論文 - 熊谷　直哉

TriQuinazoline and Related Quinoline/Quinazoline Cyclic Trimers: Unified Synthesis, Planar Discotic Architecture, and Proton Dynamics in an Atomic-Scale Cavity

Sakurai T., Tsutsumi R., Kumagai N.

Chemistry of Materials 38 （ 5 ） 2453 - 2463 2026年03月

ISSN  08974756

　概要を見る

Heteroatom-doped graphitic materials, particularly those bearing nitrogen, have attracted considerable attention because of their unique physicochemical properties, which are unattainable in pristine carbon frameworks. To rigorously investigate the effects of doping and to enable fine-tuning of their functions at the atomic scale, bottom-up synthesis of well-defined molecular surrogates provides a powerful approach. Herein, we report the design, synthesis, and physicochemical characterization of a series of quinoline/quinazoline cyclic trimers, TriQuinoline (TQ, Q3), Q2Qz1, Q1Qz2, and TriQuinazoline (TQz, Qz3), featuring an atomic-sized central cavity surrounded by three pyridinic nitrogens that mirrors the local topology of nitrogen-doped graphene defects. A modular synthetic strategy enabled facile access to all of the quinazoline-containing congeners. Systematic X-ray analysis and computational studies revealed increasing molecular planarity with increasing quinazoline incorporation, arising from stepwise elimination of destabilizing CH···HC contacts and the emergence of favorable CH···N interactions. Spectroscopic and theoretical studies demonstrated that quinazoline substitution progressively decreases the proton affinity at the central cavity owing to the electron-withdrawing nature of the quinazoline units, which markedly accelerates proton exchange. Even with these electronic modifications, supramolecular association with polycyclic aromatics, such as coronene and [12]cycloparaphenylene ([12]CPP), substantially remained preserved upon quinazoline incorporation. These findings highlight the cooperative interplay of structural planarity and heteroatom substitution in dictating the properties of discotic heteroaromatics, offering a versatile platform for material design.

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Insights into coordination and (semi-)rigidity in the molecular design of bicyclic heterocycle frameworks

Kobayashi T., Sakurai T., Kumagai N.

Chemistry Letters 55 （ 2 ）  2026年02月

ISSN  03667022

　概要を見る

Macrocyclic compounds, exhibiting unique properties arising from their large-ring frameworks, have captivated the attention of organic chemists over the last few decades. These molecules serve specific functions across disciplines, including synthetic chemistry, materials science, and biology. Representative molecules in this category, including crown ethers, calix[n]arenes, and porphyrinoids composed of ether/phenol/pyrrole subunits, exhibit unparalleled structural and functional diversity. In contrast, macrocycles exploiting quinoline/quinazoline as key building blocks to construct specific macrocyclic architectures have received limited attention and are much less explored. In this Highlight Review, we summarize our recent advances in oligo-quinoline/quinazoline macrocycles. Emphasis is focused on synthetic strategies, structural features, and emerging applications in organometallic, supramolecular, and photophysical chemistry. We anticipate that these collective results will guide new molecular designs within the broader family of heterocycle-based macrocycles.

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Revisiting C4N4 Fluorophore: Theoretical Elucidation of the Origin of Fluorescent Properties of 2,5-Diaminopyrimidines and Strategic Applications to Pd Detection

Kohei M., Kondo I., Kawamura G., Harabuchi Y., Maeda S., Kumagai N.

Chemistry A European Journal 2026年

ISSN  09476539

　概要を見る

Compact organic fluorophores are attractive scaffolds for probe design, yet their emission is often compromised by efficient nonradiative decay. Here, we introduce 2,5-diaminopyrimidine-based C4N4 as an intrinsically emissive, exceptionally small platform, which remains bright without extended π-conjugation. Systematic substitution at 4,6-positions with alkyl, alkenyl, and alkynyl groups reveals robust emission for alkyl and alkynyl derivatives, and a striking bimodality for alkenyls. TDDFT combined with ES/SC-AFIR mapped the S<inf>1</inf>→S<inf>0</inf> internal-conversion landscape, providing a rationale for substituent-dependent relaxation behavior. Manipulation at the 5-position allowed for independent trigger-responsive emission behavior. This orthogonal design, where the 4,6-substituted C4N4 core serves as the fluorophore and the 5-position operates as ON/OFF gate, enabled the development of turn-on probes for Pd²⁺.

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DiazaChrysenes (DC): Nitrogen-Containing π-Extended Molecules for Photocatalytic C–H Amination

Xu W., Iwai A., Nagasaka I., Watanabe S., Tsutsumi R., Kumagai N.

Organic Letters （American Chemical Society）  27 （ 39 ） 10937 - 10942 2025年10月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り,  ISSN  15237060

　概要を見る

We report a new class of nitrogen-containing π-extended heterocycles, DiazaChrysenes (DCs), and their dimeric analogues (dDCs) as metal-free photocatalysts for C–H amination. DCs featuring a quinolino[1,2-c]quinazolin-5-ium core were synthesized via electrophilic amide activation and arylation. The resulting compounds displayed tunable photophysical and redox properties, with CF<inf>3</inf>-substituted DCs enabling the C–H amination of arenes with azoles under visible light and aerobic conditions, achieving yields up to 85%. The reaction tolerated a range of arene and azole substrates without requiring metal salts or additives. In contrast, dDCs exhibited diminished activity, likely due to their extended π-curvature. Computational studies, including NCI, ACID, and NICS analyses, revealed locally aromatic but electronically isolated π-systems and deshielded central 8-membered cores. This work highlights the utility of DC scaffolds as synthetically accessible and redox-tunable organic photocatalysts.

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Enlarged-TriQuinoline (Enl-TQ): Disparity in Chemical Behaviors by Geometric Scaling of the Trimeric Quinoline Ring System

Yamashita M., Tsutsumi R., Kobayashi T., Kumagai N.

Chemistry an Asian Journal （Wiley）  20 （ 17 ）  2025年09月

研究論文（学術雑誌）, 最終著者, 責任著者,  ISSN  18614728

　概要を見る

TriQuinoline (TQ), a quasi-planar cyclic quinoline trimer concatenated at the 2,8-positions in a head-to-tail arrangement, strongly captures a proton at the 12-membered inner cycle and exhibits unusual physicochemical properties, including unexpected water solubility and the ability to engage in complexation with other π-conjugated molecules. In this study, we designed and synthesized its expanded analog, coined Enlarged-TriQuinoline (Enl-TQ), in which three alkyne units are embedded between three quinoline units to acquire an expanded planar 18-membered ring system. DFT calculations and X-ray crystallographic analysis revealed its planar architecture with three inwardly facing pyridinic nitrogen atoms. Despite its structural similarity to TQ, Enl-TQ displayed distinct host capability and photophysical characteristics.

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iso-TEtraQuinoline (i-TEQ): an inherently chiral N4 macrocyclic quinoline tetramer

Yagami R., Xu W., Kobayashi T., Nagata Y., Kumagai N.

Chemical Science （Royal Society of Chemistry）  16 （ 24 ） 10714 - 10721 2025年05月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  20416520

　概要を見る

Chiral macrocycles are attracting growing interest due to their broad applicability as ligands in asymmetric catalysis and as host molecules for chiral recognition. Robustness and high thermodynamic stability can be effectively achieved by strategically linking aromatic panels to construct an axially chiral macrocyclic framework. Cyclic concatenation of four quinoline units affords a fully sp²-hybridized, non-planar macrocycle featuring four inwardly oriented, coordinatively active pyridyl nitrogen atoms. The previously reported tetramer TEtraQuinoline (TEQ) exhibits head-to-tail connectivity of its quinoline units, affording an achiral architecture possessing S<inf>4</inf> symmetry. Herein, we report the design and synthesis of iso-TEtraQuinoline (i-TEQ), an inherently chiral analogue featuring head-to-head connectivity at the 2,2′- and 8,8′-positions, which gives rise to a D<inf>2</inf>-symmetric architecture. Detailed comparative investigations of the connectivity isomers i-TEQ and TEQ revealed an array of distinct characteristics, including the overall architecture, intrinsic macrocyclic strain, spatial orientation of nitrogen lone pairs, thermodynamic stability, racemisation behaviour, metal complex stability, and circularly polarised luminescence.

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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 （Wiley）  31 （ 12 ）  2025年

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  09476539

　概要を見る

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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Development of Unique Quinoline-Based Macrocyclic Systems and Strategic Applications in Versatile Chemistry

Kobayashi T., Xu W., Kumagai N.

有機合成化学協会誌 （有機合成化学協会）  83 （ 5 ） 386 - 394 2025年

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  00379980

　概要を見る

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 a multidisciplinary basis, e.g. chemistry, materials science, and biology. Crown ethers, calix [n] arenes, and porphyrinoids, which contain several ether／phenol／pyrrole subunits, represent milestones in these molecular categories with unparalleled functional diversity. In contrast, macrocycles exploiting quinoline as a key unitary element to construct specific macrocyclic architecture have received limited attention and been barely explored. In this report, we summarize the recent advances in oligo─ quinoline macrocycles TriQuinoline (TQ), oxa─TriQuinoline (o─TQ), TEtraQuinoline (TEQ), and indole／quinoline hybrid macrocycle In2Q2. Particular 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 heterocycle─based macrocycle family.

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

Xu W., Kumagai N.

Synthesis (Germany) （Thieme）  56 （ 11 ） 1765 - 1774 2024年05月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  00397881

　概要を見る

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 （Wiley）  30 （ 25 ）  2024年05月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  09476539

　概要を見る

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 （Wiley）  12 （ 9 ）  2023年09月

最終著者, 責任著者, 査読有り,  ISSN  21935807

　概要を見る

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年08月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  14337851

　概要を見る

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年07月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  00404020

　概要を見る

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年05月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  00223263

　概要を見る

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年02月

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  15237060

　概要を見る

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年01月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り

TEtraQuinolines: A Missing Link in the Family of Porphyrinoid Macrocycles

Xu W., Nagata Y., Kumagai N.

Journal of the American Chemical Society （Journal of the American Chemical Society）  145 （ 4 ） 2609 - 2618 2023年01月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り,  ISSN  00027863

　概要を見る

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年01月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り

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年

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  14770520

　概要を見る

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年

研究論文（学術雑誌）, 最終著者, 責任著者, 査読有り,  ISSN  00092673

　概要を見る

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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