Sulfenylcarbene-Mediated Carbon Atom Insertion for the Late-Stage Functionalization of N-Heterocycles

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Апрель 11, 2025

Late-stage functionalization (LSF) is a crucial strategy in drug discovery, allowing the modification of complex molecules, including pharmaceuticals, to enhance chemical diversity libraries. We harness chemoselectivity sulfenylcarbenes, which selectively react with alkenes even presence more reactive functional groups such as alcohols, carboxylic acids, and amines. This reactivity allows sulfenylcarbenes insert single carbon atom bearing diverse groups, transforming pyrroles, indoles, imidazoles into synthetically challenging pyridines, quinolines, pyrimidines, respectively. Sulfenylcarbene precursors are easily synthesized two steps from commercially available reagents. Our metal-free LSF approach employs benchtop-stable sulfenylcarbene enables late-stage natural products, amino C-glycosides. Mechanistic studies density theory (DFT) calculations were conducted investigate regio- outcomes.

Язык: Английский

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Dimethoxyacetaldehyde-N-triftosylhydrazone: Preparation and Carbene Reactivity in Cyclopropanation and Doyle–Kirmse Reactions

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

Herein, we developed the new, powerful, and easy-to-handle chemical reagent, dimethoxyacetaldehyde-N-triftosylhydrazone (DMHz-Tfs), as a convenient in situ source of dimethoxydiazoethane under mild conditions. We demonstrate carbene reactivity DMHz-Tfs iron-catalyzed cyclopropanation Doyle-Kirmse reactions, providing access to diverse acetal functionalized cyclopropanes homoallylic- allenyl-sulfides at gram-scale with high stereoselectivity. DFT calculations elucidated involvement most stable doublet spin state iron-carbene intermediate over other possible states.

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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Copper-Catalyzed Cross-Coupling of Bicyclobutanes with Triftosylhydrazone Leading to Skipped Dienes

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Март 4, 2025

Here, we report a protocol for the synthesis of skipped dienes through cross-coupling bicyclo[1.1.0]butanes with trifluoromethyl triftosylhydrazones. The reaction is run using TpBr3Cu(NCMe) as catalyst to give access library trifluoromethylated (32 examples, ≤98% yield) excellent E/Z selectivity under mild and operationally safe conditions. presented methods proved be compatible various functionalized

Язык: Английский

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Enantiodivergent dearomative single-atom skeletal editing: a magic methodology

Trends in Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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Dearomative Skeletal Editing of Benzenoids via Diradical

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Март 25, 2025

Dearomative skeletal editing of benzenoids represents a promising yet challenging strategy for the rapid construction high-value carbon frameworks from readily accessible starting materials. Büchner reaction is unique type expansive that transforms into functionalized cycloheptatrienes. However, due to challenges in compatibility and selectivity, achieving seamless integration this with dearomative cycloaddition within unified system remains undeveloped. Here, we demonstrated an energy-transfer-induced intermolecular range electronically diverse alkynes. This protocol employed N-acylimines as diradical precursors efficiently construct various structurally polycyclic high chemo-, regio-, diastereoselectivities have been previously inaccessible. The related general reactivity selectivity issues were circumvented through smooth merging photoinduced cycloaddition. Experimental computational studies performed support mechanism interpret origins observed diastereoselectivities.

Язык: Английский

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Late-Stage N-Atom Deletion of Multisubstituted 2-Azabicyclo[2.1.1]Hexanes

ACS Catalysis, Год журнала: 2025, Номер unknown, С. 5825 - 5834

Опубликована: Март 25, 2025

Rigid three-dimensional scaffolds such as 2-azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) serve unique saturated isosteres of arenes, offering distinct substitution patterns due to their differing molecular exit vectors. This study introduces a skeletal editing strategy that efficiently transforms multisubstituted aza-BCHs into BCPs via an O-diphenylphosphinylhydroxylamine-promoted N-atom deletion process. method effectively addresses the challenge creating sterically hindered (2°)C–C(3°) bonds by removing nitrogen atom encased within bulky alkyl groups, reconstructing strained aza-BCH structure more BCP without generating undesired ring-opening diene byproducts. The used can be prepared from modified intermolecular [3 + 2] cycloaddition between bicyclo[1.1.0]butanes imines, making this practical. approach achieves remarkable efficiency, with yields up 99% scalability decagram quantities. resulting carboxylates further functionalized through decarboxylation, highlighting potential for programmed divergent synthesis BCPs. broad substrate scope high functional group tolerance protocol emphasize its versatility, it particularly valuable late-stage contained peptides, natural products, pharmaceuticals.

Язык: Английский

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ANROFRC Enables Skeletal Editing of 4-Arylpyrimidines into Diverse Nitrogen Heteroaromatics

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 25, 2025

Scaffold hopping is a key strategy in drug discovery. While one-to-one scaffold strategies are thriving and evolving, one-to-multiple remain challenging to design. We present here novel for the skeletal editing of pyrimidines into wide range heteroarenes through addition nucleophiles, ring-opening, fragmentation, ring-closing (ANROFRC) processes. This method features in situ generation vinamidinium salt intermediate, which serves as unique N-C-C-C four-atom (A4) synthon that reacts with A1 A2 synthons. Mechanistic studies reveal C4-aryl substituents play crucial role stabilizing intermediate. work provides powerful tool systematic construction modification nitrogen heterocycles, thereby expanding conventional molecular techniques.

Язык: Английский

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Silver-Catalyzed Doyle–Kirmse Reaction of Allyl Sulfides with Vinyl Triftosylhydrazones

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Апрель 7, 2025

Here, we report a general and practical Doyle-Kirmse reaction of allyl/propargyl sulfides with donor-only vinyl carbenes generated in situ from triftosylhydrazones the presence silver catalyst. This protocol features mild conditions, exhibits broad substrate scope exceptional functional group tolerance, provides corresponding 1,5-dienyl 1,4-enallenyl high yields. Moreover, gram-scale synthesis, late-stage modifications complex molecules, post-synthetic transformations were performed to demonstrate applicability this protocol.

Язык: Английский

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Atom-swapping skeletal editing of benzo[c]oxepines for the construction of 2-benzodiazepines via a continuous manufacturing one-pot synthesis

Chinese Chemical Letters, Год журнала: 2025, Номер unknown, С. 111200 - 111200

Опубликована: Апрель 1, 2025

Язык: Английский

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