Skeletal editing of pyridines through atom-pair swap from CN to CC

Nature Chemistry, Год журнала: 2024, Номер 16(5), С. 741 - 748

Опубликована: Янв. 18, 2024

Abstract Skeletal editing is a straightforward synthetic strategy for precise substitution or rearrangement of atoms in core ring structures complex molecules; it enables quick diversification compounds that not possible by applying peripheral strategies. Previously reported skeletal common arenes mainly relies on carbene- nitrene-type insertion reactions rearrangements. Although powerful, efficient and applicable to late-stage heteroarene structure modification, these strategies cannot be used pyridines. Here we report the direct pyridines through atom-pair swap from CN CC generate benzenes naphthalenes modular fashion. Specifically, use sequential dearomatization, cycloaddition rearomatizing retrocycloaddition one-pot sequence transform parent into bearing diversified substituents at specific sites, as defined reaction components. Applications pyridine cores several drugs are demonstrated.

Язык: Английский

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Oxidative Dearomatization of Pyridines

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(4), С. 2358 - 2363

Опубликована: Янв. 17, 2024

Dearomatization of pyridines is a well-established synthetic approach to access piperidines. Although remarkably powerful, existing dearomatization processes have been limited the hydrogenation or addition carbon-based nucleophiles activated pyridiniums. Here, we show that arenophile-mediated dearomatizations can be applied directly introduce heteroatom functionalities without prior substrate activation. The arenophile platform in combination with olefin oxidation chemistry provides dihydropyridine cis-diols and epoxides. These previously elusive compounds are now readily accessible used for downstream preparation diversely functionalized

Язык: Английский

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Aryne Chemistry: Generation Methods and Reactions Incorporating Multiple Arynes

Chemical Reviews, Год журнала: 2024, Номер 124(20), С. 11435 - 11522

Опубликована: Окт. 9, 2024

Arynes hold significance for the efficient fusion of (hetero) arenes with diverse substrates, advancing construction complex molecular frameworks. Employing multiple equivalents arynes is particularly effective in rapid formation polycyclic cores found optoelectronic materials and bioactive compounds. However, inherent reactivity often leads to side reactions, yielding unanticipated products underlining importance a detailed investigation into use fine-tune their reactivity. This review centers on methodologies syntheses organic reactions involving arynes, categorizing based mechanisms like cycloadditions, σ-bond insertions, nucleophilic additions, ene discusses aryne polymerization. The categorization these includes two primary approaches: first entails engagement within single step while second approach involves using equivalent sequentially across steps, both requiring strict control ensure precise participation each respective step. Additionally, provides an in-depth analysis selection precursors, organized chronologically by activation strategy, offering comprehensive background that supports main theme utilization. expectation remains this will be invaluable designing advanced engaging arynes.

Язык: Английский

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Skeletal Editing through Cycloaddition and Subsequent Cycloreversion Reactions

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

Опубликована: Янв. 28, 2025

ConspectusSkeletal editing, which involves adding, deleting, or substituting single multiple atoms within ring systems, has emerged as a transformative approach in modern synthetic chemistry. This innovative strategy addresses the ever-present demand for developing new drugs and advanced materials by enabling precise modifications of molecular frameworks without disrupting essential functional complexities. Ideally performed at late stages synthesis, skeletal editing minimizes need cost- labor-intensive processes often associated with de novo thus accelerating discovery optimization complex architectures. While current efforts predominantly focus on monatomic-scale modifications, molecules through cycloaddition followed cycloreversion offers unique to manipulate double-atomic scale. introduces possibilities chemical transformations enables such double-atom transmutation, formal single-atom atom insertion. Early examples relied inherent high reactivity substrates, needed be sufficiently active undergo possess good leaving groups subsequent fragmentation (cycloreversion) step. Recently, however, structural relatively inert substrates become achievable substrate activation strategies designed enhance either step.Along these lines, we recently developed dearomative process activating pyridines. In simple high-yielding operation, oxazinopyridines are readily obtained activated dearomatized isolable intermediates. method enabled us achieve transformation pyridines into benzenes naphthalenes cycloaddition/cycloreversion sequence. this Account, related recent contributions from other research highlighted well, alongside early involving tetrazines, triazines, diazines, similar heterocycles reaction partners. By offering streamlined route modify structures, approaches have demonstrated their ability interconvert arenes heteroarenes shown significant potential late-stage applications well advancing drug synthesis bioactive molecules.In future, will undoubtedly see broader development field editing. New should devised enable not only incorporation nitrogen heteroatoms rings─rather than deletion─but also contraction expand application non-aromatic rings. We hope that advancements summarized Account inspire chemists explore methodologies. pushing boundaries approaches, researchers can unlock opportunities constructing modifying frameworks, eventually paving way chemistry, biology, science.

Язык: Английский

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Copper‐Catalyzed Dearomative 1,2‐Hydroamination

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(32)

Опубликована: Май 23, 2024

Catalytic olefin hydroamination reactions are some of the most atom-economical transformations that bridge readily available starting materials-olefins and high-value-added amines. Despite significant advances in this field over last two decades, formal nonactivated aromatic compounds remains an unsolved challenge. Herein, we report extension to π-systems by using arenophile-mediated dearomatization Cu-catalysis perform 1,2-hydroamination on arenes. This strategy was applied a variety substituted arenes heteroarenes provide general access structurally complex We conducted DFT calculations inform mechanistic understanding rationalize unexpected selectivity trends. Furthermore, developed practical, scalable desymmetrization deliver enantioenriched dearomatized products enable downstream synthetic applications. ultimately used dearomative efficiently synthesize collection densely functionalized small molecules.

Язык: Английский

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A Dual Cobalt‐Photoredox Catalytic Approach for Asymmetric Dearomatization of Indoles with Aryl Amides via C−H Activation

Angewandte Chemie International Edition, Год журнала: 2024, Номер unknown

Опубликована: Июнь 19, 2024

Abstract In this study, we unveil a novel method for the asymmetric dearomatization of indoles under cobalt/photoredox catalysis. By strategically activating C−H bonds amides and subsequent migratory insertion π‐bonds present in indole as reactive partner, achieve syn ‐selective tetrahydro‐5 H ‐indolo[2,3‐ c ]isoquinolin‐5‐one derivatives with excellent yields enantiomeric excesses up to >99 %. The developed operates without metal oxidant, relying solely on oxygen oxidant employing an organic dye photocatalyst irradiation. Control experiments stoichiometric studies elucidate reversible nature enantiodetermining activation step, albeit not being rate‐determining. This study only expands horizon cobalt‐catalyzed bond functionalization, but also showcases potential synergy between cobalt photoredox catalysis enabling synthesis complex molecules.

Язык: Английский

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Copper-Catalyzed Dearomative trans-1,2-Carboamination

ACS Catalysis, Год журнала: 2024, Номер 14(13), С. 10132 - 10137

Опубликована: Июнь 20, 2024

We have achieved the arenophile-mediated, copper-catalyzed dearomative trans-1,2-carboamination of nonactivated arenes with alkyl organometallic nucleophiles. This simple and practical procedure was used to prepare diverse, stereochemically rich alkylated cyclohexadienes from readily available arenes. Synthetic utility demonstrated through rapid preparation complex small molecules difficult access by conventional routes. Finally, we conducted DFT studies explore catalytic process, including a study reaction pathway an examination divergent regioselectivity observed substituted

Язык: Английский

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Reimagining Dearomatization: Arenophile-Mediated Single-Atom Insertions and π-Extensions

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

Опубликована: Март 11, 2025

ConspectusDearomatization of simple aromatics serves as one the most direct strategies for converting abundant chemical feedstocks into three-dimensional value-added products. Among such transformations, cycloadditions between arenes and alkenes have historically offered effective means to construct complex polycyclic architectures. However, traditionally harsh conditions, high-energy UV light irradiation, greatly limited scope this transformation. Nevertheless, recent progress has led development visible-light-promoted dearomative photocycloadditions with expanded capable preparing bicyclic structures.A fundamentally distinct approach involves visible-light activation arenophiles, which undergo para-photocycloaddition various aromatic compounds produce arene-arenophile cycloadducts. While only transiently stable subject retro-cycloaddition, further functionalization photocycloadducts allowed a wide collection dearomatization methodologies that access products orthogonal existing biological processes. Central strategy was observation photocycloaddition reveals π-system can be functionalized through traditional olefin chemistry. Coupled subsequent [4 + 2]-cycloreversion arenophile, process acts effectively isolate single from an ring. We developed several transformations bias methodology perform single-atom insertion π-extension reactions prepare unique cannot prepared easily means.Through application epoxidation, we were able develop method epoxidation pyridines arene-oxides pyridine-oxides, respectively. Notably, when arenophile chemistry is applied arenes, transposed site native olefinic reactivity, enabling site-selectivity functionalization. As result, oxygen (aza)arenes 3-benzoxepines. When applying in context cyclopropanations, accomplish cyclopropanation yield benzocycloheptatrienes upon cycloreversion. while Buchner ring expansion powerful carbon corresponding does not ring-expanded Furthermore, could utilized synthesis novel nanographenes M-region annulative (M-APEX) reaction. Traditionally, methods rely on reactivity at K- bay-region. arenophiles activate reactivity. arenophile-mediated diarylation, followed by cycloreversion, deliver π-extended exclusive selectivity.

Язык: Английский

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Enantioselective and Regiodivergent Skeletal Transformations of 1,2,3-Thiadiazoles to Alkylidene Dihydrothiophenes

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Апрель 16, 2025

By leveraging the Rh-catalyzed asymmetric skeletal editing of 1,2,3-thiadiazoles, we successfully achieve ligand-controlled enantioselective and regiodivergent synthesis structurally diverse 2- 3-alkylidene 2,3-dihydrothiophenes. Late-stage structural complex natural drug molecules is also enabled.

Язык: Английский

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Photochemical Generation and Cycloadditions of Strained Cycloalkynes

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

Опубликована: Апрель 20, 2025

Strained cycloalkynes and their utilization have enabled prospective tactical strategies for synthetic medicinal chemistry, chemical biology, materials science, allied fields. However, full potential remains largely underexplored due to the limited availability of efficient sp3-rich cycloalkyne precursors with high efficiency structural complexity. Herein, we describe an intuitive modular photochemical approach liberate analogs from cyclic diacyl peroxides, without external reagents. This disclosed platform hinges on leverage realize two distinct classes strain-promoted cycloadditions straightforward construction diverse polycyclic scaffolds production any side product except nitrogen CO2. Moreover, functional group tolerance, biorelevant molecules compatibility, scalability, late-stage functionalization bioactive demonstrate utility presented methods. These features enrich assembling cycloalkenyl-containing diversity, offering new opportunities click chemistry bioorthogonal reactions.

Язык: Английский

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