselection. The stereochemical course was positively biased by the combined use of asymmetrical achiral thiourea as a supplementary ligand for CuI, which significantly enhanced the stereoselectivity. Both aromatic and aliphatic aldehydes were implemented to provide densely and stereoselectively functionalized chiral building blocks with aliphatic and aromatic tails.

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The Different Faces of [Ru(bpy)<inf>3</inf>Cl<inf>2</inf>] and fac[Ir(ppy)<inf>3</inf>] Photocatalysts: Redox Potential Controlled Synthesis of Sulfonylated Fluorenes and Pyrroloindoles from Unactivated Olefins and Sulfonyl Chlorides

Pagire S.K., Kumagai N., Shibasaki M.

Organic Letters (Organic Letters)  22 ( 20 ) 7853 - 7858 2020.10

Research paper (scientific journal), Joint Work, Corresponding author, Accepted,  ISSN  15237060

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A cascade alkene sulfonylation that simultaneously forges C-S and C-C bonds is a highly efficient and powerful approach for directly accessing structurally diverse sulfonylated compounds in a single operation. The reaction was enabled by visible-light-mediated regioselective radical addition of sulfonyl chlorides to 2-arylstyrenes using fac[Ir(ppy)3] as a photocatalyst, demonstrating its unique role in a photocascade process to execute atom transfer radical addition (ATRA) followed by photocyclization. A new class of sulfonyl-substituted fluorenes and pyrroloindoles, which are useful in the field of photoelectronic materials and medicinal chemistry, was produced in excellent yields by this photocascade reaction. In contrast, the cyclization was interrupted when using the [Ru(bpy)3Cl2] catalyst having lower reduction potential, leading only to the formation of a C-S bond and the production of acyclic sulfonylated 2-arylstyrenes under identical reaction conditions. The synthetic utility of the present room-temperature photocatalysis is enhanced by the broad availability of bench-stable sulfonyl chlorides and unactivated olefins, thereby providing a cost-effective and broad-scope protocol.

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Design, synthesis, and application of multiboron heterocycle to direct amidation catalyst

Noda H., Shibasaki M., Kumagai N.

Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry (Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry)  78 ( 10 ) 971 - 978 2020.10

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted,  ISSN  00379980

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The synthesis of a multiboron heterocycle and its application to a direct amidation catalyst are described. The heterocycle comprised of B3NO2is called DATB. The DATB-catalyzed direct amide formation is well suited for the synthesis of a wide range of amides, including previously intractable ones. The catalysis can also be applied to peptide synthesis and N-acylation of sulfoxi- mines. The most active DATB contains four boron atoms in its structure, and the detailed mecha- nistic study revealed their distinctive roles in the catalytic cycle, depending on the given chemical environment. A pyrimidine containing analog was also developed and evaluated as a more readily accessible amidation catalyst than the original one. The Pym-DATB is now available from a commercial vendor. Current trends and future perspective in the boron - catalyzed direct amidation are also discussed.

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