Transition Metal-Catalyzed Nitrogen Atom Insertion into Carbocycles

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 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.

Language: Английский

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Reductive Amination of Carbonyl C–C Bonds Enables Formal Nitrogen Insertion

The Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 7, 2024

Given its relevance across numerous fields, reductive amination is one of the oldest and most widely used methods for amine synthesis. As a cornerstone synthetic chemistry, it has largely remained unchanged since discovery over century ago. Herein, we report mechanistically driven development complementary reaction, which reductively aminates C-C σ-bond carbonyls, not carbonyl C-O π-bond, generating value-added linear cyclic 3° amines in modular fashion. Critical to our success were mechanistic insights that enabled us modulate resting state borane catalyst, minimize deleterious disproportionation hydroxylamine nitrogen source, control migratory selectivity key nitrenoid reactive intermediate. Experiments support reaction occurring through amination/reductive Stieglitz cascade, via ketonitrone, can be interrupted under catalyst generate valuable

Language: Английский

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Molecular Ring Remodeling through C–C Bond Cleavage

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

ConspectusStable and inert C-C bonds form the fundamental framework of organic compounds. Consequently, direct transformations involving bond cleavage present an innovative approach for rapid modification remodeling molecular skeletons. In recent years, concept skeletal editing has garnered widespread attention been significantly developed, providing new opportunities late-stage bioactive molecules, high-value transformation bulk chemicals, a revolution in traditional fragment coupling strategies chemical synthesis. Notable advancements this field have focused on cyclic including ring expansion, contraction, ring-opening reactions, thereby enriching synthetic toolbox available to chemists. However, selective remains formidable challenge, especially complex due high dissociation energy difficulty achieving precise selectivity control. Over past few our group made efforts address these challenges. We demonstrated potential molecule reactions as efficient strategy synthesis molecules.Herein, we two major thematic achieved by group, utilizing cascade activation entropy-driven reconstruction via cleavage. These are characterized mild conditions, accessibility catalysts reagents, exceptional functional compatibility, emerging novel approaches through atom-incorporation mainly nitrogenation, oxygenation, halogenation synthesize pharmaceuticals, natural products, material molecules. (1) Ring expansion reactions: developed that enable insertion C-, N-, O-containing units into rings. methodologies offer practical routes synthesizing amides, amines, lactones, nitrogen-containing heterocycles. (2) Ring-opening enables construction distally difunctionalized frameworks. By transition metal catalysis radical-mediated process, successfully both single C═C double within Furthermore, tackled highly challenging arene (ARO) reaction, enabling stereoselective conjugated systems unsaturation liberation aromatic systems. Mechanistic studies DFT calculations provided critical insights processes. also identified key intermediates involved cleavage, benzyl azide, O-acetyl hydroxylamine, β-azido peroxyl radical, copper bisnitrene, 2-nitrene indazole. findings deepened understanding mechanisms strategy, which further promoted discovery related acyclic substrates.

Language: Английский

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A novel hydroxytyrosol derivative HT-3 enhances antioxidant and neuroprotective activity through efficient molecular conjugation

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 161, P. 108484 - 108484

Published: April 23, 2025

Language: Английский

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Senior Undergraduate Organic Chemistry Lab Course: Light-Driven Scaffold Editing

Journal of Chemical Education, Journal Year: 2025, Volume and Issue: unknown

Published: May 6, 2025

Language: Английский

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Skeletal Editing Strategies Driven by Total Synthesis

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: unknown

Published: May 15, 2025

ConspectusSingle-atom skeletal editing strategies that precisely modify the core frameworks of molecules have potential to streamline and accelerate organic synthesis by enabling conceptually simple, but otherwise synthetically challenging, retrosynthetic disconnections. In contrast broader remodeling rearrangement strategies, these methodologies more specifically target single-atom changes with high selectivity, even within complex such as natural products or pharmaceuticals. For past several years, our laboratory has developed methodologies, including ring contractions, expansions, transpositions both saturated unsaturated heterocycles, well other carbon scaffolds. This Account details evolution "skeletal logic" context extensive work on product total synthesis.Early in Sarpong group leveraged metal-mediated C-C bond cleavage situ-generated strained intermediates accomplish syntheses products, icetexane diterpenoids cyathane diterpenes. Continuing focus leveraging through "break-it-to-make-it" we then carvone access a variety terpenoids (including longiborneol sesquiterpenoids, phomactins, xishacorenes) from hydroxylated pinene derivatives. applying this framework alkaloid preparaherquimides lycodine-type alkaloids, recognized nitrogen-containing rings would enable direct conversion between distinct structurally related families. Thus, began developing methods selectively N-heterocycles; led deconstructive fluorination diversification piperidines ultimately recent body direct, modifications (single-atom editing). photomediated enantioselective contractions α-acylated motifs reductive cyclic hydroxylamines. azines (e.g., pyrimidine pyrazole), 15N isotopic labeling azines, phototranspositions indazoles benzimidazoles. To reaction development, cheminformatic analysis heteroaromatic edits served quantitatively inform which transformations most significantly expand accessible chemical space. Apart also reported single-nitrogen insertion amination carbonyl bonds. Ultimately, goal research is develop mild selective can be applied generally. While targeted simplified retrosyntheses logic daphenylline harringtonolide), multiple steps were still required achieve formal desired "edit". As such, continued development truly single-step, mild, reactions edit cores highly remains desirable.

Language: Английский

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Copper‐Catalyzed Aromatization‐Driven Ring‐Opening Amination and Oxygenation of Spiro Dihydroquinazolinones

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(58)

Published: Aug. 8, 2024

Abstract Mild and inexpensive copper‐catalyzed aromatization‐driven ring‐opening amination oxygenation of spiro dihydroquinazolinones are presented, respectively. These protocols provide facile atom‐economical access to the aminated carbonyl‐containing quinazolin‐4(3 H )‐ones in good yields with functional group compatibility, which difficult obtain by conventional methods. Remarkably, a telescoped procedure involving condensation ring‐opening/functionalization for simple cycloalkanone was found be accessible. Mechanistic studies suggest radical pathway this transformation.

Language: Английский

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