Synthesis of ¹⁵N-Pyridines and Higher Mass Isotopologs via Zincke Imine Intermediates

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(5), С. 2944 - 2949

Опубликована: Янв. 16, 2024

Methods to incorporate stable radioisotopes are integral pharmaceutical and agrochemical development. However, despite the prevalence of pyridines in candidate compounds, methods 15N atoms within their structures limited. Here, we present a general approach pyridine 15N-labeling that proceeds via ring-opening NTf-Zincke imines then ring-closure with commercially available 15NH4Cl salts. This process functions on range substituted pyridines, from simple building block-type compounds late-stage labeling complex pharmaceuticals, 15N-incorporation is >95% most cases. The reactivity Zincke imine intermediates also enables deuteration C3- C5-positions, resulting higher mass isotopologs required for LCMS analysis biological fluids during drug

Язык: Английский

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Photocatalytic furan-to-pyrrole conversion

Science, Год журнала: 2024, Номер 386(6717), С. 99 - 105

Опубликована: Окт. 3, 2024

The identity of a heteroatom within an aromatic ring influences the chemical properties that heterocyclic compound. Systematically evaluating effect single atom, however, poses synthetic challenges, primarily as result thermodynamic mismatches in atomic exchange processes. We present photocatalytic strategy swaps oxygen atom furan with nitrogen group, directly converting into pyrrole analog intermolecular reaction. High compatibility was observed various derivatives and nucleophiles commonly used drug discovery, late-stage functionalization furnished otherwise difficult-to-access pyrroles from naturally occurring furans high molecular complexity. Mechanistic analysis suggested polarity inversion through electron transfer initiates redox-neutral processes at room temperature.

Язык: Английский

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Synthesis of benzenes from pyridines via N to C switch

Chem, Год журнала: 2024, Номер 10(6), С. 1940 - 1949

Опубликована: Июнь 1, 2024

The skeletal editing of heteroarenes introduces new disconnections to the chemistry lexicon, enabling interconversion ring systems via selective breaking/re-making carbon framework. We describe one-pot transformation pyridines into benzene derivatives, using a nucleophilic addition ring-opening/ring-closing (ANRORC) process with soft nucleophiles such as malonate. Triflic anhydride activates pyridine ANRORC synthesis an isolable amine intermediate, which aromatizes on simple heating. reaction has been exemplified room temperature protocol, along direct syntheses drug-like, tertiary-alkylated, and isotopically labeled benzoates.

Язык: Английский

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N‐(Sulfonio)Sulfilimine Reagents: Non‐Oxidizing Sources of Electrophilic Nitrogen Atom for Skeletal Editing

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(25)

Опубликована: Апрель 16, 2024

The one-pot synthesis of λ

Язык: Английский

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N-Oxide-to-Carbon Transmutations of Azaarene N-Oxides

Organic Letters, Год журнала: 2024, Номер 26(20), С. 4280 - 4285

Опубликована: Май 13, 2024

Reactions that change the identity of an atom within a ring system are emerging as valuable tools for site-selective editing molecular structures. Herein, we describe expansion underdeveloped transformation directly converts azaarene-derived N-oxides to all-carbon arenes. This transmutation exhibits good functional group tolerance and replaces N-oxide moiety with either unsubstituted, substituted, or isotopically labeled carbon atoms in single laboratory operation.

Язык: Английский

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Carbon–nitrogen transmutation in polycyclic arenol skeletons to access N-heteroarenes

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Май 4, 2024

Abstract Developing skeletal editing tools is not a trivial task, and realizing the corresponding single-atom transmutation in ring system without altering size even more challenging. Here, we introduce strategy that enables polycyclic arenols, highly prevalent motif bioactive molecules, to be readily converted into N -heteroarenes through carbon–nitrogen transmutation. The reaction features selective nitrogen insertion C–C bond of arenol frameworks by azidative dearomatization aryl migration, followed ring-opening, ring-closing (ANRORC) achieve carbon-to-nitrogen aromatic framework arenol. Using widely available arenols as -heteroarene precursors, this alternative approach allows streamlined assembly complex heteroaromatics with broad functional group tolerance. Finally, pertinent transformations products, including synthesis biheteroarene skeletons, were conducted exhibited significant potential materials chemistry.

Язык: Английский

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Facile synthesis of 15N-Labeled amino acids using 15N-Ammonium salt

Tetrahedron Letters, Год журнала: 2025, Номер unknown, С. 155490 - 155490

Опубликована: Янв. 1, 2025

Язык: Английский

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Transition Metal-Catalyzed Nitrogen Atom Insertion into Carbocycles

Accounts of Chemical Research, Год журнала: 2025, Номер unknown

Опубликована: Фев. 26, 2025

ConspectusN-Heterocycles are essential in pharmaceutical engineering, materials science, and synthetic chemistry. Recently, skeletal editing, which involves making specific point changes to the core of a molecule through single-atom insertion, deletion, or transmutation, has gained attention for its potential modify complex substrates. In this context, insertion nitrogen atoms into carbocycles form N-heterocycles emerged as significant research focus modern chemistry owing novel logic. This distinctive retrosynthetic approach enables late-stage modification molecular skeletons provides different pathway synthesizing multiply substituted N-heterocycles. Nevertheless, atom proven challenging because inherent inertness carbon-based difficulty cleaving C-C bonds. Therefore, selective editing remains growing field Account primarily highlights contributions our laboratory active acknowledges key from other researchers. It is organized two sections based on type carbocycle. The first section explores cycloalkenes. Recent Co-catalyzed oxidative azidation strategies have enabled cyclobutenes, cyclopentenes, cyclohexenes, facilitating synthesis polysubstituted pyridines, been conventionally pyridine cross-coupling. subsequent discovery realm arenes. site-selective stable arenes We developed method intramolecular benzene rings 2-amino biaryls by suppressing competing C-H process using paddlewheel dirhodium catalyst. addition, address issues we employed arenols substrates, could act controlling elements editing. reported Cu-catalyzed arenols, proceeds dearomative azidation/aryl migration process, enabling incorporation Inspired result, recently extended reaction model Fe-catalyst facilitate ring contraction nitrogen-inserted product, achieving carbon-to-nitrogen transmutation arenols. Various polyaromatic effectively undergo desired atom's presenting considerable various applications Account, present an overview achievements reactions, with scopes, mechanistic features, applications. anticipate that will provide valuable insights propel development innovative methodologies both N-heterocycle synthesis.

Язык: Английский

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Atroposelective [4+1] Annulation for the Synthesis of Isotopic Isoindolinones Bearing both Central and Axial Chirality

Chemical Science, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Isotopically chiral molecules have drawn much attention due to their practical applications in drug discovery. However, existing studies this area are mainly limited centrally and H/D exchange. Herein, we report a phosphoric acid-catalyzed atroposelective [4+1] annulation of ketoaldehydes 1H-indol-1-amines. By means strategy, series D- 18O-labeled atropisomers featuring both central axial chiralities synthesized with high enantioselectivities diastereoselectivities good excellent isotopic incorporation. Experimental density functional theory suggest that the reaction involves sequential condensation, cyclization isomerization cascade, which second step is enantio-determining process.

Язык: Английский

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Cheminformatic Analysis of Core-Atom Transformations in Pharmaceutically Relevant Heteroaromatics

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 7, 2025

Heteroaromatics are the basis for many pharmaceuticals. The ability to modify these structures through selective core-atom transformations, or "skeletal edits", can dramatically expand landscape drug discovery and development. However, despite importance of modifications, quantitative impact such transformations on accessible chemical space remains undefined. Here, we report a cheminformatic platform analyze which skeletal edits would most increase access novel space. This study underscores significance emerging single multiple heteroaromatics in enhancing diversity, example, at late-stage campaign. Our findings provide framework prioritizing modifications heteroaromatic structural motifs, calling development new methods achieve types transformations.

Язык: Английский

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