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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Radical and ionic meta -C–H functionalization of pyridines, quinolines, and isoquinolines

Science, Год журнала: 2022, Номер 378(6621), С. 779 - 785

Опубликована: Ноя. 17, 2022

Carbon-hydrogen (C−H) functionalization of pyridines is a powerful tool for the rapid construction and derivatization many agrochemicals, pharmaceuticals, materials. Because inherent electronic properties pyridines, selective meta -C−H challenging. Here, we present protocol highly regioselective trifluoromethylation, perfluoroalkylation, chlorination, bromination, iodination, nitration, sulfanylation, selenylation through redox-neutral dearomatization-rearomatization process. The introduced dearomative activation mode provides diversification platform meta-selective reactions on other azaarenes radical as well ionic pathways. broad scope high selectivity these catalyst-free render processes applicable late-stage drugs.

Язык: Английский

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Halogenation of the 3-position of pyridines through Zincke imine intermediates

Science, Год журнала: 2022, Номер 378(6621), С. 773 - 779

Опубликована: Ноя. 17, 2022

Pyridine halogenation reactions are crucial for obtaining the vast array of derivatives required drug and agrochemical development. However, despite more than a century synthetic endeavors, processes that selectively functionalize carbon-hydrogen bond in 3-position broad range pyridine precursors remain largely elusive. We report reaction sequence pyridyl ring opening, halogenation, closing whereby acyclic Zincke imine intermediates undergo highly regioselective under mild conditions. Experimental computational mechanistic studies indicate nature halogen electrophile can modify selectivity-determining step. Using this method, we produced diverse set 3-halopyridines demonstrated late-stage complex pharmaceuticals agrochemicals.

Язык: Английский

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Transition metals-catalyzed amination of biomass feedstocks for sustainable construction of N-heterocycles

Coordination Chemistry Reviews, Год журнала: 2023, Номер 502, С. 215622 - 215622

Опубликована: Дек. 26, 2023

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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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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A Toolbox of Reagents for Trifluoromethylthiolation: From Serendipitous Findings to Rational Design

The Journal of Organic Chemistry, Год журнала: 2023, Номер 88(6), С. 3359 - 3371

Опубликована: Фев. 16, 2023

Two types of electrophilic trifluoromethylthiolating reagents were developed in the past 10 years our laboratory. The development first type reagent, trifluoromethanesulfenate I, which is highly reactive toward a variety nucleophiles, was based on an unexpected discovery initial design for reagent with hypervalent iodine skeleton. A structure–activity study disclosed that α-cumyl (reagent II) without iodo substituent equally effective. Subsequent derivatization let us develop bromodifluoromethanesulfenate III could be used preparation [18F]ArSCF3. To remediate low reactivity I Friedel–Crafts trifluoromethylthiolation electron-rich (hetero)arenes, we designed and prepared N-trifluoromethylthiosaccharin IV, exhibits broad various including arenes. comparison structure IV N-trifluoromethylthiophthalimide showed replacement one carbonyl group sulfonyl made much more electrophilic. Thus, both carbonyls two groups would further increase electrophilicity. Such rationale prompted to current most N-trifluoromethylthiodibenzenesulfonimide V, its higher than IV. We optically pure (1S)-(−)-N-trifluoromethylthio-2,10-camphorsultam VI, active trifluoromethylthio-substituted carbon stereogenic centers. Reagents I–VI now constitute powerful toolbox introduction trifluoromethylthio into target molecules.

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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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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