Late-Stage C–H Functionalization of Azines

Chemical Reviews, Год журнала: 2023, Номер 123(12), С. 7655 - 7691

Опубликована: Май 3, 2023

Azines, such as pyridines, quinolines, pyrimidines, and pyridazines, are widespread components of pharmaceuticals. Their occurrence derives from a suite physiochemical properties that match key criteria in drug design is tunable by varying their substituents. Developments synthetic chemistry, therefore, directly impact these efforts, methods can install various groups azine C–H bonds particularly valuable. Furthermore, there growing interest late-stage functionalization (LSF) reactions focus on advanced candidate compounds often complex structures with multiple heterocycles, functional groups, reactive sites. Because factors electron-deficient nature the effects Lewis basic N atom, distinct arene counterparts, application LSF contexts difficult. However, have been many significant advances reactions, this review will describe progress, much which has occurred over past decade. It possible to categorize radical addition processes, metal-catalyzed activation transformations occurring via dearomatized intermediates. Substantial variation reaction within each category indicates both rich reactivity heterocycles creativity approaches involved.

Язык: Английский

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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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meta‐Selective C−H Functionalization of Pyridines

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(42)

Опубликована: Апрель 4, 2023

The pyridine moiety is an important core structure for a variety of drugs, agrochemicals, catalysts, and functional materials. Direct functionalization C-H bonds in pyridines straightforward approach to access valuable substituted pyridines. Compared the direct ortho- para-functionalization, meta-selective far more challenging due inherent electronic properties entity. This review summarizes currently available methods meta-C-H using directing group, non-directed metalation, temporary dearomatization strategies. Recent advances ligand control are highlighted. We analyze advantages as well limitations current techniques hope inspire further developments this area.

Язык: Английский

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Tandem catalysis enables chlorine-containing waste as chlorination reagents

Nature Chemistry, Год журнала: 2024, Номер 16(5), С. 700 - 708

Опубликована: Фев. 23, 2024

Abstract Chlorinated compounds are ubiquitous. However, accumulation of chlorine-containing waste has a negative impact on human health and the environment due to inapplicability common disposal methods, such as landfill incineration. Here we report sustainable approach valorize hydrocarbon waste, including solids (chlorinated polymers) liquids solvents), based copper palladium catalysts with NaNO 3 promoter. In process, is oxidized release chlorine in presence N-directing arenes afford valuable aryl chlorides, FDA-approved drug vismodegib. The remaining component mineralized CO, CO 2 H O. Moreover, generated could be further utilized directly. Thus, mixed can serve chlorination reagents that neither generate hazardous by-products nor involve specialty reagents. This tandem catalytic represents promising method for viable management wide diverse range wastes.

Язык: Английский

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Asymmetric C3-Allylation of Pyridines

Journal of the American Chemical Society, Год журнала: 2023, Номер unknown

Опубликована: Май 17, 2023

Asymmetric intermolecular C–H functionalization of pyridines at C3 is unprecedented. Herein, we report the first examples such transformations: specifically, C3-allylation via tandem borane and iridium catalysis. First, borane-catalyzed pyridine hydroboration generates nucleophilic dihydropyridines; then, dihydropyridine undergoes enantioselective iridium-catalyzed allylation; finally, oxidative aromatization with air as oxidant gives C3-allylated pyridine. This protocol provides direct access to excellent enantioselectivity (up >99% ee) suitable for late-stage pyridine-containing drugs.

Язык: Английский

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C–H functionalization of pyridines

Organic & Biomolecular Chemistry, Год журнала: 2023, Номер 21(28), С. 5671 - 5690

Опубликована: Янв. 1, 2023

This review discusses known approaches for selective pyridine C–H editing, focusing on recent discoveries uniquely suited to pyridines.

Язык: Английский

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C–H Functionalization of Pyridines via Oxazino Pyridine Intermediates: Switching to para-Selectivity under Acidic Conditions

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(28), С. 15581 - 15588

Опубликована: Июль 10, 2023

para-Selective C-H functionalization of pyridines holds a significant value but remains underdeveloped. Site-switchable under easily tunable conditions expedites drug development. We recently reported redox-neutral dearomatization-rearomatization strategy for meta-C-H via oxazino pyridine intermediates. Here, we demonstrate that these intermediates undergo highly para-selective simply by switching to acidic conditions. A broad scope para-alkylated and arylated is prepared through radical as well ionic pathways. These mild catalyst-free methods are applied the late-stage para-functionalization drugs using limiting reagents. Consecutive meta,para-difunctionalization also achieved with complete regiocontrol relying on pH-dependent reactivity pyridines.

Язык: Английский

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N-heterocyclic carbene- and organic photoredox-catalysed meta-selective acylation of electron-rich arenes

Nature Synthesis, Год журнала: 2023, Номер 2(11), С. 1037 - 1045

Опубликована: Авг. 3, 2023

Язык: Английский

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Late‐Stage Functionalisation of Pyridine‐Containing Bioactive Molecules: Recent Strategies and Perspectives

European Journal of Organic Chemistry, Год журнала: 2023, Номер 26(16)

Опубликована: Фев. 21, 2023

Abstract Late‐Stage Functionalisation (LSF) is an innovative technique that has been successfully applied to the C−H diversification of pharmaceuticals. However, LSF pyridine ring in drug‐like molecules often unselective. As a result, mixture structurally related products obtained, thus making purification tedious and time‐consuming. This review shines light on recent strategies addressing selectivity issue complex natural or drugs containing moiety. Specifically, we have reviewed efforts reported both academia industries with hope providing guide for elaborated pyridines.

Язык: Английский

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Enantioselective C3‐Allylation of Pyridines via Tandem Borane and Palladium Catalysis

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(34)

Опубликована: Июль 3, 2023

Abstract Herein, we report a one‐pot method for enantioselective C−H allylation of pyridines at C3 via tandem borane and palladium catalysis. This involves borane‐catalyzed pyridine hydroboration to generate dihydropyridines, then palladium‐catalyzed the dihydropyridines with allylic esters, finally air oxidation allylated afford products. enables introduction an group excellent regio‐ enantioselectivities.

Язык: Английский

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